Immunology and Cell Biology (2001) 79, 547–568

Review Article
Ultraviolet light induced injury: Immunological and inflammatory
effects
G AV I N J C LY D E S DA L E , * G E O F F R E Y W DA N D I E † a n d H KO N R A D M U L L E R

Discipline of Pathology, University of Tasmania, Hobart, Tasmania, Australia

Summary This article reviews many of the complex events that occur after cutaneous ultraviolet (UV) exposure.
The inflammatory changes of acute exposure of the skin include erythema (sunburn), the production of inflam-
matory mediators, alteration of vascular responses and an inflammatory cell infiltrate. Damage to proteins and
DNA accumulates within skin cells and characteristic morphological changes occur in keratinocytes and other skin
cells. When a cell becomes damaged irreparably by UV exposure, cell death follows via apoptotic mechanisms.
Alterations in cutaneous and systemic immunity occur as a result of the UV-induced inflammation and damage,
including changes in the production of cytokines by keratinocytes and other skin-associated cells, alteration of
adhesion molecule expression and the loss of APC function within the skin. These changes lead to the generation
of suppressor T cells, the induction of antigen-specific immunosuppression and a lowering of cell-mediated immu-
nity. These events impair the immune system’s capacity to reject highly antigenic skin cancers. This review gives
an overview of the acute inflammatory and immunological events associated with cutaneous UV exposure, which
are important to consider before dealing with the complex interactions that occur with chronic UV exposure,
leading to photocarcinogenesis.

Key words: inflammation, immunosuppression, skin, ultraviolet rays.

Introduction The peak of UV-induced carcinogenicity has been shown

to lie within the UVB portion of the UV spectrum (reviewed
Ultraviolet (UV) radiation forms part of the electromagnetic
by de Gruijl2). As the primary consequence of ozone deple-
spectrum with wavelengths between 200 nm and 400 nm and
tion is an increased amount of UVB, and potentially some
is divided into three further components, UVA (320–400 nm),
UVC, reaching the earth’s surface, it may, in turn, lead to an
UVB (280–320 nm) and UVC (200–280 nm).1 Solar UVC is
increased incidence of skin cancer and eye damage.3 Com-
absorbed by ozone in the stratosphere and its relevance to
bined with the possibility that UVB alters immune responses
biological systems is limited, thus, the division between UVC
to infectious agents (reviewed by Chapman4), this has
and UVB was established at 280 nm. Discussion of UVC
brought the detrimental effects of UV exposure to the fore-
effects on the skin are, therefore, kept to a minimum is this
front of scientific discussion. This is especially relevant in
review. The energy carried by each portion of the spectrum is
Australia, where the highest incidence of any single cancer,
inversely related to its wavelength so UVC > UVB > UVA.
basal cell carcinoma, occurs.5 At times Australia also lies
However, the depth of penetration of UV light into the skin
within or near the ‘hole in the ozone layer’, perhaps, further
increases with increasing wavelength.
increasing the risk of developing such cancers in this
The skin is the organ most susceptible to damage by UV
country.6
light as it is directly exposed. Ultraviolet exposure of the skin
has a number of biological effects, many of which are detri-
mental. The following sections deal with the effects of UV Ultraviolet light methodology
light on the skin, concentrating on the inflammatory and
A variety of light sources have been used to study the
immunological events in a range of animal, human and in
changes that occur after UV exposure of the skin. These vary
vitro models.
considerably in their emission spectra and have advantages
and disadvantages relative to each experimental model exam-
ined. A summary of different UV sources used in cutaneous
Correspondence: Prof. HK Muller, Discipline of Pathology, research is given in Table 1.
University of Tasmania, PO Box 252-29, Hobart, Tas. 7001, Aust- Usually UV treatment is given as a dose per unit area.
ralia. Email: Konrad.Muller@utas.edu.au
* However, this is often referred to in terms of minimal ery-
Present address: Dr GJ Clydesdale, Pest Animal CRC, CSE Sus-
tainable Ecosystems, PO Box 284, Canberra, ACT 2601, Australia. themal dose (MED), with little or no reference to the actual
†
Present address: Dr GW Dandie, Child Health Research Institute dose received. Stern and Urbach8 stated that ‘it is not always
Inc., 7th Floor, Clarence Rieger Building, Women’s and Children’s clear whether “minimal” refers to the shade of erythema pro-
Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. duced or to the least amount in energy in one of a series of
Received 8 August 2001; accepted 8 August 2001. increasing doses that produces erythema’. Stern and Urbach8
548 GJ Clydesdale et al.

Table 1 Ultraviolet light sources used for research (adapted from Anderson7)

Light source UV emission Erythemal dose Advantages Disadvantages Peak output

spectra (nm) (time) (nm)

Terrestrial 290–400 20 min at Economical, Variable output, 400

sunlight latitude 40° large field hard to predict
June midday
Carbon arc 200–400 5–30 s at 25 cm Emission spectra Variable output, 400
close to sunlight large and bulky
Cold quartz Discontinuous, 30 s at 25 cm No increase Not relevant to 253.7
253.7 in pigment, sunlight as totally UVC
predominantly inexpensive
Hot quartz Discontinuous 30–60 s at 45 cm Inexpensive, Warm up, discontinuous 365
254,265,297 303 relatively intense UVB emission (not natural)
313 and 365
Fluorescent sun 270–390 60–120 s at 25 cm Large field size Lamp output 313
lamps when used in banks, decreases with time
intense UVB, inexpensive (70% after 500 h).
Not natural (some UVC)
Fluorescent 310–400 15–16 min at 25 cm Stimulation of pigment Long exposure time 365
black light production to generate erythema
Narrow band 311–312 5–9 min at 25 cm Exposure is less Not natural, long 312
(UVB) hazardous, study of exposure time to
specific wavelengths generate erythema
Xenon arc 290–400 12 s at 55 cm Emission spectra close Expensive, technical, 400
to natural sunlight bulky, small field size

Table 2 Minimal erythemal dose for a variety of ultraviolet sources and species

Species Average dose Main UV Source of UV irradiation Reference

for MED (J/m2) range

Guinea pigs 900 UVB Monochromatic 295 nm Eaglstein et al.12

Guinea pigs 260 UVC Monochromatic 250 nm Eaglstein et al.12
Guinea pigs 246 UVB Sunlamp Morison et al.13
Human dermal 30 (10% UVB UVB Sunlamp Cornelius et al.14
microvascular reaches the dermis)
endothelial cells
Humans 5 × 105 UVA Xenon Arc (= solar simulator) Gilchrest et al.15
Humans 8.6 × 105 UVA Xenon arc (345 filter) Kumakiri et al.16
Humans 1.2 × 106 UVA UVA sunlamp (330 nm & UG1 filter) Baadsgaard et al.17
Humans 200 UVB Monochromatic 300 nm Everett et al.18
Humans 200–300 UVB Monochromatic 300 nm Norris et al.19
Humans 264 UVB Xenon arc (345 filter) Kaidbey et al.20
Humans 291–327 UVB Sunlamp Cooper et al.21
Humans 300 UVB Sunlamp Cornelius et al.14
Humans 450 UVB Hot quartz Gilchrest et al.22
Humans 975 UVB T12 (307 nm filter) Baadsgaard et al.17
C3H Mice 1600 UVB TL20 El-Ghorr et al.23

