Review: Molecular mechanisms of endotoxin tolerance

Abstract

The phenomenon of endotoxin tolerance has been widely investigated, but to date, the molecular mechanisms of endotoxin tolerance remain to be resolved clearly. The discovery of the Toll-like receptor (TLR) family as the major receptors for lipopolysaccharide (LPS) and other bacterial products has prompted a resurgence of interest in endotoxin tolerance mechanisms. Changes of cell surface molecules, signaling proteins, pro-inflammatory and anti -inflammatory cytokines and other mediators have been examined. During tolerance expression of LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2) and TLR2 are unchanged or up-regulated, whereas TLR4 is transiently suppressed or unchanged. Proximal post-receptor signaling proteins that are altered in tolerance include augmented degradation of interleukin-1 receptor-associated kinase (IRAK), and decreased TLR4-myeloid differentiation factor 88 (MyD88) and IRAK-MyD88 association. Tolerance has also been shown to be associated with decreased G_i protein content and activity, decreased protein kinase C (PKC) activity, reduction in mitogen-activated protein kinase (MAP kinase) activity, and reduced activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB) induced gene transactivation. However, not all signaling proteins and pathways are suppressed in tolerance and induction of specific anti-inflammatory proteins and signaling pathways may serve important counter inflammatory functions. The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-κB (IκB) isoforms. Also at the nuclear level, increase in the NFκB subunit p50 homodimer expression and increased activation of peroxisome-proliferatoractivated receptors-γ (PPARγ) have been linked to tolerance phenotype. Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.

Keywords

Endotoxin tolerance Toll-like receptor signaling protein transcription factors

References

Karima R. , Matsumoto S. , Higashi H. , Matsushima K. The molecular pathogenesis of endotoxic shock and organ failure. Mol Med Today 1999; 5: 123—132.

Beeson PB Development of tolerance to typhoid bacterial pyrogen and its abolition by reticuloendothelial blockade. Proc Soc Exp Biol Med 1946; 61: 248—250.

Ziegler-Heitbrock HW Molecular mechanism in tolerance to lipopolysaccharide. J Inflamm 1995; 45: 13—26.

West MA , Heagy W. Endotoxin tolerance: a review. Crit Care Med 2002; 30 (1 Suppl): S64—S73.

Learn CA , Boger MS , Li L. , McCall CE. The phosphatidylinositol 3-kinase pathway selectively controls sIL-1RA not interleukin-1beta production in the septic leukocytes. J Biol Chem 2001; 276: 20234—20239.

Cross AS Endotoxin tolerance-current concepts in historical perspective. J Endotoxin Res 2002; 8: 83—98.

Dobrovolskaia MA , Vogel SN Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect 2002; 4: 903—914.

Cavaillon JM , Adrie C. , Fitting C. , Adib-Conquy M.

Endotoxin tolerance: is there a clinical relevance?

J Endotoxin Res 2003; 9: 101—107.

Juan TS , Hailman E. , Kelley MJ et al. Identification of a lipopolysaccharidebinding domain in CD14 between amino acids 57 and 64. J Biol Chem 1995; 270: 5219—5224.

10.

Ingalls RR , Monks BG , Savedra Jr R. et al. CD11/CD18 and CD14 share a common lipid A signaling pathway . J Immunol 1998; 161: 5413—5420.

11.

Ingalls RR , Golenbock DT CD11c/CD18, a transmembrane signaling receptor for lipopolysaccharide . J Exp Med 1995; 181: 1473—1479.

12.

Triantafilou K. , Triantafilou M. , Dedrick RL A CD14-independent LPS receptor cluster. Nat Immunol 2001; 2: 338—345.

13.

Inohara N. , Ogura Y. , Chen FF, Muto A, Nunez G. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem 2001; 276: 2551—2554.

14.

Poltorak A. , He X. , Smirnova I. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282: 2085—2088.

15.

