Acta Anaesthesiologica Taiwanica 50 (2012) 172e177

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Acta Anaesthesiologica Taiwanica

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Review Article

Mechanisms of ketamine-induced immunosuppression

Feng-Lin Liu 1, Ta-Liang Chen 2, 3, Ruei-Ming Chen 3, 4 *
1
Department of Anesthesiology, Taipei Medical UniversitydWan Fang Hospital, Taipei, Taiwan
2
Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan
3
Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan
4
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, is widely used as an intravenous
Received 26 June 2011 anesthetic agent. It is known to produce increases in blood pressure and stroke volume, which implies its
Received in revised form importance in clinical practice. Ketamine has also been shown to possess anti-inflammatory effects. Our
17 July 2012
previous studies showed that ketamine, at clinically relevant concentrations, can downregulate
Accepted 20 August 2012
endotoxin-induced macrophage activation through toll-like receptor-dependent activation of mitogen-
activated protein kinases and the transcription factors nuclear factor-kappa B and activator protein-1.
Key words:
As to the responsible mechanisms, considerable attention was devoted to ketamine-involved regula-
immunosuppression;
immunity, innate;
tion of proinflammatory gene expression. The assessment of how ketamine regulates proinflammatory
ketamine; gene expressions is significant in determining the signal cascades that are influenced by this anesthetic
mitogen-activated protein kinases; agent and its clinical application in the tactical use of ketamine in preventing sepsis. Herein, we review
signal transduction; the literature on the pharmacodynamics, pharmacokinetics, and possible mechanisms involved in ket-
toll-like receptors amine’s immunology.
Copyright Ó 2012, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights
reserved.

1. Introduction 2. Immunosuppressive effects of ketamine on immune cells

Ketamine, 2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone,
was developed by Parke Davis Laboratories in 1962 and was first
described in 1965, after assessing the side effects of behavioral and
psychological changes associated with the earlier product, phency-
clidine.1,2 Ketamine is a noncompetitive N-methyl-D-aspartate
(NMDA) receptor antagonist that can block the excitation of the
NMDA receptor induced by glutamate and aspartate.2 Among
nonvolatile anesthetics, ketamine has more stable hemodynamics
than other anesthetic agents; it is used in various clinical areas,
including pediatric anesthesia, traumatic anesthesia, and obstetrics;
and is quite widely serviceable in operating rooms and intensive care
units.3 Clinical analyses in both human and animal studies also
showed that ketamine has possible immunomodulatory and anti-
inflammatory effects. In this article, we review the literature on the
immunomodulatory effects of ketamine on immune cells and its
possible signal-transducing mechanisms.
* Corresponding author. Graduate Institute of Medical Sciences, College of
Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan.
E-mail address: rmchen@tmu.edu.tw (R.-M. Chen).
Some immune cells protect hosts from infection by organisms in
a nonspecific manner, and these cells with their mechanisms
comprise the innate immune system. Inflammation is one of the
first responses of the immune system to infection. Macrophages
and other cells of the innate immune system initiate inflammatory
responses by producing cytokines, which include tumor necrosis
factor (TNF)-a, high mobility group box 1, interleukin (IL)-1, IL-6,
and IL-8.4 Leukocytes comprising the innate immune system
include natural killer (NK) cells, mast cells, eosinophils, and baso-
phils, while phagocytes include macrophages, neutrophils, and
dendritic cells. These innate leukocytes function within the
immune system by identifying and eliminating pathogens that
intrude into a host.5
Ketamine was shown, in both human and animal models, to
possess anti-inflammatory effects, and several studies provided
in vitro data demonstrating that this intravenous anesthetic could
inhibit the function of lymphocytes, NK cells, and neutrophils.6e8
NK cells can recognize and kill the cells infected by a virus and
a variety of tumor cells during the metastatic process.9 Melamed
et al10 analyzed the count of NK cells in rat blood, and the results of
flow cytometry showed a reduction of 29% in the NK-cell count
after exposure to ketamine (Table 1). The NK-cell cytotoxic activity

1875-4597/$ e see front matter Copyright Ó 2012, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
http://dx.doi.org/10.1016/j.aat.2012.12.001
Mechanisms of ketamine-induced immunosuppression 173

Table 1 phosphorylation upregulates superoxide anion production.37

Effects of ketamine on immunosuppression. Sakamoto et al38 found that the p38 mitogen-activated protein
Study targets Importance Ketamine effect kinase (MAPK) pathway is important for chemotactic activity, and
NK cell count and Kill viral-infected or Reduced10,11 plays a crucial role in NADPH oxidase activation and superoxide
activity tumor cells anion generation in neutrophils. p38 MAPK is a subfamily of
CD11b, CD16, CD18, Cell adhesion and Reduced12e14 MAPKs. Compared to an inhibitor specific for p38 MAPK, Lu et al28
CD62L migration, bacterial
found that ketamine has a similar effect to SB203580 of inhibiting
phagocytosis
IL-1b, IL-6, TNF-a Proinflammatory Reduced15e25 the phosphorylation of p47phox and generating superoxide anions
cytokines by neutrophils by suppressing p38 MAPK activation. Both ketamine
IL-2 Cellular and humoral Preserved26,27 and SB203580 inhibit superoxide generation, and phosphorylation
immune response of the NADPH oxidase p47phox subunit and p38 MAPK. Similar
Mitochondrial membrane Macrophage function Reduced16
potential
inhibitory effects between ketamine and SB203580 strongly
LPS/LBP binding Activate inflammation Reduced17 suggest that ketamine is likely to inhibit p38 MAPK activation and
response then downregulate phosphorylation of p47phox and generation of
Ras/Raf/MEK/ERK/IKK Signal pathway for Inhibited7,17,18,28,29 superoxide anions by neutrophils (Table 1).28
proinflammatory
cytokines
NFkB, AP-1 Transcription factors for Inhibited7,14,20e22,29e31 4. Ketamine-involved inhibition of TNF-a, IL-1b, and IL-6
proinflammatory gene expressions
cytokines

Superscripts indicate reference numbers.