subsequently commented that variables such as time to gen-
erate MED or the spectral output of the light source used
were rarely mentioned. Recent publications have begun to
correct these oversights, thus allowing easier comparison
between different investigations. In humans the dose/expo-
sure time to reach MED varies from individual to individual
due to genetic differences reflected in the amount of melanin
produced and stored. Table 2 gives a short summary illus-
trating the varying doses required to generate MED in differ-
ent species and strains and the sources of UV radiation.
Generally, most researchers currently use sunlamps in
studying the effects of UV light on the immune system. The
use of sunlamps is widespread due to their relatively low cost
and high UVB output. It has been suggested that the UVC
 Ultraviolet light induced injury
output (non-solar UV) by FS40 sunlamps is sufficient to
affect the mixed lymphocyte reaction (MLR) and epidermal
cell–lymphocyte reaction (ELR) experiments.9 A study by
Roberts et al.10 also found that energy sources with spectral
emissions similar to sunlight are required when evaluating
the effects of sunscreens on UV-induced immune suppres-
sion. Conversely, Cooper et al.11 have shown that the
immunosuppression arising from 4 MED of both FS40 sun-
lamps and solar simulator lamps is identical, thus validating
the extensive use of sunlamps in this area of research.
However, there is a growing trend towards using solar simu-
lated light, as this appears more relevant to studies on
immune effects, sunscreen use and carcinogenesis that can be
related to actual sunlight exposure.
Inflammatory response
Vascular events
The initial inflammatory response of the skin to UV irradia-
tion is vasodilation of cutaneous blood vessels resulting in
erythema. Finsen24 in 1899 postulated that erythema was
caused by UV exerting a direct effect on the vessels. An alter-
nate theory by Partington,25 was that this effect was produced
by soluble vasoactive mediators acting on the vessels,
although no direct evidence was provided for either hypoth-
esis. The time course for the production of erythema is bi-
phasic with an initial immediate erythema observed before
the completion of exposure.26 This is followed by a further
increase, usually of greater magnitude, commencing 1 h later,
with a peak at 24–48 h. The reddening that results at this
stage is also due to an increase in vasodilation.26 Later studies
using more sensitive instruments, which measured reflect-
ance, demonstrated that vasodilation preceded visually per-
ceptible erythema.27 The degree of erythema observed after
treatment with UV light increases proportionally with dose
until at least 15 MED,28 depending on skin type. Eventually,
at higher doses, blistering and other signs of gross damage
are observed. Erythemal responses are also influenced by
environmental factors, including heat, wind,29 humidity and
water immersion.30
Logan and Wilhelm26,31–33 investigated the erythemal reac-
tion in a variety of animal models including rats, rabbits and
guinea pigs. They looked at various aspects, including
vascular permeability, tissue leukocytosis and the production
of erythema and found variation in the exposure times
required to provoke erythema in the different species. Vascu-
lar permeability was found to follow the same bi-phasic
pattern as the production of erythema, with an initial increase
followed by a return to normal levels after 30 min and then
followed, in turn, by a further substantial increase in vascular
permeability. This general pattern held for the three species
examined, although the timing varied slightly.31 This pattern
has also been observed in humans.34 However, while Cotran
and Pathak35 confirmed this in rats and guinea pigs, the same
pattern was not evident in hairless mice, which showed only
the characteristic delayed increase in vascular permeability.
Blood flow changes appear to be similar for the UV-
induced erythemal response using both germicidal lamps
(UVC) and sunlamps (UVB/UVA).36,37 However, when
studying UVA-induced erythema, timing is an important
549
consideration as the time course of UVA erythema in humans
differs from UVB, being maximal at 72 h compared to
24–48 h for UVB.38 Adaptive changes are also observed in
the skin after exposure to UV light. These include increased
vascularization,39 skin thickening and melanogenesis
(tanning).40 Increased skin thickening is due both to epider-
mal hyperplasia and increased thickness of the stratum
corneum.41 Increased proliferation in keratinocytes, assessed
by the presence of proliferating cell nuclear antigen, is
maximal 48 h after UV exposure of the skin and parallels
hyperplasia.42 The hyperplastic effects of a single exposure of
mouse skin can last for up to 2 weeks.42 These changes result
in an overall reduction in the barrier function of the skin.43,44
Increased melanin production provides increased protection
against the harmful effects of UV exposure,45 to the extent
that black people with a high melanin content, have a MED
33-fold higher than their Caucasian counterparts.46
Many factors have been suggested as potential mediators
for the erythemal response of skin to UV light, yet most of
these have been found to have no or only a minor effect.
Logan and Wilhelm31 thought that the early erythemal
response to UV light was similar to that of thermal injury
mediated by histamine. But, the addition of antihistamines
did not affect the induction of erythema in either the guinea
pig or rabbit models examined. The early response observed
in rats was mediated by serotonin (5-HT), as the addition of
an antagonist (BOL-148) blocked the induction of erythema,
while the addition of antihistamines had no effect. However
H1 and H2 receptor antagonists were able to eliminate the
early erythemal response in guinea pigs, but again not
the delayed erythemal response.47 Greaves and Sondergaard48
have shown that UVB erythema in humans is linked with the
action of a smooth muscle contracting agent. This agent was
clearly different from histamine, bradykinin, serotonin or
acetylcholine and was shown to be a fatty acid, possibly a
prostaglandin (PG). Indeed, an increase in the production of
PGE2 and PGF2α and their precursor arachidonate was
evident 24 h after UVB exposure of the skin.49 Inhibitors of
PG synthesis, including aspirin50 and indomethacin,51 have
been previously noted to decrease the erythemal response but
not eliminate it, providing indirect evidence for the involve-
ment of PG. Woodward and Owen52 found that increases in
skin temperature, vascular permeability and water content of
the skin were substantially reduced, but not eliminated, by
indomethacin, strongly implicating PG as a mediator of these
physiological effects of cutaneous UV exposure. The appli-
cation of indomethacin topically, intradermally or orally, has
been shown not to affect UVA or 8-methoxypsoralen/UVA
treatment (PUVA) induced erythema.53 Thus, UVA-induced
erythema is not due to a PG-mediated event.
Recently, nitric oxide (NO) was shown to be produced by
keratinocytes after UVB irradiation.54 Such NO release is
dose-dependent and keratinocytes constitutively express the
enzyme required to synthesize NO. The same study demon-
strated that in the guinea pig an inhibitor of NO synthetase
(L-NMMA) resulted in a sun (UV) protection factor (SPF) of
8.71. The authors concluded that this might be a major part
of the integrated inflammatory response to UV light leading
to vasodilation and erythema. Current evidence suggests that
DNA is the chromophore for erythema, as the action spec-
trum for the frequency of pyrimidine dimers in vivo closely
550 GJ Clydesdale et al.
matches the action spectrum for erythema up to 334 nm.55
This conclusion has been strongly supported by work con-
ducted in the South American Opossum, Monodelphis
domestica, which has shown photoreactivation of DNA via
the actions of photolyase, a DNA repair enzyme, which leads
to the reduction of erythema.56 This in turn further implicates
pyrimidine dimers as the major DNA lesion involved with the
production of erythema. Further support for this proposal
comes from studies that involved another DNA repair
enzyme specific for dimers, T4 endonuclease V (T4N5). The
application of this enzyme to the skin in liposomes has been
shown to reduce the production of oedema in hairless mice.57
Thus, the vasodilation and subsequent erythema produced
after exposure of the skin to ultraviolet light, is not due to the
production of any one substance, but is multifactorial with
NO and PG having key roles. Other inflammatory substances,
including inflammatory cytokines, may have minor, but still
important, roles in the complicated reaction to UV light.
These, in turn, affect the immune response that may be gen-
erated from the affected area by altering adhesion molecule
and cytokine expression of resident cell populations and the
induction of non-resident cell types to migrate into the area,
resulting in the generation of an ‘inflammatory’-linked
immune response.
Morphology and ultrastructural changes
One consequence of UV exposure of the skin is damage to
epidermal cells.58 This becomes evident as early as 2 h after
UV exposure.31 The earliest indicator of damage is a decrease
in keratinosomes, which results in the formation of dyskera-
totic cells;59 intracellular oedema can be seen 16–18 h after
exposure, followed at 30–48 h by intercellular oedema,
which develops around damaged keratinocytes. Sunburn cells
(damaged keratinocytes) appear shortly before the presence
of oedema is observed.31
The sunburn cell was proposed as one of the earliest
examples of apoptosis.60 Ultraviolet-induced apoptotic cells
are rapidly phagocytised by the surrounding keratinocytes.61
Macrophages are also known to bind to and phagocytose
apoptotic cells62 and their numbers in the skin increase
dramatically after UVB treatment.63 All wavelengths of the
UV spectrum, including UVC, are able to induce apoptosis
rather than necrosis in Ly-5 murine lymphoma cells.64 There
appear to be two types of UV-induced apoptosis, an immedi-
ate type and a more classical delayed apoptosis.65 The latter
is thought to be caused by UV-induced damage of DNA
rather than free radical damage.65 In addition, immediate
apoptosis appears to be due to constitutive factors that do not
require protein synthesis, while the delayed type (inducible)
apoptosis does require protein synthesis.65
Similar apoptotic changes are noted in epidermal Langer-
hans cells (LC), which are especially sensitive to the effects
of UV light,66,67 with damage observed at lower doses than
required for keratinocytes. Langerhans cells are more sensi-
tive to UV-induced damage in comparison to keratinocytes
for both UVA and UVB wavelengths.66 The degenerative
changes for LC and keratinocytes include mitochondrial
swelling and rupture, condensation of the cytoplasm and the
appearance of pyknotic nuclei.58,66–68 The observed cellular
damage is maximal at 48–72 h for the total UV range.40
Exposure in vitro of an epidermal-derived cell line to both
UVA and UVB produced cytoskeletal blebbing, this being a
characteristic of oxidative damage,69 and perhaps reflects the
major mechanism for UVA-induced damage.
As sunlight contains both UVA and UVB it is important
that the cytotoxic effects of the UVA portion of the spectrum
are not ignored, especially as a study by Tyrrell and Pidoux70
suggests that UVA-induced cytotoxicity may be just as, if not
more, important than UVB. When the sun is at its zenith
(10 AM–2 PM) and UVB maximal, UVA still makes up to
50–60% of the phototoxic wavelengths found, and this is
increased at other times.70 The wavelength of UV light influ-
ences the cytotoxicity seen, with UVB > UVA. Generally
UVB acts mainly in the epidermis, while UVA injury tends to
cause necrosis of the endothelial cells, thus damaging the
dermal blood vessels.40,71 However, it should be noted that
10–15% of UVB penetrates to the dermis and, hence, it is
possible for UVB to have a direct effect on microvascular
endothelial cells.72 In vitro studies by Cornelius et al. also
support a direct effect of UVB on endothelial cells and direct
cytotoxic effects on cells in the skin are evident after UVA
exposure.14 Sunburn cells are visible in the epidermis after
UVA irradiation, although fewer in number than the equiva-
lent dose of UVB.16,73 In contrast, a study using erythemal
doses of UVA only, showed that while sunburn cells were
absent from the epidermis, perinuclear vacuoles were present
in LC.15 The same study demonstrated the recruitment of
neutrophils into the UVA-irradiated skin. UVB doses that
cause similar amounts of erythema did not appear to induce
this change,22 although this has been reported for rodent-
based experiments.12 Detailed studies by Hawk et al.74 were
also in direct contrast to those of Gilchrest’s study;22 Hawk
et al.74 suggested that the lack of similar findings by
Gilchrest et al.22 was due to ‘failure to obtain biopsy mater-
ial at times of significant neutrophil infiltration’. However, it
must be noted that the Hawk et al.74 study utilized a sunlamp
that had an output, of which approximately one third was
UVA.
The peak infiltration of leucocytes after UVB irradiation
occurs at 4–6 h and the response concludes after 48 h.26
Studies conducted using guinea pigs showed that the peak in
dermal leukocytosis occurred before maximum erythema and
vascular permeability, suggesting a cause and effect relation-
ship. Later studies by the same authors in the rat and rabbit31
indicated that lymphocyte infiltration was not as important in
these animal models and peaked after maximum erythema
and vascular permeability. Eaglstein et al.,12 suggested that
leucocytes have a role in UVB induced-inflammation in
guinea pigs, but not in cases of inflammation caused by UVA
or UVC. The presence of neutrophils is seen in dermal
inflammation due to UVB irradiation in humans. These cells
were observed, a short time after irradiation, gradually
increasing in number until at least 48 h post-treatment.74
Neutrophils have the potential to enhance the physical
damage caused by UV light, as they are capable of releasing
a variety of substances, including reactive oxygen intermedi-
ates, which are damaging to cells and tissues.75
The mast cell is a cell resident within the dermis, which
has an important role in UV-induced inflammation. Physical
changes in mast cells have been noted after UVB exposure,
including the presence of hypogranulated and degranulated
 Ultraviolet light induced injury
cells and extracellular granules in the surrounding tissue.76 In
the lower dermis, mast cell numbers increase after chronic
UVB exposure of hairless mice; the biological effect of this
is unknown.77 The role of mast cells in immunological events
after UV exposure is discussed in later sections.
Ultraviolet damage of DNA
The heterocyclic bases of DNA are a major UV-absorbing
chromophore in the skin.78 The absorption (which is maximal
between 260 nm and 265 nm) leads to damage of the DNA,
which may result in the generation of tumours. This part of
the review concentrates on the direct physical damage of
DNA by UV light and will touch briefly on some of the
molecular events taking place as this is currently a rapidly
expanding area of research.
DNA strongly absorbs energy in the UVB region of the
spectrum and may result in DNA lesions. The main lesions
induced by UVB exposure are pyrimidine dimers and
pyrimidine–pyrimidone photoproducts, which make up
65%79 and 35%80 of the UVB-induced DNA lesions, respec-
tively. Of the pyrimidine dimers formed, 50% are thymine–
thymine dimers.81 These lesions have been shown to occur
in the epidermal basal and suprabasal layers and can be
found in LC.82 Pyrimidine dimer formation is proposed as
an initiation step in mutagenesis and tumour formation.83
Mutations in the ras oncogene were mostly found opposite
dipyrimidine sequences,84 providing more evidence for the
role of pyrimidine dimers in tumour genesis. The exposure
of skin to UV radiation also increases the proto-oncogene
c-fos.85 UVB can induce nuclear factor κB (NFκB), although
without the need for chromosomal DNA damage.86 The
induction of NFκB after UV exposure of the skin, in turn,
leads to the production of the pro-inflammatory cytokines
IL-1, IL-6 and TNF-α.87
Ultraviolet light induces mutations in p53, an anti-
oncogene.88 This has been demonstrated in squamous cell
carcinoma,88 however, mutations in p53 seem to be absent
from melanomas.89 p53 stops progression of cells through the
normal cell cycle after UV exposure, thus allowing time for
the cell to repair DNA damage. As p53 can lead to the induc-
tion of apoptosis, it is not surprising that in p53 knockout
mice (p53–/–), the induction of sunburn cells is much lower
than in wild-type mice (p53+/+).90 The heterozygote (p53+/–) in
this study displayed an intermediate phenotype, suggesting
that the loss of one functional copy of the p53 gene in a cell
is enough to have an effect. In another study, tumour devel-
opment occurred after 24 weeks of chronic UV exposure
compared to 46 weeks for the wild-type litter mates.91 Thus,
the loss of a single functional copy of this gene resulted in
increased susceptibility to UV photocarcinogenesis. More
recent evidence confirms that UV-induced apoptosis of
keratinocyes occurs via the p53/p21/bax pathway, with
sequential increases in these genes in the epidermis being
maximal at 12, 24 and 24–72 h, respectively.42 In the same
study an inverse relationship between bax and bcl-2 expres-
sion was noted. The over-expression of bcl-2 in the epidermis
has been shown to protect cells against UV-induced apopto-
sis.92 Therefore, sunlight may, by mutating a p53 gene, cause
tumour initiation (DNA mutation) and by further exposure,
may delete the normal cells (which undergo programmed cell
551
death), allowing the p53 mutant to dominate. In association
with the hyperplastic status of the skin this leads to tumour
promotion.93 There are findings to support this hypothesis,
with 87.5% of skin tumours in hairless mice subject to
chronic UV exposure being positive for p53 mutations; 52%
of these mutations occurred at codon 270, a hot spot associ-
ated with UV mutations.94
DNA damage (pyrimidine dimer formation) has also been
proposed as a chromophore for the initiation of systemic
immunosuppression in mice after UV irradiation.95 Photo-
repair of DNA damage is seen in the marsupial Mondelphis
domestica. This animal contains photorepair enzymes that
are activated by visible light and prevent the induction of UV-
induced immunosuppression.96 Treatment of mouse skin with
liposomes containing the excision repair enzyme T4 endo-
nuclease V (T4N5), increases the rate of pyrimidine dimer
repair,97 thus, preventing the UV-induced immunosuppression
of delayed-type hypersensitivity (DTH) and contact hyper-
sensitivity (CHS).95 Kripke et al.95 proposed that DNA
damage leads to the release of immunoregulatory cytokines.
Indeed preliminary unpublished data by this group found
that downregulation of IL-10 production by a UV-damaged
keratinocyte cell line (PAM212) occurred after treatment
with T4N5 liposomes, thereby, indicating a role for DNA
damage in UV-induced systemic suppression (reviewed by
Vink et al.,98). Local immunosuppression is also manipulated
by T4N5 treatment, which prevents LC loss from the epider-
mis and partially reduces local immunosuppression.99
Normally, cells with UV-damaged DNA can be observed in
the draining lymph node after UV treatment of the skin.
Treatment of these UV-damaged cells with the photolyase
photorepair enzyme restores their ability to induce a normal
immune response. This treatment also prevents the induction
of suppressor cells (reviewed by Vink et al.98). A recent study
has shown that thymidine dinucleotides alone are sufficient
to induce immunosuppression of CHS and the activation of
the TNF-α gene.100 This further increases support for the
hypothesis that DNA damage is the trigger for many events
surrounding UV-induced damage of the skin, including
immunosuppression.
Protective measures are employed to defend the body
against the toxic effects of cutaneous UV exposure. Two
DNA repair pathways exist in humans to eliminate UV-
induced DNA damage; the global genome repair pathway and
the transcription-coupled repair pathway. In humans, defi-
ciencies in these pathways leads to increased susceptibility to
UV-induced skin cancer, as seen in xeroderma pigmentosum
patients deficient in the global genome repair pathway, but
not Cockayne syndrome patients who are deficient in the
transcription-coupled repair pathway. The overwhelming
of repair mechanisms by exposure to excessive amounts of
DNA damage from UV light can lead to damaged cells being
retained in the epidermis. From recent studies using murine
models with defects in either transcription-coupled or global
genome repair pathways, it appears that oedema and erythema
are mediated by the transcription-coupled repair pathway.101
Both pathways must be abrogated before increased sensitivity
to UV immune suppression is observed.102
Exposure of human skin to 2 MED of UVB induces
keratinocyte and fibroblast induction of the protective metal-
lothionein genes in vivo.103 The metallothionein proteins are
552 GJ Clydesdale et al.