Medzhitov R. , Preston-Hurlburt P. , Janeway Jr CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity . Nature 1997; 388: 394—397.

16.

Takeuchi O. , Hoshino K. , Kawai T. et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components . Immunity 1999; 11: 443—451.

17.

Werts C. , Tapping RI , Mathison JC et al. Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nat Immunol 2001; 2: 346—352.

18.

Hirschfeld M. , Weis JJ , Toshchakov V. et al. Signaling by Toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect Immun 2001; 69: 1477—1482.

19.

Shimazu R. , Akashi S. , Ogata H. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 1999; 189: 1777—1782.

20.

Zhang G. , Ghosh S. Negative regulation of toll-like receptor-mediated signaling by TOLLIP . J Biol Chem 2002; 277: 7059—7065.

21.

Irie T. , Muta T. , Takeshige K. TAK1 mediates an activation signal from Toll-like receptor(s) to nuclear factor-kappaB in lipopolysaccharide-stimulated macrophages. FEBS Lett 2000; 467: 160—164.

22.

Woronicz JD , Gao X. , Cao Z. , Rothe M. , Goeddel DV IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK . Science 1997; 278: 866—869.

23.

McDermott EP , O'Neill LA Ras participates in the activation of p38 MAPK by interleukin-1 by associating with IRAK, IRAK2, TRAF6, and TAK-1 . J Biol Chem 2002; 277: 7808—7815.

24.

Kopp E. , Medzhitov R. , Carothers J. et al. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev 1999 ; 13: 2059—2071.

25.

Horng T. , Barton GM , Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2001; 2: 835—841.

26.

O'Neill LA Toll-like receptor signal transduction and the tailoring of innate immunity: a role for Mal? Trends Immunol 2002 ; 23: 296—300.

27.

Ferlito M. , Squadrito F. , Halushka PV , Cook JA Signal transduction events in Chinese hamster ovary cells expressing human CD14; effect of endotoxin desensitization. Shock 2001; 15: 291—296.

28.

West MA , LeMieur T. , Clair L. , Bellingham J. , Rodriguez JL Protein kinase C regulates macrophage tumor necrosis factor secretion: direct protein kinase C activation restores tumor necrosis factor production in endotoxin tolerance. Surgery 1997; 122: 204—212.

29.

Guha M. , Mackman N. The phosphatidylinositol3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 2002 ; 277: 32124—32132.

30.

Heagy W. , Hansen C. , Nieman K. , West MA Evidence for a CD14- and serum-independent pathway in the induction of endotoxin-tolerance in human monocytes and THP-1 monocytic cells. Shock 2003; 19: 321—327.

31.

Jarvelainen HA , Fang C. , Ingelman-Sundberg M. , Lindros KO Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines. Hepatology 1999; 29: 1503—1510.

32.

Vreugdenhil AC , Snoek AM , van't Veer C. , Greve JW , Buurman WA LPS-binding protein circulates in association with apoBcontaining lipoproteins and enhances endotoxin-LDL/VLDL interaction . J Clin Invest 2001; 107: 225—234.

33.

Kitchens RL , ThompsonPA, Viriyakosol S, O'Keefe GE, Munford RS. Plasma CD14 decreases monocyte responses to LPS by transferring cell-bound LPS to plasma lipoproteins. J Clin Invest 2001; 108: 485—493.

34.

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: 1431—1433.

35.

McGinley MD , Narhi LO , Kelley MJ et al. CD14: physical properties and identification of an exposed site that is protected by lipopolysaccharide . J Biol Chem 1995; 270: 5213—5218.

36.

Chow JC , Young DW , Golenbock DT , Christ WJ , Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction . J Biol Chem 1999; 274: 10689—10692.

37.

Labeta MO , Durieux JJ , Spagnoli G. , Fernandez N. , Wijdenes J. , Herrmann R. CD14 and tolerance to lipopolysaccharide: biochemical and functional analysis . Immunology 1993; 80: 415—423.