AP ¼ activator protein; ERK ¼ extracellular signal-regulated kinase; IKK ¼ inhibitor
of kappa B kinase; IL ¼ interleukin; NF-kB ¼ nuclear factor-kappa B; TNF ¼ tumor
necrosis factor.
was significantly reduced by ketamine, and an injected lung tumor
showed increased metastasis after ketamine treatment. Estes et al11
also found that NK-cell activity and cell numbers were reduced by
28% and 33%, respectively, in rats after being anesthetized using
isoflurane and ketamine.
Neutrophils play a major role in host defense. They rapidly
migrate through vascular endothelial cell monolayers to the site of
infection and destroy the invading bacteria by changing their
morphology from rounded and relatively smooth cells to elongated
and ruffled cells with pseudopodia.32 Adhesion of leukocytes to the
endothelium is mediated by distinct families of adhesion mole-
cules.33 Schmidt et al determined the rates of leukocyte adherence
and changes in microhemodynamics in rat mesenteric venules after
exposure to ketamine, using in vivo video microscopy. A 6.3-fold
increase in the number of adherent leukocytes was observed
after administration of endotoxins, while in ketamine-pretreated
rats, only a 2.6-fold increase in leukocyte adherence occurred
after endotoxin exposure, suggesting a reduced expression of
adhesion molecules.34 In lipopolysaccharide (LPS)-stimulated
leukocytes, ketamine was reported to attenuate cell adherence and
migration of human neutrophils through human umbilical endo-
thelial cell monolayers to 52%.35 Weigand et al12 used adhesion
molecules as markers and found that ketamine inhibited upregu-
lation of CD18 and CD62L in activated human neutrophils (Table 1).
CD11b and CD16 can bind to complement- or immunoglobulin-
opsonized particles and microorganisms, and enhance their
phagocytosis.13 Welters et al14 studied the effects of racemic ket-
amine on expressions of CD11b and CD16 by neutrophils after
stimulation of whole blood with LPS. They found that LPS-
stimulated increases in both CD11b and CD16 expressions by
human neutrophils were significantly inhibited by ketamine.
3. Ketamine-involved downregulation of chemotactic activity
and oxidant production
Chemotactic activity and oxidant production by neutrophils
were also demonstrated to be suppressed by ketamine.12,36 Nico-
tinamide adenine dinucleotide phosphate (NADPH) oxidase is
a critical regulator of the production of superoxide anions by
neutrophils; p47phox is one subunit of NADPH oxidase, and its
As a type of neutrophil, macrophages are also important in
cellular host defense against infection and tissue injury. Macro-
phages can destroy invading microorganisms and tumor cells
during inflammation by adopting reactions such as chemotaxis,
phagocytosis, oxidant production, and inflammatory cytokine
release.39 In LPS-activated macrophages, ketamine was reported to
reduce TNF-a and nitric oxide production, both of which play
critical roles during inflammation, and inhibition of these activities
may affect macrophage-mediated immunity (Table 1).15,40 To
evaluate the possible mechanism of ketamine-induced immuno-
suppression in macrophages, Chang et al16 studied TNF-a, IL-1b,
and IL-6 messenger RNA (mRNA) syntheses in murine macrophages
and found that ketamine inhibited mRNA syntheses by LPS-
activated macrophages. Therefore, those studies also provide
in vitro data to support the theory that ketamine exerts suppressive
effects on macrophage functions via inhibition of phagocytic
activities, oxidative ability, and TNF-a, IL-1b, and IL-6 mRNA
syntheses; ketamine-induced suppression of TNF-a and IL-6
syntheses occurs at the transcriptional level (Table 1). Chang et al
also found that ketamine can reduce the mitochondrial membrane
potential. Because depolarization of the mitochondrial membrane
can lead to mitochondrial dysfunction or even cell insult,41 they
proposed that ketamine suppresses macrophage function by
reducing the mitochondrial membrane potential but not through
a reduction in cell viability, which could possibly be one of the
mechanisms explaining the suppression of macrophage
functions.16
5. Roles of nuclear factor-kB and AP-1 in ketamine-induced
gene inhibition
Studies showed that ketamine can inhibit TNF-a gene expres-
sion through suppression of nuclear factor (NF)-kB activation
(Table 1).7,29 During inflammation, LPS first binds to the LPS-
binding protein (LBP) in the bloodstream.42 Then, the LPSeLBP
complex induces certain gene expressions via toll-like receptor