Table 3 Reduced resistance to infection by cutaneous ultraviolet exposure

Microorganism Effect Model Reference:

Mycobacterium bovis Decreased DTH response Murine Jeevan et al.127

Mycobacterium leprae Decreased DTH response Murine Cestari et al.128
Listeria monocytogenes Decreased DTH response Murine Goettsch et al.129
Candida albicans Decreased DTH response Murine Denkins et al.130
Murine leukemia virus Increased liver damage Murine Brozek et al.131
Rat cytomegalovirus Increased viral load, inflammation and tissue necrosis Rat Goettsch et al.132
Garssen et al.133
Herpes simplex virus-1 Decreased DTH response, increased recrudesence and lesion severity Murine Ross et al.134 Howie et al.135
after secondary infection Ross et al.136
El-Ghorr et al.137
Herpes simplex virus-2 Severity of infection increased plus suppression of DTH and Murine Yasumoto et al.138
lymphocyte proliferation
Herpes labilis Increased lesions and virus shedding Human Rooney et al.139
Borreilia burgdorferi Switch from Th1 to Th2 antibody isotypes and a reduced DTH Murine Brown et al.140
response
Trichinella spiralis Increased parasite load and reduced T-cell immunity to parasite Rat Goettsch et al.132
Goettsch et al.141
Goettsch et al.142

DTH, delayed-type hypersensitivity.

