2004 akira toll-like receptors and sepsis

7/27/2019 2004 AKIRA Toll-Like Receptors and Sepsis

1/6

Toll-like Receptors and SepsisKen J. Ishii, MD, PhD, and Shizuo Akira, MD, PhD*

Address

*Akira Innate Immunity Project, ERATO, Japan Science and Technology

Agency; Department of Host Defense, Research Institute for Microbial

Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.E-mail: [email protected]

Current Infectious Disease Reports 2004, 6:361366

Current Science Inc. ISSN 1523-3847

Copyright 2004 by Current Science Inc.

IntroductionThe immune system discriminates self and nonself by using

multiple components in the body [1,2,3]. Physical

barriers such as mucosal membranes in the gut and epithe-

lium in the lung play a major role in clearing infectious

organisms. Once infectious organisms invade such barriers,

innate immune cells (eg, macrophages) play a secondary

role in clearing (phagocytosis) and discriminating nonself

from self by sensing specific molecular pattern expressed in

pathogens (eg, Toll-like receptor [TLR], mannose receptor)

[4,5]. As a result, protective innate and adaptive immune

responses initiate and are followed by tissue repair/remodeling to maintain the host homeostasis.

An overwhelming burden of pathogens, as seen in

massive infection or inefficient immune responses, can

break such homeostasis, resulting in sepsis. Systemic

inflammation during sepsis develops into a syndrome with

multiple manifestations, such as tissue injury, increased

vascular permeability, and ultimately, multiorgan failure

and shock [6].

The recent discovery of TLRs has led us to further

understanding of the molecular mechanism(s) by which

infection initiates such strong innate immune activation.

Lipopolysaccharide is one of the major causative agents

of sepsis and triggers strong proinflammatory responses

and the related pathogenesis (eg, endotoxin shock), with

high mortality. Although CD14 and lipopolysaccharide-

binding proteins (LBP) were known to bind lipopolysac-

charide, a sole receptor that recognizes lipopolysac-

charide and initiates the proinflammatory response had

been sought for decades until human TLRs were found

that were homologous to the fly Toll receptors [7]. Most

strikingly, it was shown that mice mutated in or lacking

TLR4 were hyporesponsive to lipopolysaccharide [8,9].Ther ef or e, TLR4 was th e l on g- so ug ht rece ptor fo r

lipopolysaccharide. The other TLRs were also found to

recognize specific microbial products, many of which

are also known to cause a robust inflammatory response

[1017]. Since then, extensive research on TLRs has

been conducted to understand the precise mechanisms

by which these microbial products activate innate

immune responses and to understand their physiologic

relevance [4].

Such strong inflammatory responses mediated by TLRs

must have tight regulation through a negative feedback

system to maintain host homeostasis. Certain TLR-induced

genes are involved in negative regulation of secondary TLRactivation, so-called endotoxin tolerance. In addition,

cells involved in innate immunity (eg, macrophages)

possess a variety of receptors capable of recognizing a wide

range of protein, saccharide, lipid, and nucleic acid ligands

of endogenous or exogenous origin, some of which are

involved in TLR-negative regulation to balance innate

immune activation and termination/suppression. This

review focuses on the roles of TLRs and related molecules

in triggering and regulating innate immune responses

during infection, sepsis, or related pathogenesis.

Toll-like ReceptorsToll-like receptors are type I transmembrane proteins that

are evolutionarily conserved between insects and humans,

now well-known as pattern recognition receptors capable

of recognizing pathogen-associated molecular patterns

(PAMPs) [1]. Toll was first identified as an essential mole-

cule for development in Drosophila and was subsequently

shown to be essential for antifungal immunity [18]. A

homologous family of Toll receptors, the so-called TLRs, was

found in mammals [7]. Eleven members of the TLRs have

been reported (TLRs 111) [17,1922]. TLR family members

Recent evidence suggests that Toll-like receptors (TLRs)

play a major role in innate immunity to recognize specific

molecular patterns derived from pathogens, including lipid,

protein, DNA, and RNA, and to fight against pathogens.Each TLR displays a difference in the expression pattern,

intracellular localization, and signaling pathway, resulting

in the distinct immune responses. The resultant immune

activation augments host resistance to a variety of infec-

tious organisms. However, such responses may exceed

the threshold to maintain host homeostasis in the case

of sepsis. TLR-mediated innate immune activation also

induces several molecules shown to negatively regulate

TLR signaling. Thus, TLRs may play an important role in

positive and negative regulation of immune responses

during sepsis.