38.

Ziegler-Heitbrock HW , Wedel A. , Schraut W. et al. Tolerance to lipopolysaccharide involves mobilization of nuclear factor kappa B with predominance of p50 homodimers . J Biol Chem 1994; 269: 17001—17004.

39.

Mathison J. , Wolfson E. , Steinemann S. , Tobias P. , Ulevitch R. Lipopolysaccharide (LPS) recognition in macrophages. Participation of LPS-binding protein and CD14 in LPS-induced adaptation in rabbit peritoneal exudate macrophages. J Clin Invest 1993; 92: 2053—2059.

40.

McCall CE , Grosso-Wilmoth LM , LaRue K. , Guzman RN , Cousart SL Tolerance to endotoxin-induced expression of the interleukin-1 beta gene in blood neutrophils of humans with the sepsis syndrome. J Clin Invest 1993; 91: 853—861.

41.

Ziegler-Heitbrock HW , Petersmann I. , Frankenberger M. p50 (NF-kappa B1) is upregulated in LPS tolerantP388D1 murine macrophages. Immunobiology 1997; 198: 73—80.

42.

Nomura F. , Akashi S. , Sakao Y. et al. Endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface Toll-like receptor 4 expression. J Immunol 2000; 164: 3476—3479.

43.

Martin M. , Katz J. , Vogel SN , Michalek SM Differential induction of endotoxin tolerance by lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli. J Immunol 2001; 167: 5278—5285.

44.

Sato S. , Nomura F. , Kawai T. et al. Synergy and cross-tolerance between Toll-like receptor (TLR) 2- and TLR4-mediated signaling pathways. J Immunol 2000; 165: 7096—7101.

45.

Medvedev AE , Lentschat A. , Wahl LM , Golenbock DT , Vogel SN Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells . J Immunol 2002 ; 169: 5209—5216.

46.

Adib-Conquy M. , Cavaillon JM Gamma interferon and granulocyte/monocyte colony-stimulating factor prevent endotoxin tolerance in human monocytes by promoting interleukin-1 receptor-associated kinase expression and its association to MyD88 and not by modulating TLR4 expression. J Biol Chem 2002; 277: 27927—27934.

47.

Medvedev AE , Kopydlowski KM , Vogel SN Inhibition of lipopolysaccharide-induced signal transduction in endotoxintolerized mouse macrophages: dysregulation of cytokine, chemokine, and Toll-like receptor 2 and 4 gene expression. J Immunol 2000; 164: 5564—5574.

48.

Medvedev AE , Henneke P. , Schromm A. et al. Induction of tolerance to lipopolysaccharide and mycobacterial components in Chinese hamster ovary/CD14 cells is not affected by overexpression of Toll-like receptors 2 or 4. J Immunol 2001; 167: 2257—2267.

49.

Matsuguchi T. , Musikacharoen T. , Ogawa T. , Yoshikai Y. Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol 2000; 165: 5767—5772.

50.

Frantz S. , Kobzik L. , Kim YD et al. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 1999; 104: 271—280.

51.

Muzio M. , Bosisio D. , Polentarutti N. et al. Differential expression and regulation of Toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells . J Immunol 2000; 164: 5998—6004.

52.

Faure E. , Thomas L. , Xu H. , Medvedev A. , Equils O. , Arditi M. Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol 2001; 166: 2018—2024.

53.

Yeo SJ , Yoon JG , Hong SC , Yi AK CpG DNA induces self and cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopolysaccharide: alterations in IL-1 receptor-associated kinase expression. J Immunol 2003; 170: 1052—1061.

54.

Medvedev AE , Vogel SN Overexpression of CD14, TLR4, and MD-2 in HEK 293T cells does not prevent induction of in vitro endotoxin tolerance . J Endotoxin Res 2003; 9: 60—64.

55.