(TLR)-dependent mechanisms. TLRs, which are type-I trans-
membrane proteins with extracellular domains, consist largely of
leucine-rich repeats and intracellular signaling domains; at least 12
members of TLRs have been found in mammalian cells.43 TLRs
recognize essential structures expressed by pathogens and also
some endogenous mediators released by injured tissue.44 During
inflammation, LPS first specifically activates TLR4 on macrophages,
and then stimulates translocation of the transcription factors, NF-
kB and activator protein (AP)-1, from the cytoplasm to nuclei,
eventually inducing gene expression of inflammatory cytokines
174
such as TNF-a and IL-6.45 To determine the signal-transducing
mechanisms of ketamine-caused inhibition of TNF-a and IL-6
gene expressions in LPS-activated macrophages, Wu et al30 evalu-
ated phosphorylation of c-Jun N-terminal kinase (JNK)1/2 and
translocations of c-Jun and c-Fos from the cytoplasm to nuclei in
macrophages (Table 1). They found that treatment with ketamine
not only decreased LPS-induced JNK1/2 phosphorylation but also
inhibited LPS-caused increases in nuclear c-Jun and c-Fos. Wu
et al30 suggested that ketamine reduces the biosynthesis of TNF-
a and IL-6 in LPS-activated macrophages through suppression of
TLR4-dependent JNK activation and AP-1 translocation and trans-
activation. In neutrophils and mononuclear cells, inhibition of LPS-
induced NF-kB/AP-1 activity by ketamine was also observed
(Table 1).14,31
6. Cascade downregulation of MAPK phosphorylation
Recently, a study showed that transduction of TLR signaling to
various biological functions, such as cell growth and differentiation,
might be mediated by the Ras protein.46 After being phosphory-
lated by the Ras protein, the activated Raf kinase sequentially
triggers MAPKs, (MEK)1/2, and extracellular signal-regulated
kinases, (ERK)1/2.47,48 They trigger ERK1/2 and then transactivate
the inhibitor of kB kinase (IKK) by stimulating the translocation and
transactivation of NF-kB, which in turn induces expressions of
certain inflammatory genes.49,50 Previous studies showed that
ketamine could alleviate LPS-induced NF-kB activation in the rat
jejunum and lung.7,29 Chen et al17 tried to evaluate the role of the
Ras/Raf/MEK/ERK/IKK cascade in ketamine-induced regulation of
these inflammatory gene expressions in the RAW 264.7 murine
macrophage cell line (Table 1). A therapeutic concentration of
ketamine not only interfered with LPS binding to the LBP, but also
downregulated LPS-induced increases in Ras activity and Raf
phosphorylation, and then disrupted LPS-induced phosphoryla-
tions of MEK1/2, ERK1/2, and IKK. Consequentially, the trans-
location and transactivation of NF-kB induced by LPS were
significantly depressed after exposure to ketamine, which subse-
quently decreased the production of TNF-a, IL-1b, and IL-6.17
Recently, the increasing prevalence of sepsis from Gram-positive
bacterial pathogens prompted another examination of the molec-
ular pathogenesis of septic shock. Lipoteichoic acid (LTA) is a major
component of the outer membranes of Gram-positive bacteria and
was shown to be one of the key factors participating in the path-
ogenesis of sepsis by Gram-positive bacteria.51 The TLR2 receptor
was reported to be responsible for LTA activation in macrophages.52
A previous study reported that ketamine could decrease syntheses
of TNF-a and IL-6 in Gram-negative endotoxin LPS-activated
macrophages. Chang et al18 showed that ketamine also sup-
pressed TNF-a and IL-6 productions in Gram-positive endotoxin
LTA-activated macrophages by inhibiting TNF-a and IL-6 gene
expressions (Table 1). This suppression of TNF-a and IL-6 gene
expressions occurs through NF-kB-involved transcriptional regu-
lation due to decreased phosphorylation of ERK1/2. TLR2-mediated
signal-transducing activation of ERK1/2 may be one of the multiple
pathways that regulate ketamine-involved downregulation of NF-
kB activation and TNF-a and IL-6 gene expressions. These data
indicate that ketamine has an anti-inflammatory effect, which
reveals its possible role in treating septic patients.34
7. Roles of TLRs in ketamine-caused gene inhibition
Despite a decrease in mortality over the last decade, sepsis
remains one of the most common causes of death in Western
countries. A study in 2009 estimated that 1.21% of patients devel-
oped postoperative sepsis after elective surgery in the USA.53 In
F.-L. Liu et al.