proposed to have a possible protective role in the skin against
photo-oxidative stress,104 which induces strand breaks in
DNA and interferes with the transcription of other genes such
as c-fos.105 Thus, expression of high levels of metallo-
thioneins by basal keratinocytes may protect cells from
UV-induced DNA damage.103
Hence, UV light is capable of directly damaging DNA
causing mutations that may give rise to tumours, especially
when mutations in oncogene and anti-oncogenes occur. DNA
damage is the primary change required for the initiation of
tumours, however, for a tumour to become established a
tumour promotion step is required. This secondary change
may be provided by alteration of immune function and
immunosurveillance within the skin after subsequent expo-
sure to UV light.106
Ultraviolet-induced immunosuppression
In 1963 Hanisko and Suskind,107 observed that the contact
hypersensitivity response in skin sensitized to dinitro-
chlorobenzene (DNCB) was reduced if skin was previously
exposed to suberythemal doses of UVB. This important
observation was the first of many examining the effects of
UV on the immune system. The next set of important obser-
vations were made by Kripke,108 who investigated the anti-
genicity of UV-induced tumours and showed that the induced
tumours were highly immunogenic and were only trans-
plantable to immunosuppressed hosts. Kripke and Fisher109
found that UV-induced tumours were able to grow in the
primary host due to a systemic alteration in the host’s
immune response to the tumour. This was due to the UV
exposure received, as UV-irradiated recipients were unable
to reject the tumours. This effect was transferable with T
lymphocytes.110 UVB exposure has been shown to result in
suppression of many immune parameters including lympho-
cyte function111 and recirculation,112 CHS responses113 and
DTH.114 However, little effect was shown on levels of anti-
body production,115 while some reduction of antibody level
was observed by Spellman.116
The UV dose used for generating immune suppression
varies greatly from model to model and antigen to antigen. To
investigate local immune suppressive effects on APC, a
single low dose (< 1 kJ/m2) is generally used. To study the
effects of systemic immune suppression by UV light, a single
high acute dose can be used or alternatively four exposures to
400 J/m2. However, it also needs to be stated that low-dose
UV can cause systemic immune suppression as well as local,
but the systemic effects develop more slowly.117–119 The dose
required to suppress DTH or CHS is different for specific
antigens, so these differing methodologies must be taken into
account when making comparisons between different studies.
Many investigations have been undertaken since the early
discovery of UV-induced suppressor cell activity, aimed at
identification and characterization of these cells. Thy1.2+
cells have been shown to abrogate suppressive activity after
UVB exposure. This was found to be specific for the hapten
applied through the irradiated skin.120 Treatment with Lyt1
antibodies was shown to remove suppression and allow rejec-
tion of tumours, suggesting that these cells are required for
immune suppression.121 The presence of suppressor cells in
strains of UV-resistant and UV-sensitive mice indicated that
mice of the UV-sensitive phenotype were sensitive due to
interruption of effector mechanisms, not the induction of
suppressor cells.122 This hypothesis was supported by the
fact that UVB exposure converts LC from immunologically
potent APC, to tolerogenic APC; stimulation of Th1 cells is
reduced, while the ability to stimulate a Th2 response
remains.123 Clonal anergy also results in Th1 cells in response
to UV-exposed LC.123 This provides a mechanism whereby a
‘suppressor’ cell is induced (Th2 cell) and the effector cell
(Th1) is eliminated or anergized. Simon124 demonstrated that
Th1 cells in draining lymph node cells from normal and
 Ultraviolet light induced injury
hapten-treated murine skin produced IL-2 and IFN-γ.
However, after UVB exposure and hapten treatment of the
skin these cytokines could not be detected. This implies that
the UV-irradiated skin immune system would lose immuno-
surveillance against tumours or infectious agents requiring a
cellular response.125 This alteration of the immune response
may be due to the action of IL-10 post-UV exposure.126
Ultraviolet-induced immunosuppression results in many
aberrant responses to microorganisms, especially those of
intracellular bacteria and viruses in which immunity relies
extensively on the cellular arm of the immune system. From
the studies summarized in Table 3, it is evident that decreased
cellular immunity observed after UVB exposure of the skin
can lead to alterations in the body’s ability to respond to a
variety of viral and intracellular microbes.
Studies on Borrelia burgdorferi infection illustrate the
switch from cellular to humoral immunity that is now thought
to occur after UV exposure.140 Brown et al.140 demonstrated
that following UV exposure and immunization with B.
burgdorferi, IgG2a and IgG2b isotypes were downregulated
(Th1 isotypes), while IgG1 was unaffected (Th2 isotype).
Although the identity of the suppressor cells remains to be
elaborated, Yagi143 was able to generate a line of Th2-like
cells that expressed CD3+CD4+CD8–Vβ7+ from UVB-
pre-irradiated, tetracholorosalicylanilide photosensitized
mice that had received repeated antigenic stimulation. These
cells were shown to suppress contact photosensitivity, both in
vivo and in vitro. This activity was neutralized by anti-IL-10
mAb, but not by anti-IL-4 mAb. This cell type may reflect the
suppressor cell population(s) that occurs in vivo. Recently,
evidence from a murine model of DTH suggests that a rela-
tively minor T-cell population expressing the NK cell marker,
DX5, has been shown to be the cell type responsible for the
generation of UV-induced immune suppression.144 After UV
exposure, one million cells of this phenotype were shown
to be sufficient to transfer immune suppression to non-
irradiated mice in an antigen-specific manner. This effect
could be linked to the ability of these cells to produce high
levels of IL-4 during the early stages of an immune response.
Ultraviolet-induced immunosuppression is a serious com-
plication arising from the natural cutaneous response to UV
exposure. Present evidence suggests that it results from the
generation of T-suppressor cells, which inhibit the effector
cells of Th1 type. It appears that UV-induced immuno-
suppression depresses the function of Th1 cells and enhances
the activity of Th2 cells via cytokines (reviewed by Ullrich145).
The combination of these events shifts the normal cutaneous
immune response away from cell-mediated immunity. In turn,
this causes decreased immunity to intracellular pathogens,
including bacteria and viruses. This loss of cellular immunity
may lead to a loss of immunosurveillance to tumours, possi-
bly arising from the direct action of UV on the skin, as it
appears that individuals who are susceptible to UV-induced
immunosuppression are more susceptible to skin cancer.146
UVA-induced immunosuppression
Recently the role of UVA in UV-induced immunosuppression
has become an area of active research. Many of the studies in
the previous section were performed using lamps with output
in both the UVA and UVB regions. Today, through the use of
553
various light sources and combinations of filters, studies may
now be manipulated to examine the effects of UVA, or indeed
specific regions in the UVA range, on the immune system.
Although older studies had indicated that UVA exposure
appears to be less immunosuppressive than UVB,147 UVA
wavelengths greater than 315 nm are weakly immuno-
suppressive.148 The contrasting effects of UVA and UVB have
recently been confirmed by a study in which human skin was
exposed to equivalent erythemal doses. UVB was shown to
depress sensitization to the contact allergen diphenylcyclo-
propenone, while UVA did not result in decreased immu-
nization rates.149 Studies by Reeve et al.150 have shown that
wavelengths in the UVA region may be photoprotective if
given before UVB exposure. More recently this group has
linked this photoprotective effect to the production of IFN-γ,
as UVA photoprotection was not seen in IFN-γ knockout
mice.151 Furthermore, this photoprotection was mediated by
increased levels of the enzyme, heme oxygenase.152 Skov
et al.153 found that UVA1 and UVB differentially regulate the
production of TNF-α, with UVA1 causing a downregulation
in the levels of TNF-α in comparison to normal unirradiated
skin. This contrasts with UVB-irradiated skin in which an
upregulation of TNF-α is observed. Longuet-Perret et al.154
confirmed these findings in vitro, and have also shown that
UVA exposure leads to the inhibition of vascular endothelial
cell growth factor (VEGF) production by keratinocytes. The
findings of Skov et al.,153 Reeve et al.150 and Longuet-Perret
et al.154 suggest that UVA, especially UVA1, exposure of the
skin may have beneficial effects. In contrast, Damian et al.155
have shown that UVA alone is sufficient to downregulate
the recall response to nickel in humans, suggesting that the
photoprotective effects may be overcome. These findings are
causing researchers in photobiology to shift away from the
use of non-solar simulated light sources, such as the fluores-
cent sunlamp, the output of which contains low amounts of
UVA relative to UVB in comparison with sunlight.
Genetic basis for immunosuppression
Genes that regulate skin pigmentation affect the susceptibil-
ity of an individual to skin cancer. Other genes, which can be
detected before tumours arise, play a role in UVB-induced
immunosuppression (reviewed by Streilein156). Using CHS as
a test of cutaneous immune response, there are distinct
phenotypes within the human population, UVB-resistant and
UVB-sensitive (UVB-R and UVB-S).146 This does not corre-
late with skin pigmentation as 40% of dark-skinned individ-
uals display the UVB-S phenotype.157 Providing further
evidence that UV-induced immunosuppression has a role in
skin cancer, is a study by Yoshikawa and Streilein,146 who
found that among basal cell and squamous cell carcinoma
patients, 90% were of the UVB-S phenotype.
Streilein and Bergstresser158 originally demonstrated that
the C3H/HeN and C57Bl strains of mice were UVB-S, while
the BALB/c strain was UVB-R. F1 hybrids of UVB-R and
UVB-S strains were UVB-S, suggesting that this phenotype
is dominant. C3H/HeJ were found to be UVB-R, despite
differing from C3H/HeN at only the LPS locus, indicating
that polymorphisms at this locus are important in producing
the phenotype.158 This locus regulates the production of the
pro-inflammatory cytokines IL-1, IL-6 and TNF-α.158 The
554 GJ Clydesdale et al.
TNF-α locus is considered important, as there is a 100%
correlation between the TNF-αd allele and the UVB-R
phenotype.159
Noonan and Hoffman160,161 also investigated the control of
UVB immunosuppression in a wide variety of mouse strains
and found a more complex system of genetic control. Three
distinct phenotypes with differing susceptibilities to UV
