• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Nov 1995; 96(5): 2339–2347.
PMCID: PMC185885

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.

Abstract

Previous studies in vivo have shown that IL-10 infusion can prevent lethal endotoxic shock. Mice deficient in the production of IL-10 (IL10T) were used to investigate the regulatory role of IL-10 in the responses to LPS in three experimental systems. In a model of acute endotoxic shock, it was found that the lethal dose of LPS for IL10T mice was 20-fold lower than that for wild type (wt) mice suggesting that endogenous IL-10 determines the amount of LPS which can be tolerated without death. The high mortality rate of IL10T mice challenged with modest doses of LPS was correlated to the uncontrolled production of TNF as treatment with anti-TNF antibody (Ab) resulted in 70% survival. Additional studies suggested that IL-10 mediates protection by controlling the early effectors of endotoxic shock (e.g., TNF alpha) and that it is incapable of directly antagonizing the production and/or actions of late appearing effector molecules (e.g., nitric oxide). We also found that IL10T mice were extremely vulnerable to a generalized Shwartzman reaction where prior exposure to a small amount of LPS primes the host for a lethal response to a subsequent sublethal dose. The priming LPS dose for IL10T mice was 100-fold lower than that required to prime wt mice implying that IL-10 is important for suppressing sensitization. In agreement with this assumption, IL-10 infusion was found to block the sensitization step. Interestingly, IL-10 was not the main effector of endotoxin tolerance as IL10T mice could be tolerized to LPS. Furthermore, IL-10 infusion could not substitute for the desensitizing dose of LPS. These results show that IL-10 is a critical component of the host's natural defense against the development of pathologic responses to LPS although it is not responsible for LPS-induced tolerance.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.5M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Watson RW, Redmond HP, Bouchier-Hayes D. Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses. J Leukoc Biol. 1994 Jul;56(1):95–103. [PubMed]
  • Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. [PubMed]
  • Beutler B, Cerami A. Cachectin/tumor necrosis factor: an endogenous mediator of shock and inflammation. Immunol Res. 1986;5(4):281–293. [PubMed]
  • Dinarello CA. The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J Infect Dis. 1991 Jun;163(6):1177–1184. [PubMed]
  • Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest. 1988 Apr;81(4):1162–1172. [PMC free article] [PubMed]
  • Doherty GM, Lange JR, Langstein HN, Alexander HR, Buresh CM, Norton JA. Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha. J Immunol. 1992 Sep 1;149(5):1666–1670. [PubMed]
  • Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. [PubMed]
  • Ohlsson K, Björk P, Bergenfeldt M, Hageman R, Thompson RC. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature. 1990 Dec 6;348(6301):550–552. [PubMed]
  • Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA. A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits. FASEB J. 1991 Mar 1;5(3):338–343. [PubMed]
  • Kohler J, Heumann D, Garotta G, LeRoy D, Bailat S, Barras C, Baumgartner JD, Glauser MP. IFN-gamma involvement in the severity of gram-negative infections in mice. J Immunol. 1993 Jul 15;151(2):916–921. [PubMed]
  • Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. [PubMed]
  • de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. [PMC free article] [PubMed]
  • Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed]
  • Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. [PMC free article] [PubMed]
  • Hsu DH, Moore KW, Spits H. Differential effects of IL-4 and IL-10 on IL-2-induced IFN-gamma synthesis and lymphokine-activated killer activity. Int Immunol. 1992 May;4(5):563–569. [PubMed]
  • Gérard C, Bruyns C, Marchant A, Abramowicz D, Vandenabeele P, Delvaux A, Fiers W, Goldman M, Velu T. Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. J Exp Med. 1993 Feb 1;177(2):547–550. [PMC free article] [PubMed]