spite of progress in better recognizing and improving standards of
care, mortality still ranges from 30% to 50% in patients with septic
shock.54 Roles of proinflammatory cytokines and TLR signaling in
the pathogenesis and development of sepsis were reviewed
recently.55,56 The discovery of the TLR explained the missing link
between endotoxin recognition by LBP and CD14, and how this
intracellular signaling pathway activates and translocates NF-kB to
nuclei and subsequently transactivates the production of proin-
flammatory cytokines. To prevent overactivation of the TLR and its
likely side effects, hosts develop strategies to control TLR expres-
sion and signaling. For instance, RP105, a TLR-like homolog mainly
expressed by B cells, directly interacts with the TLR4 signaling
complex, reduces its ability to bind to LPS, and prevents TLR4 from
overstimulation.57 Since LPS is a specific ligand for the TLR4
signaling pathway and TLR4 expression by monocytes is enhanced
in septic patients, TLR4 and its signaling pathway have garnered
more attention.19 Although the concept of anti-inflammatory
effects of ketamine is well accepted and documented in many
in vitro animal and human models, the effects on TLR expression
were only recently explored. In a rat model, both intravenous LPS-
induced TLR4 expression and NF-kB activation in the intestines and
lungs were shown to be reduced by ketamine (Table 1).20,21 In
another model, rats had polymicrobial sepsis after cecal ligation
and puncture, but treatment with ketamine after the procedure
decreased proinflammatory cytokines such as TNF-a and IL-6, as
well as NF-kB activation and TLR4 and TLR2 mRNA expressions in
the intestines and lungs. Ketamine also improved the survival of
rats after cecal ligation and puncture.22,23 Chen et al17 studied the
mechanisms of action of ketamine in the cultured murine RAW
264.7 macrophage cell line. They found that ketamine interfered
with LPS binding to LBP and also decreased phosphorylation of
various kinases involved in TLR4 intracellular signaling, thereby
inhibiting the signal pathway. When stimulated with the TLR2
agonist LTA, ketamine decreased TNF-a and IL-6 production by
macrophages. This results from decreased phosphorylation of
ERK1/2, an upstream protein kinase for activating the IKK, leading
to decreased NF-kB translocation to nuclei.18 The clinical relevance
of those results has to be assessed for patients with sepsis and those
sedated with ketamine. However, those studies provide useful
information for future effective and targeted treatment for patients
with sepsis.
8. Ketamine-induced postoperative immunoresponses
The immune system of a patient undergoing surgery is affected
by tissue damage, anesthesia, postoperative pain, and psychological
stress, which may have adverse influences on the postoperative
outcome. Surgical trauma can induce a complex system of cytokine
cascades with different effects on the host patient; for example,
some proinflammatory cytokines in the immune system are
excessively stimulated, while some cell-mediated immunity is
suppressed.24 Some undesirable effects, such as hypotension, shock,
and multiple organ failure, may occur and put the patients in grave
danger if the proinflammatory response is exaggerated.25 It was
suggested that there are interactions and regulation between
nociceptive and proinflammatory cytokines.58 Therefore, it is
important to attenuate postoperative pain, then reduce suppression
of the lymphocyte-mediated immune response, and attenuate the
proinflammatory cytokine reaction to surgery by undertaking
effective pain management to reduce surgical stress responses
during the postoperative period.59 In a study of patients after
coronary artery bypass grafting, ketamine inhibited leukocyte
reactivity and suppressed superoxide anion produced by neutro-
phils, thus demonstrating an anti-inflammatory effect.60 Roytblat
et al61 also reported that giving small doses of ketamine to patients
Mechanisms of ketamine-induced immunosuppression 175

Fig. 1. Molecular mechanisms of ketamine-induced downregulation of proinflammatory cytokine gene expressions. Administration of ketamine can result in the dysfunction of TLR
4 pathway via interference with LPSeLBP binding and reduction of LPS-induced increases in Ras activity, and then in the suppression of the LPS-induced signal transduction of
MEK1/2, ERK1/2, and IKK. Through the inhibition of the Ras/Raf/MEK/ERK/IKK cascade, the translocation and transactivation of nuclear factor NF-kB induced by LPS were depressed
after exposure to ketamine, which then suppressed the production of TNF-a, IL-1b, and IL-6. AP ¼ activator protein; ERK ¼ extracellular signal-regulated kinase; IKK ¼ inhibitor of
kappa B kinase; IL ¼ interleukin; JNK ¼ c-Jun N-terminal kinase; LPB ¼ lipopolysaccharide-binding protein; LPS ¼ lipopolysaccharide; NADPH ¼ nicotinamide adenine dinucleotide
phosphate; NF-kB ¼ nuclear factor-kappa B; TLR ¼ toll-like receptor; TNF ¼ tumor necrosis factor.