immunosuppression were found. These were classed as
LO (low susceptibility, 50% immunosuppression with
9–12.3 kJ/m2 UV) HI (high susceptibility, 50% immuno-
suppression with 0.7–2.3 kJ/m2 UV) and intermediate pheno-
type (intermediate susceptibility, 50% immunosuppression
with 4.7–6.9 kJ/m2 UV). To relate this to the work of
Streilein’s group, BALB/c were classified as LO, C3H/HeN
intermediate and C57BL as HI. These phenotypes do not
correlate with the MHC haplotype and the findings of
Noonan and Hoffman160,161 disagree with Streilein’s146 obser-
vations, as by their definition C3H/HeN and C3H/HeJ strains
did not differ in their susceptibility, despite the differences at
the LPS loci. Also, as the TNF-α loci are located within the
MHC loci, differences in these genes likewise failed to affect
the UVB-immunosuppressive phenotype observed. Noonan
and Hoffman161 did, however, find that UVB-induced
immunosuppression was controlled by at least three separate
loci (Uvs1, Uvs2 and Uvs3), one of which was sex-linked,
while the other two were autosomal. None of these genes was
found to be linked to pigment loci.
Streilein’s group has now further characterized the loca-
tion of the UVB susceptibility gene to between the Bat5 and
H2-D loci on chromosome 17 in the mouse.162 There are a
number of candidate genes within this region and further
analysis will be required to pinpoint a specific gene for this
trait. These genes are also present in the human genome and,
therefore, may be associated with UVB susceptibility in
humans. From these studies in experimental inbred animals,
it is clear that the genetic control of the UVB-immunosup-
pressive phenotype is complex; this is likely to be even more
so in the human population. If current progress is maintained
it may lead to the identification of the gene or genes respon-
sible for the UVB sensitivity trait being identified. This could
allow the possibility of screening and therapy for susceptible
persons.
Adhesion and co-stimulatory molecules
A wide variety of adhesion molecules are expressed by cells
of the skin and the blood vessels in the dermis, including
integrins, selectins, addressins and those of the immuno-
globulin super-family. Many of these adhesion molecules
play a role in inflammatory responses triggered by a variety
of factors, such as ultraviolet light. E-Selectin (ELAM-1) is
expressed at high levels at sites of acute UVB inflammation
and acts as a vascular homing molecule for neutrophils and
memory T lymphocytes.19 The intracellular adhesion mole-
cule (ICAM) and vascular cell adhesion molecule (VCAM)
families of adhesion molecules are thought to act in a similar
way during immune responses.
E-selectin is upregulated on dermal postcapillary venules
during inflammatory responses,163 including upregulation
on vascular endothelium and polymorphonuclear cells after
UV exposure.19 Norris et al.19 also examined VCAM-1 and
ICAM-1 expression in human skin after a 2 or 8 MED dose
exposure of UVB. They found that there was no significant
induction of either adhesin during the 72 h post-UV treat-
ment, although slight upregulation of ICAM-1 occurred on
endothelial cells.
UVB treatment of melanocytes or a melanoma cell line
shows a similar effect of UVB on ICAM-1,164 although a
variety of cytokines in the same study were found to upregu-
late this molecule (IFN-γ, IL-1, IL-6, IL-7 and TNF-β).
ICAM-1 has also been shown to be downregulated on cul-
tured monocytes after UV exposure, thereby reducing their
ability to act as accessory cells for T-cell activation.165
Intracellular adhesion molecule-1 is an important adhe-
sion molecule in the skin as it mediates the binding of T cells
to keratinocytes,166 and is one of the major adhesion mole-
cules involved in the interaction of T cells and APC. The
effect of UV on keratinocyte expression of ICAM-1 is
bi-phasic with an initial downregulation at 24 h followed by
significant induction at later timepoints; this effect was also
dose-related.167 Langerhans cells constitutively express this
molecule168 and, hence, downregulation of this molecule
could affect the ability of LC to stimulate T cells. Tang and
Udey169 suggested that doses of UV light, which were suffi-
cient to cause downregulation of ICAM-1, were ultimately
cytotoxic for the LC.
Alterations in adhesion molecule interaction between
dendritic cells (DC) and T cells do occur after UV exposure
of the skin, as shown by the reduced ability of fluorescein
isothiocynate (FITC)+ APC from UV-irradiated mice to
cluster to T cells. Also observed was an increase in the
numbers of CD8+ T cells in the clusters.170 The alteration
in T-cell subsets may mean different adhesins are active, or
that LC are expressing different combinations of adhesion
molecules.
More recently decreased expression of E and P cadherins
has been shown to be induced in melanocytes following UV
irradiation,171 which may alter melanoma binding to keratino-
cytes. This may increase the metastatic potential of trans-
formed cells and has an inverse relationship with disease
progression in melanoma.171
The Fas/Fas ligand (FasL) system mediates T-cell
responses, including peripheral tolerance and the initiation of
apoptosis in activated lymphocytes and DC. Because apop-
tosis is induced in skin after UV exposure, recent studies
have investigated the role of these molecules. Leverkus172
found that following UV exposure, keratinocytes undergo
UV-induced apoptosis associated with an increased expres-
sion of Fas; this could be inhibited by the addition of a
Fas-neutralizing antibody. The role of Fas activation in induc-
ing apoptosis after UV exposure is supported by studies by
Rehemtulla et al.173 and Aragane et al.174 The latter group
found that the transfer of UV-induced suppression was criti-
cally dependent on the expression of both Fas and FasL by the
recipient mice that received the suppressor cells; it was
not required on the transferred T suppressor cells.175 Co-
incubation of these cells with DC in vitro was associated with
enhanced DC apoptosis, which was dependent on Fas and
FasL expression by the DC. This effect could be overcome by
the addition of IL-12, which was postulated to rescue DC
from apoptosis by downregulating Fas expression on DC.175
Hill et al.176 found that FasL expression is not essential for
 Ultraviolet light induced injury
the transfer of UV-induced immune suppression against
alloantigen, unlike antigens such as C. albicans and FITC.
However, it was essential when the allogeneic cells were
disrupted, suggesting that either a different APC population
was involved or that FasL expression on the intact allogeneic
cells was responsible for this effect. Immune responses to
alloantigen could not be restored by DNA repair, which also
suggested that a different pathway is involved, perhaps
involving urocanic acid.
While it appears that the Fas/Fas ligand system is
extremely important in the production of UV-induced
immunosuppression, the interactions of cell surface and
adhesion molecules after UV exposure will continue to be
an important area of study. No doubt, such investigations
will expand to include other adhesion and costimulatory
molecules.
Cytokines and soluble factors produced after cutaneous
ultraviolet exposure
Urocanic acid
De Fabo and Noonan177 proposed that urocanic acid (UCA),
a compound found within the epidermis, was the chro-
mophore for UV-induced immunosuppression. This sub-
stance is produced by the deamination of histidine by the
enzyme histidine ammonia lyase (histidase). The enzyme is
present in high amounts in only two tissues, the skin and
liver.178 Urocanic acid accumulates in the skin due to a lack
of the catabolic enzyme urocanase.178 Urocanic acid absorbs
light in the ultraviolet region, undergoing photoisomerization
from the trans to the cis isomer (reviewed by Noonan and De
Fabo148).
Urocanic acid was proposed as the photoreceptor
mediating UV-induced immunosuppression due to UCA’s
absorption spectrum closely matching that of the immuno-
suppression action spectrum (more so than DNA), together
with its superficial location in the stratum corneum and
photochemical properties.177 The administration of UV-
irradiated urocanic acid (UV-UCA) to mouse skin suppresses
DTH to herpes simplex virus,134 as well as increasing UV-
induced tumour yield and malignancy in the hairless
mouse.179 In addition cis-UCA impairs induction of CHS and
induces tolerance.180 Cis-UCA treatment also inhibits
alloantigen presentation by LC-enriched epidermal cells in
MLR experiments.181 Urocanic acid increases keratinocyte
production of PGE in the presence of histamine and induces
weak ICAM-1 expression, which is increased when com-
bined with TNF-α.182
Ulraviolet-irradiated urocanic acid causes defects in anti-
gen presentation by splenic DC,183 as well as reducing their
numbers, and altering the morphology of LC in mouse skin180
in a manner similar to the observed effects of cutaneous UVB
treatment. In contrast to these results, topical application of
cis-UCA had no effect on the number of DC within the drain-
ing lymph node.184 The addition of anti-TNF-α antibodies
was able to block the decrease in LC from the epidermis, but
this did not eliminate the changes in morphology observed by
Kurimoto and Streilein.180 Moreover, the suppression of CHS
by UV-UCA appears to be mediated via TNF-α, although the
induction of tolerance or DTH was not mediated via this
555
cytokine.185 However, treatment with antibodies against cis-
UCA fully restored DTH responses, but did not restore CHS
responses.23,186 Hart and colleagues found that the use of anti-
bodies against cis-UCA partially restored the CHS response
to 2,4,6-trinitrochlorobenzene (TNCB),187 indicating that
UV-UCA is playing a major role, but that other mechanisms
may be involved. Furthermore, they have suggested that mast
cells play a critical role in the UCA-mediated suppression of
CHS responses.188
After UV exposure of the skin, mast cells are thought to
release histamine which, in turn, leads to the production of
PG.159 This sequential production of histamine and PG must
be downstream of the photo-isomerization of UCA, as cis-
UCA and histamine effects are not cumulative. Likewise the
same study demonstrated that the effects of histamine and
prostanoid antagonists were not cumulative and, thus, pro-
vided further evidence that they were produced sequentially
in this pathway. Additional evidence, although perhaps more
circumstantial, is that cis-UCA can induce mast-cell degran-
ulation161 and that the extent of UV-induced suppression has
been linked in some mouse strains to mast cell number and
function.162 However, another group presents evidence that
the suppressive signal arises in the epidermis and that mast
cells are not an essential requirement, but IL-10 production
by epidermal cells appeared to be.117 They found that trans-
planting UV-irradiated epidermis to the body wall of mast
cell-deficient mice still generated UV-induced immune
suppression. An alternative explanation is that the time
between UV exposure and the harvesting of the epidermis
allowed soluble factors, produced by the degranulation of
mast cells, sufficient time to penetrate the epidermal layer.