2/6

362 Sepsis

are expressed differentially in a variety of cell types and

capable of recognizing and responding to different PAMPs,

including lipid, protein, DNA, and RNA. Individual TLRs

were found to recognize distinct ligands (Table 1). There are

also reports of endogenous ligands acting as TLR agonists,

some of which may not have excluded the possibility of

lipopolysaccharide contamination [23]. Although leucine-rich repeats found in all TLRs seem to be involved in

direct binding with ligands and ligand specificity, structural

analysis of TLRs and their interaction with respective ligands

is needed to clarify their specificities.

Based on the similarity in the cytoplasmic portions

(designated the TollIL-1R [TIR] domain), TLRs are related

to interleukin-1 receptors (IL-1Rs), whereas the extra-

cellular domain is quite distinct between each family [24].

TLRs are shown to activate nuclear factorB (NF-B) and

mitogen-activated protein (MAP) kinase pathways through

MyD88 (myeloid differential factor 88), a common

adaptor molecule recruited toward a TIR domain of TLRs

[25]. Subsequent studies using MyD88-deficient mice haverevealed that some TLRs possess a MyD88-independent

pathway, which is represented by interferon- production

induced by lipopolysaccharide or double-stranded RNA

stimulation [26]. TRIF, TIR domaincontaining adapter

inducing interferon, was shown to be an essential adaptor

molecule for the MyD88-independent pathway in

TLR3 and TLR4 signaling [27] . Most recently, TRAM,

the fourth TIR domaincontaining adaptor, TRIF-related

adaptor molecule, was identified and shown to be critical

for TLR4- but not TLR3-mediated TRIF-dependent pathway

[28]. These adaptor molecules are involved in distinct

TLRs, thereby resulting in the specific biologic responses

of each TLR.

Distinct Functions Between Toll-like ReceptorsToll-like receptors are expressed in a variety of cell types,

including immune and nonimmune cells. For example,

myeloid cells express TLR1 and TLR6 constitutively. Macro-

phages and myeloid dendritic cells preferentially express

TLR2, 3, 4, and 8 [29], whereas plasmacytoid dendrit ic

cells express TLR7 and TLR9 [30]. B cells express TLR7, 9,

and 10, the ligand of which is not yet known [31]. TLR2

expression in CD4+ T cells and NK cells is reported, but

its physiologic relevance must be clarified [32,33]. Such

differential TLR expression in immune cells indicates its

distinct roles in natural infection. TLR3 and TLR4 are also

expressed or upregulated in nonimmune cells [34,35].

TLR upregulation in nonimmune cells after init ial TLR-

mediated response may trigger secondary immuneresponses such as activation of endothelial cells that

augments adhesion molecule expression followed by

macrophage infiltration and vascular permeability during

infection. This cascade may result in a systemic septic

syndrome including tissue perfusions, imbalanced coagu-

lation cascade, or organ failure.

The other hallmark of TLRs is their distinct intracellular

localization. TLR1, 2, 4, 5, and 6 are shown to reside on the

cell surface, whereas TLR3 and TLR9, and possibly TLR7

and TLR8, are expressed in intracellular compartments such

as endoplasmic reticulum (ER) and phagosomes [36,37].