undergoing cardiopulmonary bypass during induction of anesthesia
can reduce serum levels of IL-6 significantly during the course of 7
postoperative days (Table 1). Takahashi et al62 used an animal model
to demonstrate that ketamine anesthesia can effectively improve
mouse survival after LPS and Escherichia coli challenge compared to
sevoflurane anesthesia. In that study, mice were anesthetized with
ketamine or sevoflurane during a laparotomy, and then mouse
survival rates and cytokine secretions were examined after chal-
lenging mice with E. coli or LPS. Compared with sevoflurane anes-
thesia, ketamine anesthesia increased the mouse survival rate from
the LPS challenge after laparotomy, whereas such an effect of ket-
amine was not observed after E. coli challenge. However, if bacterial
growth was controlled using an antibiotic, ketamine anesthesia
produced higher mice survival than sevoflurane anesthesia.62
Neutralization of TNF-a with an antibody also improved survival
in mice challenged with sevoflurane anesthesia, indicating that
better survival rate with ketamine may be due to suppression of
TNF-a. TNF-a is the cytokine that stimulates the production of IL-6
and IL-8 by macrophages. TNF-a and IL-6 are involved in both acute
and chronic inflammation, and in the case of polymicrobial sepsis in
animal studies, production of both TNF-a and IL-6 was inhibited by
ketamine.62 These data suggest that suppression of IL-6 and TNF-
a production by ketamine may have favorable influences on
a patient’s recovery.63,64 The timing of ketamine treatment is also
important in boosting the survival rate of infected rats. A trend
toward better survival and lower IL-6 production with ketamine
administered close to the insult, either burn injury or E. coli chal-
lenge, was obtained compared to ketamine treatment 24 hours
before and 2 hours after the insult (Table 1).65e67
9. Summary and conclusions
Nowadays, ketamine is used as an anti-inflammatory drug,
which emphasizes the importance of research on its interactions
with the immune system. Major surgery or sepsis causes the release
of proinflammatory cytokines, which, in excessive amounts, can
cause some undesirable effects, such as hypotension, shock, and
multiple organ failure. Ketamine was proved to be a modulator of
proinflammatory cytokines such as TNF-a, IL-1, and IL-6 in in vivo
and animal models. Although limited data are available from
176
human studies, it was revealed that a single dose of ketamine
administered prior to anesthesia induction reduced the post-
operative serum level of IL-6. The results imply the importance of
future studies with more cases and exploration of relationships
between IL-6 and mortality and morbidity.
The postulated effects of ketamine on proinflammatory gene
expressions are summarized in Fig. 1. Administration of ketamine
can result in TLR4 pathway dysfunction via downregulation of LPS-
induced increases in Ras activity and Raf phosphorylation, followed
by suppression of LPS-induced signal transduction of MEK1/2,
ERK1/2, and IKK. Inhibition of the binding between LPS and LBP is
also another way to inhibit TLR4 activation by ketamine. Through
inhibition of the Ras/Raf/MEK/ERK/IKK cascade, the translocation
and transactivation of NF-kB induced by LPS were depressed after
exposure to ketamine. As a result, ketamine suppressed the
production of TNF-a, IL-1b, and IL-6.
Recently, anticytokine therapy was applied to control sepsis.
Huang et al68 used an extracorporeal hemoperfusion device that
specifically absorbs mediators such as cytokines by a neutral
microporous resin, to treat sepsis. They found that the hemo-
perfusion group showed significantly lower levels of plasma IL-6
and IL-8; significant increases in the cardiac index, systemic
vascular resistant index, and withdrawal of vasoactive agents; and
decreases in the heart rate compared to controls. Although a small
dose of ketamine was observed to reduce postoperative serum
levels of TNF-a and IL-6 in humans (Table 1),27,28 unfortunately
there were no multicenter evaluations or randomized controlled
trials. In addition, NK cytotoxic activity was reduced significantly by
ketamine, and the injected lung tumor showed increased metas-
tasis after ketamine treatment in rats.10 These findings, if confirmed
with more studies, may impact the choice of anesthetics for
surgical patients under tumor excision, because any intervention
that may lead to an increased risk of tumor metastasis in patients
with suppressed NK cell activity should be withheld. However, it
reveals the tactical use of ketamine to prevent sepsis. There is still
a need for more efforts to elucidate detailed mechanisms of
ketamine-caused suppression of the proinflammatory cascade and
its influence in the future.