The difference may also be due to differing UV-exposure
regimes, in which the latter study used a series of low-dose
exposures whereas Hart et al.159 used a single high-dose
exposure. Thus, from recent studies it is clear that mast cells
do play an important role in the generation of immuno-
suppression; however, the exact role remains uncertain.
From the accumulating evidence it is clear that UCA has
a major role in UV-induced immunosuppression of DTH
responses and a lesser one in CHS responses. However, the
actions of cis-UCA do not exclude DNA damage being
important as both UCA and DNA mediate effects associated
with immunosuppression.189
Cytokines
Ultraviolet light exposure of the skin induces many changes
to the skin microenvironment, including the production of
cytokines.190–192 In the epidermis the main secretor of cyto-
kines after UV exposure are the keratinocytes, and the
changes in the cytokine profile of this cell have been the
subject of intensive study (reviewed by Takashima and
Bergstresser192). Langerhans cell production of cytokines
after UV exposure of skin, while undoubtedly important, has
not been extensively investigated. Further studies on many of
these cytokines are required to define their role in altering the
skin immune system.
Interleukin-1 The IL-1 system consists of interaction
between IL-1α, IL-1β, the IL-1 receptor antagonist (IL-1RA)
and the IL-1 receptors, type 1 and type 2. Exposure of the
556 GJ Clydesdale et al.
skin to UV light may alter the balance of this complex
cytokine system. Ansel et al.193 found that exposure of cul-
tured keratinocytes to UVB results in increased production of
IL-1 both intra- and extracellularly. UVB exposure of murine
skin in vivo caused epidermal cells to produce IL-1. Inter-
leukin-1 production has been detected in the skin, post-UV
exposure in humans.194,195 While LC production of IL-1
appears to be unaltered by UV,196 the production of a specific
inhibitor of IL-1 is also observed after UV exposure of epi-
dermal cells and keratinocytes.197 The inhibitor was termed
contra-IL-1 and was found in the serum of UVB-irradiated
mice.198 A possible candidate is IL-1RA, which binds to the
IL-1 receptor but produces no activation.199 Hirao200 demon-
strated that a 100-fold excess of IL-1RA is needed to inhibit
the biological function of IL-1 and that in human skin un-
exposed to UV, IL-1α dominates. However, in UV-exposed
skin IL-1RA is dominant.200 Furthermore, in the same study,
a UV dose of 2 MED was shown to dramatically upregulate
IL-1RA in the stratum corneum of human volunteers, leading
to the suggestion that this could inhibit excessive inflamma-
tion and may account for some of the UVB-induced immuno-
suppression.
Studies using the HeCat keratinocyte cell line, have
demonstrated that TGF-α, TGF-β, IFN-γ, IL-6 and TNF-α
increase IL-1α production, while no effect on mRNA of
IL-1RA was evident. This suggests that the balance between
IL-1α and IL-1RA is due to the levels of IL-1α, not IL-1RA,
which remain constant.201 This is in direct contrast to Hirao’s
hypothesis.
Interestingly, while proposed as antagonistic in inflam-
mation, immunosuppressive effects of both IL-1RA and
IL-1α have been demonstrated. IL-1RA injection into the
skin prior to sensitization with 2,4-dinitrofluorobenzene
(DNFB) inhibits ear swelling by 36–43%.202 IL-1α has been
shown to suppress the ability of LC to present tumour anti-
gens to CD4+ T cells,203 as well as reducing CHS.204 Enk
et al.205 demonstrated that LC from IL-1α-injected mice have
reduced capacity to stimulate anti-CD3 treated T cells. It
appears that IL-1α and IL-1β, which is only produced by LC
in the epidermis, have different roles in CHS responses, with
IL-1β being crucial in the induction of CHS.205 IL-1β expres-
sion is increased in LC after contact sensitizer application to
the skin206 but, as yet, no evidence has been forthcoming on
IL-1β production after UV exposure.
In the skin, interactions between IL-1α, IL-1β and IL-1
receptor type 1 regulate inflammatory reactions; IL-1RA
and IL-1 receptor type 2 appear to downregulate these
responses.207 Further studies of the interaction of this system
after UV exposure of the skin should reveal in detail the role
of the IL-1 family in the suppression of cutaneous immune
responses.
Interleukin-4 While there is no evidence for IL-4 produc-
tion by cells of the skin after UV light, IL-4 can be detected
in lymph nodes draining the irradiated site.208 CD4+ Th2 cells
isolated from the spleen of UV-irradiated mice produce
IL-4.143 Furthermore, antibodies to IL-4 are able to reduce
the ability of UV-induced suppressor cells to suppress DTH
responses, but no reduction for CHS responses was
observed.209 This suggests that the suppression of these
responses involves different mediators. A more recent study
in IL-4-deficient mice has confirmed these findings210
and while IL-4-deficient mice were susceptible to local
immune suppression, they did not develop systemic immune
suppression.211
Interleukin-10 Schwarz et al.197 showed that serum from
UVB-irradiated mice was able to induce systemic suppres-
sion. Furthermore, UVB exposure of cultured human
keratinocytes resulted in the production of IL-10 in vitro,
which caused systemic immunosuppression when the super-
natants were injected into mice.126 Additional evidence of
UV-induced IL-10 production by human keratinocytes was
shown both in vitro212,213 and in vivo.212 Grewe et al.213 found
that UVB strongly stimulated IL-10 production; however,
UVA-1 (340–400 nm) wavelengths were found to be the most
stimulatory. In contrast, Jackson et al.214 reported that human
keratinocytes were unable to produce IL-10. This was
supported by Teunissen et al.,215 who were unable to detect
IL-10 secretion from normal or transformed keratinocytes.
Higher doses of UV were required to produce barely
detectable IL-10 mRNA production with extensive PCR, but
no protein was detected. In reply Grewe et al.216 suggested
that the RT-PCR method used by Jackson may have lacked
the sensitivity of their system and also argued that the use of
non-neutralizing antibodies in their enzyme-linked immuno-
assays increased sensitivity.
Although human keratinocyte production of IL-10 is
controversial, this may be a minor contributor of epidermal
IL-10, as Kang et al.217 only detected slight increases in
keratinocyte IL-10 mRNA after UVB exposure. They
reported that large amounts of IL-10 were produced by
CD11b+ macrophages, which have been shown to infiltrate
the epidermis post-UVB exposure.21 This group demon-
strated that the production of IL-10 by skin-infiltrating
macrophages far outweighed that of the keratinocytes,
suggesting that infiltrating macrophages were the major
source of IL-10 in the epidermis after UVB exposure of
human skin.
Interleukin-10 has been shown to downregulate many
aspects of the skin immune system, including the CHS reac-
tion.218 Such inhibition of CHS occurred during the effector
phase of CHS and not during the induction of CHS.219
However, in the same study, IL-10 inhibited both the initia-
tion of DTH and its effector phase. This was supported by
Rivas and Ullrich,209 who found that the systemic adminis-
tration of anti-IL-10 antibodies to mice blocked the activity
of UV suppressor cells in DTH, but not the cells that suppress
CHS. Ullrich’s group140 has also demonstrated that the
injection of an anti-IL-10 antibody into UV-irradiated,
B. Burgdorferi-immunized animals restored the IgG2a and
IgG2b antibody responses and DTH to normal. This provided
further evidence for the role of IL-10 in altering the balance
of the immune responses after cutaneous UV exposure.
Local IL-10 production in the skin, by infiltrating
macrophages, restricts the ability of LC to stimulate an
effective Th1 cell response. Instead anergy of Th1 cells has
been observed, but the ability to stimulate a Th2 response was
unaltered.220 This is supported by Ullrich221 who found that
adding IL-10 from UV-irradiated cultured keratinocytes to
splenic APC caused inhibition of antigen presentation to Th1
cells and enhanced stimulation of Th2 responses. LC also
 Ultraviolet light induced injury
lose their ability to stimulate a primary allogeneic response
when incubated with IL-10.222 This may be due to the loss of
important costimulators such as downregulation of B7-2 that
occurs after addition of IL-10 to human peripheral blood
DC.223 The ability of LC to present tumour antigens is also
downregulated by incubation with IL-10, which overcomes
the GM-CSF-induced maturation of normal LC APC func-
tion. Ullrich145 showed both in vitro and in vivo that adminis-
tration of anti-IL-10 mAb restores the lost APC function of
splenic DC.
The many downregulatory effects of IL-10 on, for
example, CHS, DTH and APC function of LC, and its ability
to stimulate Th2 cells while inhibiting Th1 cells has resulted
in IL-10 being regarded by some as ‘the primary mediator of
UVB-induced local, as well as systemic, suppression’.192
Other Interleukins The production of a number of other
interleukins occurs after UV-light exposure of the epidermis.
While IL-3 is produced in mouse skin after irradiation it
does not appear to be generated by human keratinocytes and
IL-3-like activity in human skin can be inhibited by anti-
bodies to GM-CSF and IL-6.224
Interleukin-6 is a pro-inflammatory cytokine that is
produced by human keratinocytes;225 the peak serum levels
occur 12 h after severe sunburning, correlating with the
development of fever.226 IL-6 is involved with the production
of acute phase proteins, but its role in the skin immune
system is unknown, although there is some evidence that,
after UVB irradiation, the appearance of IL-10 in plasma
may be IL-6 regulated.227
Interleukin-8 is a pro-inflammatory cytokine produced in
the epidermis and it causes neutrophil chemotaxis to sites of
inflammation. IL-8 production is greatly increased within an
hour of UV exposure (reviewed by Luger and Schwarz191);
the levels of IL-8 mRNA increased 11–13-fold.228 The accu-
mulation of neutrophils in sunburned skin26,74 correlates with
the production of this cytokine.72
Interleukin-12 has been demonstrated to be upregulated in
human keratinocytes after UVA, but not UVB, exposure.229
IL-10 was not found to be upregulated in this study, provid-
ing further evidence of the photoprotective effect of UVA put
forward by Reeve et al.150
The induction of IL-15 by keratinocytes and dermal
fibroblasts has been noted after UV exposure.230 Blauvelt
et al.231 reported that freshly isolated keratinocytes and cul-
tured keratinocytes expressed IL-15 mRNA in vitro, which
was downregulated by UV exposure in a time- and dose-
dependent manner. Blauvelt et al.231 were unable to explain
their contrasting results with those of Mohamadzadeh et al.230
Blauvelt et al.231 also showed that IL-15 mRNA was
expressed by LC and blood DC, and proposed that IL-15 may
contribute to the enhancement of Th1-like responses. Hence,
downregulation of its production after UVB exposure may
contribute to UV-induced reduction of Th1-like responses.
Before the role of this cytokine can be established in the
immune alterations following UV exposure, further studies