Cell surface expression of TLR4 was facilitated by MD-2

protein forming a complex to recognize lipopolysaccharidewi th TL R4 on th e ce ll su rf ace [38] . TL R2 an d TLR6

expressed on the cell surface are recruited and accumulated

into phagosomes during gram-positive bacterial infection

of macrophages [39]. TLR9 resides in ER, possibly recruited

to and fused into phagolysosomes through PI3 kinase

[37,40]. Although physiologic meanings of such distinct

localization of TLRs within cells are yet unclear, one

possible explanation is that cell surface TLRs recognize the

outer structure of microbes such as lipopolysaccharide

expressed on bacterial cell wall or membrane, whereas

intracellular TLRs recognize nucleic acid molecules exposed

in phagosomes or in cytoplasm by intracellular bacteria or

virus during infection. Degradation of virion or bacteriain phagolysosomes may result in release of DNA or RNA,

which then interact with TLR9 or TLR7, respectively. This

multistep TLR recognition indicates a safety mechanism of

innate immune system through 1) discriminating bacteria

(with conserved outer structure, such as lipopolysacchar-

ides, proteins such as flagellin, or lipoproteins) from

virus (with unique st ructure in nucleic ac ids such as

double-stranded or single-stranded RNA, or cytosine

phosphate guanine dinucleotide [CpG] DNA); and/or

2) discriminating between nonreplicable (lipid, protein, or

Table 1. TLRs and respective ligands

TLR Ligands and their descriptions Studies

TLR2 + TLR1 Triacylated lipoproteins or lipopeptides [10]TLR2 + TLR6 Diacylated lipoproteins or lipopeptides [11]TLR3 Double-stranded RNA during viral replication [34]TLR4 Bacterial lipopolysaccharide [8,9]

TLR5 Flagellin in bacterial flagella [13]TLR7(8) Guanine uridinerich single-stranded RNA possibly from virus [15,16]TLR9 Bacterial and certain viral DNAcontaining CpG motifs [14]

CpGcytosine phosphate guanine dinucleotides; TLRToll-like receptor.


3/6

Toll-like Receptors and Sepsis Ishii and Akira 363

polysaccharides) and replicable agent (DNA and RNA)

derived from any microbes.

Two distinct pathways have been recently described in

TLR-mediated signaling (Fig. 1). MyD88 is an essential TLR

adaptor molecule for TLR2, 7, and 9 and is involved in

innate immune activation including NF-Bdependent

cytokine productions, upregulation of costimulatory

molecules, and productions of interferon [14,41]. Toll

interleukin-1 receptor domain-containing adaptor protein(TIRAP) specifies the MyD88-dependent pathway through

TLR2 and TLR4 [42]. In contrast, TRIF and TRAM mediate

MyD88-independent pathway through TLR4 [27]. TLR3

seems to use only TRIF. Significant difference in each TLR-

mediated signaling may shed light on the pathogenesis

in septic shock. Treatment of mice with TLR4 ligand

(lipopolysaccharide) alone causes septic shock with

mortality, whereas other TLR ligands require that the

animals are sensitized with the other agent(s) to mimic

biological phenomenon observed during sepsis or septic

shock. In addition to MyD88-dependent NF-B and MAP

kinase pathway, MyD88-independent pathway, which

regulates mostly type I interferon and related genes, hasprofound effect on lipopolysaccharide-induced shock and

lethality [43]. Hence, TLR4 induced MyD88-dependent

and -independent pathways, resulting in induction of

septic shock with high mortality.

Negative Regulation ofToll-like Receptor SignalingAs descr ibed earlier, most of the TIR-containing genes

such as IL-1/18 receptors and TLRs are activators of innate

immune cells. Conversely, two other members of the TIR

domaincontaining super family are reported to negatively

regulate TLR signaling. ST2, known to be expressed on T

helper 2 (Th2) cells but not on T helper 1 (Th1) cells [44],

was shown to inhibit TLR4- but not TLR3-mediated signal-

ing [45]. ST2 -/- mice have exaggerated cytokine responses to

the stimulation of IL-1R and TLR2, 4, and 9 but not TLR3

[45]. ST2 -/- mice have similar mortality to wild-type mice

after initial lipopolysaccharide-induced shock but fail toinduce lipopolysaccharide tolerance in vivo. Single