References
1. Ashton H, Young MD. Davies’ textbook of adverse drug reactions. UK: Chapman
Hall Medical Publications; 1998.
2. Craven R. Ketamine. Anaesthesia 2007;62:48e53.
3. White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and therapeutic
uses. Anesthesiology 1982;56:119e36.
4. Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear
weapon in the immune arsenal. Nat Rev Immunol 2005;5:331e42.
5. Janeway C, Travers P, Walport M, Shlomchik M. Immunobiology. 5th ed. New
York, London: Garland Science; 2001.
6. Rofael HZ, Turkall RM, Abdel-Rahman MS. Effect of ketamine on cocaine-
induced immunotoxicity in rats. Int J Toxicol 2003;22:343e58.
7. Yang J, Li W, Duan M, Zhou Z, Lin N, Wang Z, et al. Large dose ketamine inhibits
lipopolysaccharide-induced acute lung injury in rats. Inflamm Res 2005;54:
133e7.
8. Suliburk JW, Mercer DW. Ketamine attenuates early lipopolysaccharide-
induced gastric dysfunction: role of stress-inducible phosphoproteins.
J Trauma 2007;62:316e9.
9. Herberman RB, Ortaldo JR. Natural killer cells: their role in defenses against
diseases. Science 1981;214:24e30.
10. Melamed R, Bar-Yosef S, Shakhar G, Shakhar K, Ben-Eliyahu S. Suppression of
natural killer cell activity and promotion of tumor metastasis by ketamine,
thiopental, and halothane, but not by propofol: mediating mechanisms and
prophylactic measures. Anesth Analg 2003;97:1331e9.
11. Estes S, Dinh T, Garrett N. A brief report of basic science: the effects of
preincisional low-dose ketamine on natural killer cell activity in male
Fischer 344 rats after intra-abdominal surgery. Dimens Crit Care Nurs
2009;28:41e4.
12. Weigand MA, Schmidt H, Zhao Q, Plaschke K, Martin E, Bardenheuer HJ. Ket-
amine modulates the stimulated adhesion molecule expression on human
neutrophils in vitro. Anesth Analg 2000;90:206e12.
F.-L. Liu et al.
13. Maekawa K, Futami S, Nishida M, Terada T, Inagawa H, Suzuki S, et al. Effects of
trauma and sepsis on soluble L-selectin and cell surface expression of L-selectin
and CD11b. J Trauma 1998;44:460e8.
14. Welters ID, Hafer G, Menzebach A, Muhling J, Neuhauser C, Browning P, et al.
Ketamine inhibits transcription factors activator protein 1 and nuclear factor-
{kappa}B, interleukin-8 production, as well as CD11b and CD16 expression:
studies in human leukocytes and leukocytic cell lines. Anesth Analg 2010;110:
934e41.
15. Sakai T, Ichiyama T, Whitten CW, Giesecke AH, Lipton JM. Ketamine suppresses
endotoxin-induced NF-nB expression. Can J Anaesth 2001;47:1019e24.
16. Chang Y, Chen TL, Sheu JR, Chen RM. Suppressive effects of ketamine on
macrophage functions. Toxicol Appl Pharmacol 2005;204:27e35.
17. Chen TL, Chang CC, Lin YL, Ueng YF, Chen RM. Signal-transducing mechanisms
of ketamine-caused inhibition of interleukin-1b gene expression in
lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells. Tox-
icol Appl Pharmacol 2009;240:15e25.
18. Chang HC, Lin KH, Tai YT, Chen JT, Chen RM. Lipoteichoic acid-induced TNF-
a and IL-6 gene expressions and oxidative stress production in macrophages
are suppressed by ketamine through downregulating toll-like receptor 2-
mediated activation of ERK1/2 and NFkB. Shock 2010;33:485e92.
19. Härter L, Mica L, Stocker R, Trentz O, Keel M. Increased expression of toll-like
receptor-2 and -4 on leukocytes from patients with sepsis. Shock 2004;22:
403e9.
20. Yu M, Shao D, Yang J, Feng S, Xu J. Ketamine suppresses intestinal TLR4
expression and NF-kB activity in lipopolysaccharide-treated rats. Croat Med J
2006;47:825e31.
21. Yu M, Shao D, Feng X, Duan M, Xu J. Effects of ketamine on pulmonary TLR4
expression and NF-kB activation during endotoxemia in rats. Methods Find Exp
Clin Pharmacol 2007;29:395e9.
22. Yu M, Shao D, Liu J, Zhu J, Zhang Z, Xu J. Effects of ketamine on levels of
cytokines, NF-kB and TLRs in rat intestine during CLP-induced sepsis. Int
Immunopharmacol 2007;7:1076e82.
23. Yu M, Shao D, Yang R, Feng X, Zhu S, Xu J. Effects of ketamine on pulmonary
inflammatory responses and survival in rats exposed to polymicrobial sepsis.