are required to determine whether its production is enhanced
or suppressed by UV light.
Tumour necrosis factor-α Tumour necrosis factor-α (TNF-α)
is a pro-inflammatory cytokine that is produced by a number
557
of different cell types in the skin. These include mast cells,232
in which it is stored preformed; it is induced in keratino-
cytes,233 activated LC234 and dermal DC.235 Two TNF-α
receptors are described; TR60 (Type I, 55 kDa) and TR80
(type II, 75 kDa), with lymphoid cells expressing mainly type
II and cells of epithelial origin, type I receptors.236 The
expression of this cytokine is dramatically increased after
exposure of the skin to UVB irradiation.195 TNF-α is
considered to have a major role in UVB-induced changes in
inflammatory and immune reactions, including downregula-
tion of CHS responses.237 Cis-UCA generated by the UV
exposure of the epidermis appears to mediate its effects on
CHS via TNF-α.180
Tumour necrosis factor-α affects inflammatory and
immunological responses in the body. These include the
induction of other cytokines, including IL-1α, but not its
receptor antagonist.201 TNF-α also has a role in the recruit-
ment of cells to areas of inflammation by altering adhesion
molecule expression in the surrounding environment.72 Intra-
dermal injection of recombinant human TNF-α upregulates
ICAM-1, VCAM-1 and E-selectin in vivo.238 E-selectin was
upregulated on dermal microvascular endothelial cells after
release of TNF-α by dermal mast cells.163 CD44 also appears
to be upregulated, allowing increased binding of leucocytes
to the endothelial surfaces.239 The increased expression of
CD44 and E-selectin is involved with increased infiltrates
of neutrophils and mononuclear cells following UV light
exposure.19,72,239
Additional evidence of the importance of TNF-α comes
from the study of Walsh76 who found that UVB irradiation
in vitro and in vivo resulted in TNF-α release from mast cells.
This, in turn, led to increased ICAM-1 and E-selectin expres-
sion on endothelium within 2 h of UVB exposure. This was
independent of the epidermis, suggesting that keratinocytes
only make a small contribution to the acute release of
TNF-α. However, due to the extent of the epidermis and the
keratinocyte production of this cytokine after UVB irradia-
tion, it is likely that TNF-α release by keratinocytes
contributes, in particular, to the later stages of the UVB-
inflammatory process.
Tumour necrosis factor-α was originally named because
of its ability to kill tumour cell lines. Today it is a cytokine
known to be involved with the induction of apoptosis.236
T-cell mediated TNF-α-induced apoptosis occurs for mature
T cells via the TR-80 receptor. This is more important in
mediating CD8+ T-cell apoptosis than CD4+ T-cell apoptosis,
which is mediated mostly via Fas and Fas L interaction.240
The 55 kDa version of the TNF receptor is expressed by
keratinocytes and has a ‘death domain’ homologous to that of
Fas. This has been implicated in the induction of apoptosis in
non-lymphoid cell apoptosis.236 TNF-α has recently been
shown to be involved in the formation of sunburn cells,241 as
the injection of anti-TNF-α antibody reduced UV-induced
sunburn cell formation, although the cytokine by itself was
not sufficient to induce sunburn cells.
Tumour necrosis factor-α has a role in regulating the
survival and migration of DC found in the skin. TNF-α
supports the survival of LC in the murine system, but this did
not result in the acquisition of accessory cell function.233 In
the ovine immune system, TNF-α supports survival of affer-
ent lymph DC, whereas GM-CSF does not.242
558 GJ Clydesdale et al.
Tumour necrosis factor-α has been proposed to stimulate
LC migration from the skin to the draining lymph node.243
When increasing doses of TNF-α were injected intradermally
into BALB/c mice it was observed that DC accumulation in
the lymph node was increased after just 2 h.243 Subsequently
it was found that TNF-α was required for both DC migration
and optimal contact sensitization.244 In contrast, Yoshikawa237
reported that injection of 50 ng TNF-α (identical in amount
and activity to that used by the previous group) intradermally,
followed by cutaneously applied hapten, led to the retention
of LC within the epidermis. However, previous studies by
Streilein’s group157 had shown that there was indeed a 30%
reduction of Ia+ (LC) within the epidermis after 2 h, but LC
numbers returned to normal within 24 h.157 These data
suggest that the differing time courses of experiments may
have led to variation in the results of these two groups.
Further evidence for the DC-depleting effect of TNF-α
comes from work, in which systemic administration of the
cytokine depleted DC from the heart, kidney and skin.245
More recently it was found using skin organ culture that low
doses of TNF-α (50–100 U/mL) enhanced LC emigration.246
However, high doses (> 1000 U/mL) suppressed emigration,
possibly due to toxicity.246 At this time it is not known
whether TNF-α acts on DC directly or via other mechanisms
(e.g. CD40 ligation).247
Prostaglandins
Increases in prostaglandin (PG) production after UV expo-
sure of the skin have been demonstrated,248 and the
prostaglandins produced are PGE2, PGF2α and PG6-oxo-F1α.
Treatment of the skin with indomethacin (an inhibitor of PG
synthesis) after UV exposure led to a decrease in inflamma-
tion,249,250 but did not prevent decreases in the density of
LC.250 This was partially due to indomethacin acting as a sun-
screening agent; however, oral administration did not stop LC
depletion, but did partially restored CHS responses after UV
exposure.251,252 Interestingly both TNF-α and IL-1α, are pro-
duced in the skin after UV exposure, affecting DC function
and upregulating keratinocyte synthesis of PGE2.253 PGE2
interacts with the cytokine cascade including IL-4 and IL-10,
which are responsible for the UV-induced systemic immune
suppression.254 This more recent finding has highlighted the
importance of PGE in the cutaneous UV response.
Complement
Recent studies have shown that the complement component
C3 may be involved with the generation of UV immuno-
suppression and antigenic tolerance.255 Using a variety of
systems, including C3 knockout mice and the inhibition of
cleavage of C3 to C3b, the photoimmunosuppression to
DNFB was reversed and the use of a soluble receptor for
complement reduced the infiltration of CD11b+ macro-
phages. Furthermore, ligation of the iC3b receptor has a
similar effect on UV-induced immunosuppression.255 The
interaction between these two molecules appears to reduce
the production of IL-12, while increasing IL-10, which is
considered to be a crucial step for the generation of immuno-
suppression.
Transforming growth factor-β
Transforming growth factor-β (TGF-β), in particular the
TGF-β1 isoform, has been shown to mediate inflammatory
and immune effects, some of which have similar characteris-
tics to UVB-mediated effects.256 Because human keratino-
cytes have been shown to upregulate the production of this
cytokine 24 h after UV exposure,256 it is likely that further
study of this cytokine will contribute to our understanding of
UV-induced immunosuppression.
Other soluble factors
The production of other cytokines and soluble factors after
UV exposure of the skin requires further investigation. These
include VEGF, basic fibroblast growth factor (bFGF)257 and
nerve growth factor (NGF),258 which provide mitogenic
stimuli to endothelial cells, keraintocytes, fibroblast and
nerve cells. The production of bFGF together with a decrease
in IFN-β is thought to lead to increased angiogenesis and the
formation of new blood vessels.259 It also appears that neuro-
peptides, such as substance P and calcitonin gene-related
peptide (CGRP), are increased after cutaneous UV exposure.
CGRP can induce mast-cell degranulation and the release of
TNF-α. Futhermore, the injection of CGRP into the skin
reduces LC density and impairs CHS induction, while the
addition of CGRP anatagonists can overcome the suppression
of CHS induced by UV exposure. The roles of cytokines and
soluble factors are crucial to immunological events following
UV exposure of the skin. It also appears to be multifactorial
and future studies will elaborate further on individual com-
ponents of this complicated event.
Effects of ultraviolet on Langerhans cells and antigen
presentation
Langerhans cells are the only constituent APC type found
within the epidermis and after exposure to UV alterations in
LC morphology and kinetics have been observed.66,67 Alter-
ations in LC were first shown by Fan et al.,260 who found they
were difficult to demonstrate in human epidermis after expo-
sure to UV light. In 1967 Wolff and Winkelmann261 treated
guinea pig skin with UV light, but no changes in LC distrib-
ution were observed. While the exposure times were noted,
no treatment dose was given in either study. In contrast to
this, a single exposure of human skin to 6 MED of sunlight,
reported by Zelickson and Mottaz,262 showed that the number
of LC present in the epidermis decreased. Ultraviolet-
damaged LC expressing thymine dimers have been shown to
migrate to the lymph node 1 h after UV exposure,263 indicat-
ing that the depletion of LC from the skin after UV irradia-
tion may be associated with increased cell migration. This
has now been confirmed by significant, dose-dependent
increases in the rate of LC migration from sheep skin after
exposure to varying doses of UVB.264,265
While the depletion of LC from the skin would reduce the
immunological ability of the epidermis to respond to foreign
antigens, this is not the only effect UV light has on LC. It has
been extensively demonstrated that UV irradiation affects
APC function. Levis et al.266 showed that the ability of UV-
treated APC to stimulate hapten (DNCB)-specific autologous
 Ultraviolet light induced injury
lymphocytes in primary culture was abrogated, and the ability
to stimulate blast cells in secondary culture was diminished,
but not eliminated. The effect of UV light on APC function
was also studied in vivo by Greene et al.,113 who reported that
TNP-derivatized APC from UV-irradiated mice failed to
induce an immune response in UV-irradiated syngeneic mice,
when compared to normal APC. This failure to induce immu-
nity was associated with suppressor T cells. In vitro studies
by Stingl et al.267 have shown that the ability of epidermal
cells to stimulate T cells was reduced in a dose-dependent
fashion after exposure to UV. No epidermal cell death was
observed, however, as LC made up only 3–5% of epidermal
cells, specific cytotoxic effects on these cells could not be
ruled out, although similar percentages of LC were found in
epidermal cell preparations, both before and after irradiation.
The loss of cell surface markers was suggested as the most
likely explanation for these events. This suggestion was con-
sistent with data showing that exposure of LC to UV light
lowers ATPase activity in vivo.268 Exposure to milder doses of
UV light in vitro (200 J/m2) had little effect on the retention
of Ia (murine MHC II) antigen or the T6 antigens.269 Recent
work suggests that no reduction in MHC II expression is