immunoglobulin IL-1Rrelated molecule (SIGIRR), the

other TIR domaincontaining receptor, was found to inhibit

IL-1R signaling when overexpressed in vitro, and SIGIRR -/-

mice were more susceptible to lipopolysaccharide-induced

lethality [46]. ST2 are expressed in macrophages, Th2 cells,

and mast cells, whereas SIGIRR expression is mostly

restricted in epithelial cells, suggesting that similar but

distinct functions between ST2 and SIGIRR may have a

differential role in negative regulation of proinflammatory

responses during sepsis (Fig. 2).

Among the genes that are induced or upregulated by TLR

stimulation, IL-1Rassociated kinase-M (IRAK-M) [47] andsuppressor of cytokine signaling (SOCS-1) [48,49] are

reported to act as negative regulators for TLR signaling.

IRAK-M -/- and SOCS-1 -/- mice showed exaggerated

proinflammatory responses to TLR4 ligand, and more

importantly, they were unable to induce lipopolysaccharide

tolerance. IRAK-M and SOCS-1 probably contribute to nega-

tive signaling cascades in TLR signaling that are essential for

suppression of excessive inflammation. These multiple

genes involved in negative regulation in innate immunity

may play a role in maintenance of homeostasis during

Figure 1. Summary of Toll-like receptor (TLR)localization and signaling. Distinct signalingpathways and localization of TLRs are shown.Myeloid differential factor 88 (MyD88)dependent and independent pathwaysare activated through TLR4. MyD88 is asole adaptor molecule for TLR7 and TLR9,whereas Tollinterleukin-1 receptor domain-

containing adaptor protein (TIRAP) is alsorequired for TLR2. TLR3 uses TRIF as a soleadaptor molecule. TLR1, 2, 4, and 6 areinitially on the cell surface, whereas TLR3and TLR9 (and possibly TLR7) are withinthe intracellular compartment. ERendo-plasmic reticulum; IRAKinterleukin-1receptorassociated kinase; NF-Bnuclearfactor B.


4/6

364 Sepsis

sepsis. It will be of interest to determine whether these

genes are also involved in linking the innate and adaptive

immunity, regulating antigen-specific Th1/Th2 response

or tolerance.

Interaction of Toll-like Receptors and theother Pathogen-recognizing Receptors

Among pathogen-recognizing receptors, TLRs are equippedfor innate immune activation by eliciting proinflammatory

responses. Conversely, the other well-known pathogen-

recognizing receptors such as scavenger receptors are shown

to have a dual role in activation and suppression in innate

immunity [50]. Mice lacking scavenger receptor-A (SR-A) are

more susceptible to lipopolysaccharide-induced shock than

are wild-type mice and demonstrate an exaggerated tumor

necrosis factor response, suggesting an inhibitory role

of SR-A in lipopolysaccharide-mediated inflammatory

responses [51]. Recent evidence suggests that signaling cross-

talk between downstream of scavenger receptors and TLRs

takes place during infection. Two recent reports have

demonstrated that TLR signaling and scavenger receptormediated cholesterol efflux interfere with each other

through liver X receptors (LXRs), known as nuclear receptors

for oxysterols through low-density lipoprotein uptake in

macrophages [52,53]. LXR signaling was inhibited by

bacterial and viral infection or by stimulation of TLR3 and

TLR4, but not TLR2 or TLR9, through an interferon regula-

tory factor 3dependent manner, whereas LXR agonists

inhibit TLR4-mediated proinflammatory responses. TLR3

and TLR4 stimulation did not inhibit peroxisome prolifera-

tor activator receptor-g signaling and its target gene, CD36

[53]. It is conceivable that many more players are involved

in regulation of inflammatory responses mediated by TLR

through cross-talk during sepsis.