Musikacharoen T. , Matsuguchi T. , Kikuchi T. , Yoshikai Y. NF-kappa B and STAT5 play important roles in the regulation of mouse Toll-like receptor 2 gene expression. J Immunol 2001; 166: 4516—4524.

56.

Wang T. , Lafuse WP , Takeda K. , Akira S. , Zwilling BS Rapid chromatin remodeling of Toll-like receptor 2 promoter during infection of macrophages with Mycobacterium avium. J Immunol 2002; 169: 795—801.

57.

Li L. , Cousart S. , Hu J. , McCall CE Characterization of interleukin-1 receptor-associated kinase in normal and endotoxin-tolerant cells. J Biol Chem 2000 ; 275: 23340—23345.

58.

Yamamoto M. , Sato S. , Hemmi H. et al. Essential rolefor TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 2002; 420: 324—329.

59.

Horng T. , Barton GM , Flavell RA , Medzhitov R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors . Nature 2002; 420: 329—333.

60.

Ferlito M. , Romanenko OG , Guyton K. et al. Implication of Gα proteins and Src tyrosine kinases in endotoxin-induced signali transduction events and mediator production. J Endotoxin Res 2003; 8: 427—435.

61.

Tempel GE , Brown AN , Morinelli TA , Halushka PV , Cook JA Changes in vascular responsiveness to a thromboxane mimetic in endotoxin tolerance . Shock 2001; 16: 389—392.

62.

Makhlouf M. , Ashton SH , Hildebrandt J. et al. Alterations in macrophage G proteins are associated with endotoxin tolerance. Biochim Biophys Acta 1996; 1312: 163—168.

63.

Makhlouf M. , Zingarelli B. , Halushka PV , Cook JA Endotoxin tolerance alters macrophage membrane regulatory G proteins. Prog Clin Biol Res 1998; 397: 217—226.

64.

Fernando LP , Makhlouf M. , Fernando AN , Ashton S. , Halushka PV , Cook JA Tolerance to LPS decreases macrophage G protein content. Shock 1999; 11: 330—335.

65.

Monick MM , Robeff PK , Butler NS et al. Phosphatidylinositol 3-kinase activity negatively regulates stability of cyclooxygenase 2 mRNA. J Biol Chem 2002; 277: 32992—33000.

66.

Bowling WM , Hafenrichter DG , Flye MW , Callery MP Endotoxin tolerance alters phospholipase C-gamma 1 and phosphatidylinositol-3'-kinase expression in peritoneal macrophages. J Surg Res 1995; 58: 592—598.

67.

Bowling WM , Flye MW , Qiu YY , Callery MP Inhibition of phosphatidylinositol-3'-kinase prevents induction of endotoxin tolerance in vitro. J Surg Res 1996 ; 63: 287—292.

68.

Yamin TT , Miller DK The interleukin-1 receptor-associated kinase is degraded by proteasomes following its phosphorylation. J Biol Chem 1997; 272: 21540—21547.

69.

Suzuki N. , Suzuki S. , Duncan GS et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002; 416: 750—756.

70.

Swantek JL , Tsen MF , Cobb MH , Thomas JA IL-1 receptor-associated kinase modulates host responsiveness to endotoxin . J Immunol 2000; 164: 4301—4306.

71.

Li L. , Jacinto R. , Yoza B. , McCall CE Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes. J Endotoxin Res 2003; 9: 39—44.

72.

Kobayashi K. , Hernandez LD , Galan JE , Janeway Jr CA, Medzhitov R, Flavell RA. IRAK-M is a negative regulator of Toll-like receptor signaling . Cell 2002; 110: 191—202.

73.

Yamashina S. , Wheeler MD , Rusyn I. , Ikejima K. , Sato N. , Thurman RG Tolerance and sensitization to endotoxin in Kupffer cells caused by acute ethanol involve interleukin-1 receptor-associated kinase. Biochem Biophys Res Commun 2000; 277: 686—690.