present in FITC+ DC migrating after a dose of 2 kJ/m2.170
The loss of important costimulator expression may, in
turn, provide a partial explanation for the reduction in LC
function observed after UV exposure. This has been shown as
a reduced T-cell proliferative response267 and by a loss of the
DTH response.270 Loss of CHS response after UV irradiation
is also associated with deficient antigen presentation.178
It should also be noted that splenic APC function is down-
regulated after UV exposure1 perhaps mediated by cis-
UCA,183 suggesting a systemic reduction in APC function
after UV exposure of the skin. Locally, the physical damage
of the migrating DC may be responsible for the LC loss of
function, as LC migrating from UVB-irradiated sheep skin
have a profound loss of dendritic processes compared to LC
migrating from normal skin.264 It is likely these physical
defects would reduce the ability of LC to act as APC.
The ability of enriched T6+ LC to effectively induce
a mixed epidermal cell lymphocyte reaction is reduced
immediately after exposure of the skin to UV, compared to
non-irradiated controls.271 This reduction in allostimulatory
activity was not reversed by the addition of indomethacin or
IL-1 to the culture system. It can be speculated that the
production of IL-10, by keratinocytes or UV-induced
macrophages, may be able to downregulate the costimulator
B7-2 on LC, as has been demonstrated after addition of
IL-10 to human peripheral blood DC.223 IL-10 is proposed to
mediate the systemic suppression of APC function observed
after UVB exposure.145 Recent evidence supports this argu-
ment.272 LC can be induced to express the B7-1 and B7-2
costimulatory molecules in vitro. However, UVB exposure of
epidermal cell suspensions, with doses ranging from 100 to
200 J/m2, reduced functional B7-1 and B7-2 expression in a
dose-dependent manner. This was partially restored with
submitogenic doses of anti-CD28 mAb.273 Because LC could
not be returned to their full allostimulatory capacity, Weiss
et al.273 suggest that this may be due to the presence of
an inhibitory cytokine, possible candidates include PGE,
IL-1, IL-10 or TNF-α, which are produced after UVB
exposure.
559
Ullrich et al.274 was able to inhibit UV-induced suppres-
sion by the in vivo addition of mAb to B7-2, but not B7-1.
The antibodies to B7-2 also stopped secretion of IL-10 into
the plasma, providing a mechanism for the lack of suppres-
sion observed in vivo. Any loss of B7 expression and/or
upregulation following UV exposure of the skin would render
the LC migrating to the lymph node less able to stimulate
T cells and, hence, lead to anergy275 and specific downregu-
lation of Th1 responses.276 In support of this hypothesis is
crucial evidence presented by Simon et al.,277 which shows
that LC from UV-irradiated skin are able to stimulate Th2
cells, but not Th1 cells. LC from UV-treated skin can induce
anergy in Th1 cells,123 which are essential for cellular
immune responses such as DTH and CHS. This also provides
a mechanism for generating Th2 ‘suppressor cells’ and reduc-
ing or eliminating Th1 ‘effector cells’, both of which are
required for the generation of UV immunosuppression.122 The
interaction between the APC and the antigen specific T cell
are crucial to any immune process and this interaction is
altered after UV exposure, contributing to the antigen-
specific suppressive events that occur after such an exposure.
Ultraviolet-induced macrophages
While UV irradiation reduces the allostimulatory capacity of
DC isolated from the epidermis immediately after treatment,
Cooper and colleagues found cells isolated from skin 3 days
later had an enhanced allostimulatory capacity.271 This
increased allostimulatory activity was due to T6– DC, which
had infiltrated the epidermis at this later time.271 These infil-
trating DC expressed the monocyte specific marker, OKM5
(CD36),271 suggesting that these cells were of the mono-
cyte/macrophage lineage. They had the ability to induce
T-cell proliferation and were able to act as stimulators of an
autologous mixed epidermal cell lymphocyte reaction,271 and
were subsequently shown to express MHC II.17
A later study by Cooper et al.21 showed that a subpopula-
tion of the infiltrating cells were non-dendritic neutrophils,
which is consistent with data obtained from studies on rats,
rabbits, guinea pigs26,32 and humans.74 Another subpopulation
of infiltrating cells were dendritic, and expressed high levels
of the macrophage marker CD11b, and coexpressed high
levels of MHC II. Timing of the peak infiltration of this sub-
population coincided with an increase in post-UVB epider-
mal APC function from 21% to 59%, a time when LC
depletion was maximal. Hammerberg et al.278 found that this
subpopulation of infiltrating cells, when isolated from UVB-
exposed, hapten-treated mouse skin, led to re-sensitization
rather than tolerance. These cells were also shown to stimu-
late suppressor inducer cells (Th2) and CD8 cells in the pres-
ence of IL-2.279,280
Ultraviolet-induced macrophages are a major source of
IL-10 secreted in the epidermis post-irradiation.217 As IL-10
is a potent downregulator of Th1 (cellular) immune
responses,281 this provides a mechanism by which the infil-
trating macrophage population can suppress cellular immune
responses generated by LC. Recent experiments indicate that
infiltrating UV-induced macrophages appear to come from
the expansion of a subset of dermal macrophages that are
CD36+ CD11b+CD1–.282
560 GJ Clydesdale et al.
Kurimoto et al.283 have produced data from murine exper-
iments that contradict Cooper’s theory278 that macrophages
mediate the downregulation of immune function after UV.
The investigation of Kurimoto et al. used liposomes contain-
ing dichloromethylene diphosphonate, which selectively kills
phagocytic macrophages, and showed that these cells play a
role in generating CHS responses in UV-resistant mice, but
have no effect on tolerance induction.283 Although they
endeavoured to compare their results to those of Cooper’s
group, their UV irradiation consisted of four treatments,
whereas Cooper’s group used a single dose. No immunohis-
tochemical studies were performed to show that macrophages
were depleted from the skin by the dichloromethylene
diphosphonate, which may be important as Weber-Matthiesen
and Strerry284 found that OKM5+ macrophages are non-
phagocytic, thus, they may not have ingested the liposomes.
While clear evidence exists in humans and mice for the
infiltration of macrophages into the skin after UV, less is
known about what subsequently occurs to these cells. Evi-
dence gathered from mice suggests that following UVB
exposure of the skin, macrophages do appear in the lymph
nodes285 and an increased proportion of DC expressing
CD11b (Mac1) are found binding to CD4 and an increased
proportion of CD8 positive cells.170
The timing of the maximum migration of UV-induced
macrophages into the skin coincides with the maximal deple-
tion of LC. As they secrete IL-10217 and stimulate suppressor
inducer T cells,279,280 which both result in downregulation of
Th1 immune responses, it is likely that the infiltrating
macrophages may contribute to suppression of immune
responses after UV irradiation.
γδ T-cell changes
Ultraviolet-B exposure of murine skin can also completely
deplete dendritic epidermal T cells (DETC) from the epider-
mis.286,287 In these experiments depletion was sustained and
Thy1 DETC did not reappear until 14–22 weeks following
exposure of the skin, whereas the influx of LC into the skin
was continuous.286 The doses used were four exposures to
700 J/m2 or a single exposure of 1000 J/m2. Chronic exposure,
such as that used by Alcalay et al.,287 consisting of 8 kJ/m2
three times per week until the mice developed tumours,
resulted in DETC being consistently absent for up to 43 weeks
post-treatment. LC were observed to return to the skin and
infiltrate tumours.287 This suggested to the authors that the
tumours persisted because of the lack of Thy1 DETC and their
cytotoxic potential. Love-Schimenti and Kripke288 found that
DETC incubated in the presence of IL-2 were capable of
deleting hapten specific autologous T cells. Thus, it is possi-
ble that loss of these cells from murine skin may play an
important role in UV-induced carcinogenesis. This observa-
tion is limited to animal species that have a network of DETC
in the skin; the lack of such a network in human skin suggests
that they are not important in the human defence system.
Conclusions: Immunity is compromised by cutaneous
ultraviolet exposure
Human skin is often exposed to UV light in sunlight. This
downregulates the skin immune system by inducing a number
of cellular changes. The trigger(s) for these effects are
thought to be direct DNA damage of cells, or photoisomer-
ization of trans to cis-UCA and its subsequent interaction
with cells in the skin. Until now, detailed mechanistic studies
have largely been performed in animal models rather than in
humans. Investigations of the human response to UV expo-
sure have concentrated on endpoints such as erythema, DTH
responses and the development of cutaneous cancer. What is
now required, are parallel investigations in humans, which
could serve to define the cellular, biochemical and molecular
events that occur in human skin after UV exposure.
These alterations induce changes in the cytokine profile of
keratinocytes. Many factors are produced after cutaneous UV
exposure, while others are reduced, with local and systemic
effects. After an initial increase in NO, histamine and PGE2,
which leads to increased vascular permeability, the produc-
tion of pro-inflammatory cytokines such as IL-1, TNF-α,
IL-6 and IL-8 closely follows together with the activation of
complement components. This in turn leads to the down-
stream production of the anti-inflammatory mediators
TGF-β, IL-10 and IL-1RA. There are many other factors of
uncertain role, including neuropeptides, chemokines and
other cellular growth factors.
After UV exposure, LC APC function is altered with the
Th1/Th2 balance directed in favour of Th2-cell function. In
addition, a population of macrophages that secrete IL-10,
thereby, suppressing Th1 responses, migrates into the epi-
dermis. These events combine, leading to the generation of
suppressor T cells, which produce Th2 cytokines, further dis-
rupting cell-mediated immune responses by inhibiting effec-
tors of the Th1 subtype. The induction of specific suppression
of CHS and DTH responses is evident and is believed to be
mediated by TNF-α and IL-10, respectively. IL-10 suppresses
the effector phase of both, possibly by inhibiting APC pro-
duction of IL-12 via downregulation of costimulators. These
changes in the cellular arm of the skin immune system would
increase susceptibility to viral infection and greatly reduce
any effective immune response to tumours, which may arise
in the skin as a result of UV-induced mutation.
Acknowledgements
The authors acknowledge the support of the National Health
and Medical Research Council of Australia and the Cancer
Council of Tasmania who have funded research projects
related to this review.
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