J Pharm Pharm Sci 2007;10:434e42.
24. Ni Choileain N, Redmond HP. Cell response to surgery. Arch Surg 2006;141:
1132e40.
25. Dinarello CA. Proinflammatory and anti-inflammatory cytokines as mediators
in the pathogenesis of septic shock. Chest 1991;112:321Se7S.
26. Beilin B, Rusabrov Y, Shapira Y, Roytblat L, Greemberg L, Yardeni IZ, et al. Low-
dose ketamine affects immune responses in humans during the early post-
operative period. Br J Anaesth 2007;99:522e7.
27. Roussabrov E, Davies JM, Bessler H, Greemberg L, Roytblat L, Yardeni I, et al.
Effect of ketamine on inflammatory and immune responses after short-
duration surgery in obese patients. Open Anesthesiol J 2008;2:40e5.
28. Lu HW, He GN, Ma H, Wang JK. Ketamine reduces inducible superoxide
generation in human neutrophils in vitro by modulating the p38 mitogen-
activated protein kinase (MAPK)-mediated pathway. Clin Exp Immunol
2010;160:450e6.
29. Sun J, Wang XD, Liu H. Ketamine suppresses endotoxin-induced NF-kappaB
activation and cytokines production in the intestine. Acta Anaesthesiol Scand
2004;48:317e21.
30. Wu GJ, Chen TL, Ueng YF, Chen RM. Ketamine inhibits tumor necrosis factor-
alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated
macrophages through suppression of toll-like receptor 4-mediated c-Jun N-
terminal kinase phosphorylation and activator protein-1 activation. Toxicol
Appl Pharmacol 2008;228:105e13.
31. Yu Y, Zhou Z, Xu J, Liu Z, Wang Y. Ketamine reduces NFkappaB activation and
TNFalpha production in rat mononuclear cells induced by lipopolysaccharide
in vitro. Ann Clin Lab Sci 2002;32:292e8.
32. Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood
1994;84:2068e101.
33. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to
specificity and diversity. Cell 1991;67:1033e6.
34. Schmidt H, Ebeling D, Bauer H, Bach A, Bohrer H, Gebhard MM, et al. Ketamine
attenuates endotoxin-induced leukocyte adherence in rat mesenteric venules.
Crit Care Med 1995;23:2008e14.
35. Hofbauer R, Moser D, Hammerschmidt V, Kapiotis S, Frass M. Ketamine
significantly reduces the migration of leukocytes through endothelial cell
monolayers. Crit Care Med 1998;26:1545e9.
36. Zahler S, Heindl B, Becker BF. Ketamine does not inhibit inflammatory
responses of cultured human endothelial cells but reduces chemotactic acti-
vation of neutrophils. Acta Anaesthesiol Scand 1999;43:1011e6.
37. Morel F, Doussiere J, Vignais PV. The superoxide-generating oxidase of
phagocytic cells: physiological, molecular and pathological aspects. Eur J Bio-
chem 1991;201:523e46.
38. Sakamoto K, Kuribayashi F, Nakamura M, Takeshige K. Involvement of p38
MAP kinase in not only activation of the phagocyte NADPH oxidase induced by
Formylemethionyleleucylephenylalanine but also determination of the
extent of the activity. J Biochem 2006;140:739e45.
39. Aderem A. Role of toll-like receptors in inflammatory response in macro-
phages. Crit Care Med 2001;29:S16e8.
40. Shimaoka M, Iida T, Ohara A, Taenaka N, Mashimo T, Honda T, et al. Ketamine
inhibits nitric oxide production in mouse activated macrophage-like cells. Br J
Anaesth 1996;77:238e42.
Mechanisms of ketamine-induced immunosuppression
41. Pearce LL, Epperly MW, Greenberger JS, Pitt BR, Peterson J. Identification of
respiratory complexes I and III as mitochondrial sites of damage following
exposure to ionizing radiation and nitric oxide. Nitric Oxide 2001;5:128e36.
42. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for
complexes of lipopolysaccharide (LPS) and LPS binding protein. Science
1990;249:1431e3.
43. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity.
Cell 2003;124:783e801.
44. Wittebole X, Castanares-Zapatero D, Laterre PF. Toll-like receptor 4 modulation
as a strategy to treat sepsis. Mediat Inflamm 2010;2010:568396.
45. Fan H, Peck OM, Tempel GE, Halushka PV, Cook JA. Toll-like receptor 4 coupled
GI protein signaling pathways regulate extracellular signal-regulated kinase
phosphorylation and AP-1 activation independent of NFkappaB activation.
Shock 2004;22:57e62.
46. Kogut MH, Genovese KJ, He H. Flagellin and lipopolysaccharide stimulate the
MEK-ERK signaling pathway in chicken heterophils through differential acti-
vation of the small GTPases, Ras and Rap1. Mol Immunol 2007;44:1729e36.
47. Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors.