ConclusionsDiscovery of human TLRs has brought significant attention

to the role of innate immunity in the natural course of

infection, but also to the role of TLRs in the pathophysiol-

ogy of infection. For example, TLR4 was found to be a sole

receptor for lipopolysaccharide-mediated innate immune

activation and the resultant pathogenesis of gram-negative

sepsis. Common and specific features of TLRs and related

signaling molecules determine the course and magnitude

of the innate immune responses. These findings should

lead us to a better understanding of basic immunobiology

and to novel therapeutic approaches for sepsis and related

pathogenesis, including antagonists of TLRs, inhibitors of

TLR signaling pathways, and stimulators of the inhibitory

signaling pathways for TLRs. However, our understandingof such complex biological phenomenon during sepsis

or related pathogenesis is far from completion because

there are more questions than answers.

AcknowledgmentsWe thank all members of our laboratory for helpful discus-

sions and suggestions, and M. Hashimoto and members of

the ERATO office for secretarial assistance.

References and Recommended Reading

Papers of particular interest, published recently, have beenhighlighted as: Of importance Of major importance

1. Janeway CA Jr, Medzhitov R: Innate immune recognition.Annu Rev Immunol 2002, 20:197216.

2. Matzinger P:The danger model: a renewed sense of self.Science 2002, 296:301305.

This excellent review discusses self-nonself definition and its physio-logic relevance.

3. Medzhitov R, Janeway CA Jr: Decoding the patterns of selfand nonself by the innate immune system. Science 2002,296:298300.

This excellent review discusses self-nonself definition and its physio-logic relevance.

4. Takeda K, Kaisho T, Akira S:Toll-like receptors.Annu Rev

Immunol 2003, 21:335376.

5. Akira S, Takeda K, Kaisho T:Toll-like receptors: critical proteinslinking innate and acquired immunity.Nat Immunol 2001,2:675680.

6. Riedemann NC, Guo RF, Ward PA:The enigma of sepsis.J ClinInvest2003, 112:460467.

This is an excellent review of recent evidence and progress in clinicaltrials for possible interventions in the context of sepsis.

7. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr:A humanhomologue of the Drosophila Toll protein signals activationof adaptive immunity.Nature 1997, 388:394397.

8. Poltorak A, He X, Smirnova I, et al.: Defective LPS signaling inC3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.Science 1998, 282:20852088.

Figure 2. Summary of negative regulation of Toll-like receptors (TLRs).Negative regulators of TLR-mediated innate immune activations

are shown. IL-1Rinterleukin-1 receptor; IRAKIL-1Rassociatedkinase; MyD88myeloid differential factor 88; SIGIRRsingleimmunoglobulin IL-1Rrelated molecule; SOCSsuppressor of cyto-kine signaling; TIRAPToll IL-1R domain-containing adaptor protein.


5/6

Toll-like Receptors and Sepsis Ishii and Akira 365

9. Hoshino K, Takeuchi O, Kawai T, et al.: Cutting edge: Toll-likereceptor 4 (TLR4)-deficient mice are hyporesponsive tolipopolysaccharide: evidence for TLR4 as the Lps geneproduct.J Immunol 1999, 162:37493752.

10. Takeuchi O, Sato S, Horiuchi T, et al.: Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbiallipoproteins.J Immunol 2002, 169:1014.

11. Takeuchi O, Kawai T, Muhlradt PF, et al.: Discrimination ofbacterial lipoproteins by Toll-like receptor 6. Int Immunol2001, 13:933940.

12. Takeuchi O, Hoshino K, Kawai T, et al.: Differential roles ofTLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity1999,11:443451.

13. Hayashi F, Smith KD, Ozinsky A, et al.:The innate immuneresponse to bacterial flagellin is mediated by Toll-likereceptor 5.Nature 2001, 410:10991103.

14. Hemmi H, Takeuchi O, Kawai T, et al.:A Toll-like receptorrecognizes bacterial DNA.Nature 2000, 408:740745.

15. Heil F, Hemmi H, Hochrein H, et al.: Species-specific recogni-tion of single-stranded RNA via Toll-like receptor 7 and 8.Science 2004, 303:15261529.