74.

Maschera B. , Ray K. , Burns K. , Volpe F. Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappaB. Biochem J 1999; 339: 227—231.

75.

Knop J. , Martin MU Effects of IL-1 receptor-associated kinase (IRAK) expression on IL-1 signaling are independent of its kinase activity. FEBS Lett 1999; 448: 81—85.

76.

West MA , Clair L. , Bellingham J. , Wahlstrom K. , Rodriguez JL Defective lipopolysaccharide-dependent ERK 1/2 activation in endotoxin tolerant murine macrophages is reversed by direct protein kinase C stimulation . Shock 2000; 14: 169—175.

77.

Kraatz J. , Clair L. , Rodriguez JL , West MA Macrophage TNF secretion in endotoxin tolerance: role of SAPK, p38, and MAPK . J Surg Res 1999; 83: 158—164.

78.

Kraatz J. , Clair L. , Rodriguez JL , West MA In vitro macrophage endotoxin tolerance: defective in vitro macrophage map kinase signal transduction after LPS pretreatment is not present in macrophages from C3H/HeJ endotoxin resistant mice. Shock 1999; 11: 58—63.

79.

Ferlito M. , Romanenko OG , Ashton S. , Squadrito F. , Halushka PV , Cook JA Effect of cross-tolerance between endotoxin and TNF-alpha or IL-1beta on cellular signaling and mediator production. J Leukoc Biol 2001; 70: 821—829.

80.

Mendez C. , Jaffray C. , Wong V. et al. Involvement of p38 mitogen-activated protein kinase in the induction of tolerance to hemorrhagic and endotoxic shock. J Surg Res 2000; 91: 165—170.

81.

Gilmore TD , Morin PJ The I kappa B proteins: members of a multifunctional family. Trends Genet 1993; 9: 427—433.

82.

Whiteside ST , Epinat JC , Rice NR , Israel A. I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel NF-kappa B activity. EMBO J 1997; 16: 1413—1426.

83.

Yamazaki S. , Muta T. , Takeshige K. A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappaB in the nuclei. J Biol Chem 2001 ; 276: 27657—27662.

84.

Inoue J. , Kerr LD , Kakizuka A. , Verma IM I kappa B gamma, a 70 kD protein identical to the C-terminal half of p110 NF-kappa B: a new member of the I kappa B family. Cell 1992; 68: 1109—1120.

85.

Dobrzanski P. , Ryseck RP , Bravo R. Specific inhibition of RelB/p52 transcriptional activity by the C-terminal domain of p100. Oncogene 1995; 10: 1003—1007.

86.

Kravchenko VV , Steinemann S. , Kline L. , Feng L. , Ulevitch RJ Endotoxin tolerance is induced in Chinese hamster ovary cell lines expressing human CD14. Shock 1996; 5: 194—201.

87.

Wahlstrom K. , Bellingham J. , Rodriguez JL , West MA Inhibitory kappaBalpha control of nuclear factor-kappaB is dysregulated in endotoxin tolerant macrophages . Shock 1999; 11: 242—247.

88.

Kohler NG , Joly A. The involvement of an LPS inducible I kappa B kinase in endotoxin tolerance . Biochem Biophys Res Commun 1997 ; 232: 602—607.

89.

Shames BD , Meldrum DR , Selzman CH et al. Increased levels of myocardial IkappaB-alpha protein promote tolerance to endotoxin. Am J Physiol 1998; 275: H1084—H1091.

90.

Dobrovolskaia MA , Medvedev AE , Thomas KE 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 NF-kappa B signaling pathway components. J Immunol 2003; 170: 508—519.

91.

Adib-Conquy M. , Adrie C. , Moine P. et al. NF-kappaB expression in mononuclear cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance. Am J Respir Crit Care Med 2000; 162: 1877—1883.

92.

Kinjyo I. , Hanada T. , Inagaki-Ohara K. et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 2002; 17: 583—591.