Nat Rev Mol Cell Biol 2005;6:827e37.
48. Kholodenko BN. Untangling the signalling wires. Nat Cell Biol 2007;9:247e9.
49. Dobrovolskaia MA, Medvedev AE, Thomas KE, Cuesta N, Toshchakov V, Ren T, et al.
Induction of in vitro reprogramming by toll-like receptor (TLR)2 and TLR4 agonists
in murine macrophages: effects of TLR “homotolerance” versus “heterotolerance”
on Nfkappa B signaling pathway components. J Immunol 2003;170:508e19.
50. Siwak DR, Shishodia S, Aggarwal BB, Kurzrock R. Curcumin-induced anti-
proliferative and proapoptotic effects in melanoma cells are associated with
suppression of IkappaB kinase and nuclear factor kappaB activity and are
independent of the B-Raf/mitogen-activated/extracellular signal-regulated
protein kinase pathway and the Akt pathway. Cancer 2005;104:879e90.
51. Wu CH, Chen TL, Chen TG, Ho WP, Chiu WT, Chen RM. Nitric oxide modulates
pro- and anti-inflammatory cytokines in lipopolysaccharide-activated macro-
phages. J Trauma 2003;55:540e5.
52. Yoshioka M, Fukuishi N, Iriguchi S, Ohsaki K, Yamanobe H, Inukai A, et al.
Lipoteichoic acid downregulates FcepsilonRI expression on human mast cells
through toll-like receptor 2. J Allergy Clin Immunol 2007;120:452e61.
53. Vogel TR, Dombrovskiy VY, Carson JL, Graham AM, Lowry SF. Postoperative
sepsis in the United States. Ann Surg 2010;252:1065e71.
54. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis
occurrence in acutely ill patients’ investigators. Sepsis in European intensive
care units: results of the SOAP study. Crit Care Med 2006;34:344e53.
177
55. Salomão R, Martins PS, Brunialti MK, Fernandes Mda L, Martos LS, Mendes ME,
et al. TLR signaling pathway in patients with sepsis. Shock 2008;30:73e6.
56. Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H. Role of
toll-like receptors in the development of sepsis. Shock 2009;29:315e21.
57. Miyake K, Yamashita Y, Hitoshi Y, Takatsu K, Kimoto M. Murine B cell prolif-
eration and protection from apoptosis with an antibody against a 105-kD
molecule: unresponsiveness of X-linked immunodeficient B cells. J Exp Med
1994;180:1217e24.
58. Watkins LR, Mair SF, Goehler LE. Immune activation: the role of pro-
inflammatory cytokines in inflammation, illness responses, and pathological
pain states. Pain 1995;63:289e302.
59. Beilin B, Shavit Y, Trabekin E, Mordashev B, Mayburd E, Zeidel A, et al. The
effects of postoperative pain management on immune response to surgery.
Anesth Analg 2003;97:822e7.
60. Zilberstein G, Levy R, Rachinsky M, Fisher A, Greemberg L, Shapira Y, et al.
Ketamine attenuates neutrophil activation after cardiopulmonary bypass.
Anesth Analg 2005;95:531e6.
61. Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, et al.
Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass.
Anesth Analg 1998;87:266e71.
62. Takahashi T, Kinoshita M, Shono S, Habu Y, Ogura T, Seki S, et al. The effect of
ketamine anesthesia on the immune function of mice with postoperative
septicemia. Anesth Analg 2010;111:1051e8.
63. Song XM, Li JG, Wang YL, Zhou Q, Du ZH, Jia BH, et al. Effects of ketamine on
proinflammatory cytokines and nuclear factor kappa B in polymicrobial sepsis
rats. World J Gastroenterol 2006;12:7350e4.
64. Lankveld DP, Bull S, Van Dijk P, Fink-Gremmels J, Hellebrekers LJ. Ketamine
inhibits LPS-induced tumor necrosis factor- and interleukin-6 in an equine
macrophage cell line. Vet Res 2005;36:257e62.
65. Gurfinkel R, Czeiger D, Douvdevani A, Shapira Y, Artru AA, Sufaro Y, et al.
Ketamine improves survival in burn injury followed by sepsis in rats. Anesth
Analg 2006;103:396e402.
66. Shaked G, Czeiger D, Dukhno O, Levy I, Artru AA, Shapira Y, et al. Ketamine
improves survival and suppresses IL-6 and TNF-alpha production in a model of
Gram-negative bacterial sepsis in rats. Resuscitation 2004;62:237e42.
67. Taniguchi T, Shibata K, Yamamoto K. Ketamine inhibits endotoxin-induced
shock in rats. Anesthesiology 2001;95:928e32.
68. Huang Z, Wang SR, Su W, Liu JY. Removal of humoral mediators and the effect
on the survival of septic patients by hemoperfusion with neutral microporous
resin column. Ther Apher Dial 2010;14:596e602.