16. Diebold SS, Kaisho T, Hemmi H, et al.: Innate antiviral responsesby means of TLR7-mediated recognition of single-strandedRNA. Science 2004, 303:15291531.

17. Zhang D, Zhang G, Hayden MS, et al.:A Toll-like receptor thatprevents infection by uropathogenic bacteria. Science 2004,303:15221526.

18. Lemaitre B, Nicolas E, Michaut L, et al.:The dorsoventralregulatory gene cassette spatzle/Toll/cactus controls thepotent antifungal response in Drosophila adults. Cell 1996,86:973983.

19. Rock FL, Hardiman G, Timans JC, et al.:A family of humanreceptors structurally related to Drosophila Toll. Proc NatlAcad Sci U S A 1998, 95:588593.

20. Takeuchi O, Kawai T, Sanjo H, et al.:TLR6: a novel memberof an expanding Toll-like receptor family. Gene 1999,231:5965.

21. Du X, Poltorak A, Wei Y, et al.:Three novel mammalian Toll-like receptors: gene structure, expression, and evolution.Eur Cytokine Netw 2000, 11:362371.

22. Chuang T, Ulevitch RJ: Identification of hTLR10: a novel humanToll-like receptor preferentially expressed in immune cells.Biochim Biophys Acta 2001, 1518:157161.

23. Tsan MF, Gao B: Endogenous ligands of Toll-like receptors.J Leukoc Biol 2004, In press.

24. Akira S:Toll-like receptor signaling.J Biol Chem 2003,278:3810538108.

25. Kawai T, Adachi O, Ogawa T, et al.: Unresponsiveness ofMyD88-deficient mice to endotoxin. Immunity1999,11:115122.

26. Kawai T, Takeuchi O, Fujita T, et al.: Lipopolysaccharidestimulates the MyD88-independent pathway and results inactivation of IFN-regulatory factor 3 and the expression ofa subset of lipopolysaccharide-inducible genes.J Immunol2001, 167:58875894.

27. Yamamoto M, Sato S, Hemmi H, et al.: Role of adaptor TRIF inthe MyD88-independent toll-like receptor signaling pathway.

Science 2003, 301:640643.28. Yamamoto M, Sato S, Hemmi H, et al.:TRAM is specifically

involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway.Nat Immunol 2003,4:11441150.

29. Hornung V, Rothenfusser S, Britsch S, et al.: Quantitativeexpression of toll-like receptor 1-10 mRNA in cellularsubsets of human peripheral blood mononuclear cellsand sensitivity to CpG oligodeoxynucleotides.J Immunol2002, 168:45314537.

30. Kadowaki N, Ho S, Antonenko S, et al.: Subsets of humandendritic cell precursors express different toll-like receptorsand respond to different microbial antigens.J Exp Med 2001,194:863869.

31. Bernasconi NL, Onai N, Lanzavecchia A:A role for Toll-likereceptors in acquired immunity: up-regulation of TLR9 byBCR triggering in naive B cells and constitutive expressionin memory B cells. Blood 2003, 101:45004504.

32. Chalifour A, Jeannin P, Gauchat JF, et al.: Direct bacterialprotein PAMPs recognition by human NK cells involvesTLRs and triggers {alpha}-defensin production. Blood2004, In press.

33. Komai-Koma M, Jones L, Ogg GS, et al.:TLR2 is expressed onactivated T cells as a costimulatory receptor. Proc Natl Acad SciU S A 2004, 101:30293034.

34. Alexopoulou L, Holt AC, Medzhitov R, et al.: Recognition ofdouble-stranded RNA and activation of NF-kappaB by Toll-likereceptor 3.Nature 2001, 413:732738.

35. Zhang FX, Kirschning CJ, Mancinelli R, et al.: Bacterial lipopoly-saccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelialcells and mononuclear phagocytes.J Biol Chem 1999,274:76117614.