93.

Nakagawa R. , Naka T. , Tsutsui H. et al. SOCS-1 participates in negative regulation of LPS responses. Immunity 2002 ; 17: 677—687.

94.

Schmitz ML , Baeuerle PA The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J 1991; 10: 3805—3817.

95.

Ryseck RP , Bull P. , Takamiya M. et al. RelB, a new Rel family transcription activator that can interact with p50-NF-kappa B. Mol Cell Biol 1992; 12: 674—684.

96.

Franzoso G. , Bours V. , Park S. , Tomita-Yamaguchi M. , Kelly K. , Siebenlist U. The candidate oncoprotein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition. Nature 1992; 359: 339—342.

97.

Goldring CE , Reveneau S. , Pinard D. , Jeannin JF Hyporesponsiveness to lipopolysaccharide alters the composition of NF-kappaB binding to the regulatory regions of inducible nitric oxide synthase gene. Eur J Immunol 1998; 28: 2960—2970.

98.

Tominaga K. , Saito S. , Matsuura M. , Nakano M. Lipopolysaccharide tolerance in murine peritoneal macrophages induces downregulation of the lipopolysaccharide signal transduction pathway through mitogen-activated protein kinase and nuclear factor-kappaB cascades, but not lipopolysaccharide-incorporation steps. Biochim Biophys Acta 1999; 1450: 130—144.

99.

Kastenbauer S. , Ziegler-Heitbrock HW NF-kappaB1 (p50) is upregulated in lipopolysaccharide tolerance and can block tumor necrosis factor gene expression . Infect Immun 1999; 67: 1553—1559.

100.

Wedel A. , Frankenberger M. , Sulski G. et al. Role of p52 (NF-kappaB2) in LPS tolerance in a human B cell line. Biol Chem 1999; 380: 1193—1199.

101.

Bohuslav J. , Kravchenko VV , Parry GC et al. Regulation of an essential innate immune response by the p50 subunit of NF-kappaB. J Clin Invest 1998; 102: 1645—1652.

102.

Wysocka M. , Robertson S. , Riemann H. et al. IL-12 suppression during experimental endotoxin tolerance: dendritic cell loss and macrophage hyporesponsiveness . J Immunol 2001; 166: 7504—7513.

103.

Blackwell TS , Blackwell TR , Christman JW Induction of endotoxin tolerance depletes nuclear factor-kappaB and suppresses its activation in rat alveolar macrophages . J Leukoc Biol 1997 ; 62: 885—891.

104.

Fujihara M. , Ikebuchi K. , Maekawa TL et al. Lipopolysaccharide-induced desensitization of junB gene expression in a mouse macrophage-like cell line, P388D1. J Immunol 1998; 161): 3659—3665.

105.

Kliewer SA , Umesono K. , Noonan DJ , Heyman RA , Evans RM Convergence of 9-cis-retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors . Nature 1992; 358: 771—774.

106.

Jiang C. , Ting AT , Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines . Nature 1998; 391: 82—86.

107.

Ricote M. , Li AC , Willson TM , Kelly CJ , Glass CK The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998; 391: 79—82.

108.

Uchimura K. , Nakamuta M. , Enjoji M. et al. Activation of retinoic X receptor and peroxisome proliferator-activated receptor-gamma inhibits nitric oxide and tumor necrosis factor-alpha production in rat Kupffer cells . Hepatology 2001; 33: 91—99.

109.

Von Knethen A A. , Brune B. Delayed activation of PPARgamma by LPS and IFN-gamma attenuates the oxidative burst in macrophages. FASEB J 2001; 15: 535—544.

110.

LaRue KE , McCall CE A labile transcriptional repressor modulates endotoxin tolerance. J Exp Med 1994; 180: 2269—2275.

111.