36. Matsumoto M, Funami K, Tanabe M, et al.: Subcellular local-ization of Toll-like receptor 3 in human dendritic cells.J Immunol 2003, 171:31543162.

37. Latz E, Schoenemeyer A, Visintin A, et al.:TLR9 signals aftertranslocating from the ER to CpG DNA in the lysosome.Nat Immunol 2004, 5:190198.

This is an excellent paper demonstrating that TLR9 resides in ER andbinds to CpG directly, whereas TLR4 is on the cell surface.

38. Nagai Y, Akashi S, Nagafuku M, et al.: Essential role of MD-2in LPS responsiveness and TLR4 distribution.Nat Immunol2002, 3:667672.

39. Underhill DM, Ozinsky A, Hajjar AM, et al.:The Toll-like receptor2 is recruited to macrophage phagosomes and discriminatesbetween pathogens.Nature 1999, 401:811815.

40. Ishii KJ, Takeshita F, Gursel I, et al.: Potential role of phospha-tidylinositol 3 kinase, rather than DNA-dependent proteinkinase, in CpG DNA-induced immune activation.J Exp Med2002, 196:269274.

41. Hemmi H, Kaisho T, Takeuchi O, et al.: Small anti-viralcompounds activate immune cells via the TLR7 MyD88-dependent signaling pathway.Nat Immunol 2002,3:196200.

42. Yamamoto M, Sato S, Hemmi H, et al.: Essential role for TIRAPin activation of the signaling cascade shared by TLR2 andTLR4.Nature 2002, 420:324329.

43. Karaghiosoff M, Steinborn R, Kovarik P, et al.: Central role fortype I interferons and Tyk2 in lipopolysaccharide-inducedendotoxin shock.Nat Immunol 2003, 4:471477.

44. Xu D, Chan WL, Leung BP, et al.: Selective expression of a stablecell surface molecule on type 2 but not type 1 helper T cells.J Exp Med 1998, 187:787794.

45. Brint EK, Xu D, Liu H, et al.: ST2 is an inhibitor of interleukin1 receptor and Toll-like receptor 4 signaling and maintainsendotoxin tolerance.Nat Immunol 2004, 5:373379.

46. Wald D, Qin J, Zhao Z, et al.: SIGIRR, a negative regulator ofToll-like receptor-interleukin 1 receptor signaling.Nat Immunol2003, 4:920927.

47. Kobayashi K, Hernandez LD, Galan JE, et al.: IRAK-M is anegative regulator of Toll-like receptor signaling. Cell 2002,

110:191202.48. Nakagawa R, Naka T, Tsutsui H, et al.: SOCS-1 participates

in negative regulation of LPS responses. Immunity2002,17:677687.

49. Kinjyo I, Hanada T, Inagaki-Ohara K, et al.: SOCS1/JAB is anegative regulator of LPS-induced macrophage activation.Immunity2002, 17:583591.

50. Gordon S: Pattern recognition receptors: doubling up for theinnate immune response. Cell 2002, 111:927930.

51. Haworth R, Platt N, Keshav S, et al.:The macrophage scavengerreceptor type A is expressed by activated macrophages andprotects the host against lethal endotoxic shock.J Exp Med1997, 186:14311439.


6/6

366 Sepsis

52. Joseph SB, Castrillo A, Laffitte BA, et al.: Reciprocal regulationof inflammation and lipid metabolism by liver X receptors.Nat Med 2003, 9:213219.

This paper implies the possible cross-talk between innate immuneresponses and lipid metabolism to maintain homeostasis.

53. Castrillo A, Joseph SB, Vaidya SA, et al.: Crosstalk betweenLXR and Toll-like receptor signaling mediates bacterialand viral antagonism of cholesterol metabolism.Mol Cell2003, 12:805816.

This paper implies the possible cross-talk between innate immuneresponses and lipid metabolism to maintain homeostasis.

2004 akira toll-like receptors and sepsis

Documents