Yoza BK , Wells JD , McCall CE Interleukin-1beta expression after inhibition of protein phosphatases in endotoxin-tolerant cells. Clin Diagn Lab Immunol 1998; 5: 281—287.

112.

Fernando LP , Fernando AN , Ferlito M. , Halushka PV , Cook JA Suppression of Cox-2 and TNF-alpha mRNA in endotoxin tolerance: effect of cycloheximide, actinomycin D, and okadaic acid . Shock 2000; 14: 128—133.

113.

Meldrum DR , Raiesdana A. , Meldrum K. et al. Upregulation of soluble TNF receptor 1 (sTNFR1) response to LPS during the development of endotoxin tolerance. Shock 2003; 19(Suppl 1): 89—90.

114.

Frankenberger M. , Pechumer H. , Ziegler-Heitbrock HW Interleukin-10 is upregulated in LPS tolerance. J Inflamm 1995 ; 45: 56—63.

115.

Sfeir T. , Saha DC , Astiz M. , Rackow EC Role of interleukin-10 in monocyte hyporesponsiveness associated with septic shock. Crit Care Med 2001; 29: 129—133.

116.

Berg DJ , Kuhn R. , Rajewsky K. et al. Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J Clin Invest 1995; 96: 2339—2347.

117.

Rieser C. , Papesh C. , Herold M. et al. Differential deactivation of human dendritic cells by endotoxin desensitization: role of tumor necrosis factor-alpha and prostaglandin E2 . Blood 1998; 91: 3112—3117.

118.

Randow F. , Syrbe U. , Meisel C. et al. Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta. J Exp Med 1995; 181: 1887—1892.

119.

Bulger EM , Maier RV Lipid mediators in the pathophysiology of critical illness. Crit Care Med 2000; 28(4 Suppl): N27—N36.

120.

Hafenrichter DG , Roland CR , Mangino MJ , Flye MW The Kupffer cell in endotoxin tolerance: mechanisms of protection against lethal endotoxemia . Shock 1994; 2: 251—256.

121.

Li MH , Seatter SC , Manthei R. , Bubrick M. , West MA Macrophage endotoxin tolerance: effect of TNF or endotoxin pretreatment . J Surg Res 1994; 57: 85—92.

122.

Seatter SC , Li MH , Bubrick MP , West MA Endotoxin pretreatment of human monocytes alters subsequent endotoxin-triggered release of inflammatory mediators. Shock 1995; 3: 252—258.

123.

Zingarelli B. , Halushka PV , Caputi AP , Cook JA Increased nitric oxide synthesis during the development of endotoxin tolerance. Shock 1995; 3: 102—108.

124.

Fahmi H. , Ancuta P. , Perrier S. , Chaby R. Preexposure of mouse peritoneal macrophages to lipopolysaccharide and other stimuli enhances the nitric oxide response to secondary stimuli . Inflamm Res 1996; 45: 347—353.

125.

Tominaga K. , Saito S. , Matsuura M. , Funatogawa K. , Matsumura H. , Nakano M. Role of IFN-gamma on dissociation between nitric oxide and TNF/IL-6 production by murine peritoneal cells after restimulation with bacterial lipopolysaccharide. J Leukoc Biol 1999; 66: 974—980.

126.

Severn A. , Xu D. , Doyle J. et al. Pre-exposure of murine macrophages to lipopolysaccharide inhibits the induction of nitric oxide synthase and reduces leishmanicidal activity . Eur J Immunol 1993; 23: 1711—1714.

127.

Spitzer JA , Zheng M. , Kolls JK , Vande Stouwe C , Spitzer JJ Ethanol and LPS modulate NF-kappaB activation, inducible NO synthase and COX-2 gene expression in rat liver cells in vivo. Front Biosci 2002; 7: a99—a108.

128.

Zingarelli B. , Hake PW , Cook JA Inducible nitric oxide synthase is not required in the development of endotoxin tolerance in mice . Shock 2002; 17: 478—484.