  • Howard M, Muchamuel T, Andrade S, Menon S. Interleukin 10 protects mice from lethal endotoxemia. J Exp Med. 1993 Apr 1;177(4):1205–1208. [PMC free article] [PubMed]
  • Durez P, Abramowicz D, Gérard C, Van Mechelen M, Amraoui Z, Dubois C, Leo O, Velu T, Goldman M. In vivo induction of interleukin 10 by anti-CD3 monoclonal antibody or bacterial lipopolysaccharide: differential modulation by cyclosporin A. J Exp Med. 1993 Feb 1;177(2):551–555. [PMC free article] [PubMed]
  • Marchant A, Bruyns C, Vandenabeele P, Ducarme M, Gérard C, Delvaux A, De Groote D, Abramowicz D, Velu T, Goldman M. Interleukin-10 controls interferon-gamma and tumor necrosis factor production during experimental endotoxemia. Eur J Immunol. 1994 May;24(5):1167–1171. [PubMed]
  • Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. [PubMed]
  • Billiau A. Gamma-interferon: the match that lights the fire? Immunol Today. 1988 Feb;9(2):37–40. [PubMed]
  • Brozna JP. Shwartzman reaction. Semin Thromb Hemost. 1990 Oct;16(4):326–332. [PubMed]
  • Mengozzi M, Ghezzi P. Cytokine down-regulation in endotoxin tolerance. Eur Cytokine Netw. 1993 Mar-Apr;4(2):89–98. [PubMed]
  • Ho AS, Liu Y, Khan TA, Hsu DH, Bazan JF, Moore KW. A receptor for interleukin 10 is related to interferon receptors. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11267–11271. [PMC free article] [PubMed]
  • Abrams JS, Roncarolo MG, Yssel H, Andersson U, Gleich GJ, Silver JE. Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples. Immunol Rev. 1992 Jun;127:5–24. [PubMed]
  • Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, Trinchieri G, Sher A. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994 Sep 15;153(6):2533–2543. [PubMed]
  • D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. [PMC free article] [PubMed]
  • Schmidt HH, Wilke P, Evers B, Böhme E. Enzymatic formation of nitrogen oxides from L-arginine in bovine brain cytosol. Biochem Biophys Res Commun. 1989 Nov 30;165(1):284–291. [PubMed]
  • Brocke S, Gaur A, Piercy C, Gautam A, Gijbels K, Fathman CG, Steinman L. Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen. Nature. 1993 Oct 14;365(6447):642–644. [PubMed]
  • Powrie F, Menon S, Coffman RL. Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo. Eur J Immunol. 1993 Nov;23(11):3043–3049. [PubMed]
  • Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992 Jul 3;257(5066):88–91. [PubMed]
  • Cunha FQ, Assreuy J, Moss DW, Rees D, Leal LM, Moncada S, Carrier M, O'Donnell CA, Liew FY. Differential induction of nitric oxide synthase in various organs of the mouse during endotoxaemia: role of TNF-alpha and IL-1-beta. Immunology. 1994 Feb;81(2):211–215. [PMC free article] [PubMed]
  • Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF. Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun. 1990 Nov 15;172(3):1132–1138. [PubMed]
  • Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF. NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci U S A. 1990 May;87(9):3629–3632. [PMC free article] [PubMed]
  • Dinarello CA, Gelfand JA, Wolff SM. Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. JAMA. 1993 Apr 14;269(14):1829–1835. [PubMed]
  • Heremans H, Dijkmans R, Sobis H, Vandekerckhove F, Billiau A. Regulation by interferons of the local inflammatory response to bacterial lipopolysaccharide. J Immunol. 1987 Jun 15;138(12):4175–4179. [PubMed]
  • Heremans H, Van Damme J, Dillen C, Dijkmans R, Billiau A. Interferon gamma, a mediator of lethal lipopolysaccharide-induced Shwartzman-like shock reactions in mice. J Exp Med. 1990 Jun 1;171(6):1853–1869. [PMC free article] [PubMed]
  • Heremans H, Dillen C, van Damme J, Billiau A. Essential role for natural killer cells in the lethal lipopolysaccharide-induced Shwartzman-like reaction in mice. Eur J Immunol. 1994 May;24(5):1155–1160. [PubMed]
  • Ozmen L, Pericin M, Hakimi J, Chizzonite RA, Wysocka M, Trinchieri G, Gately M, Garotta G. Interleukin 12, interferon gamma, and tumor necrosis factor alpha are the key cytokines of the generalized Shwartzman reaction. J Exp Med. 1994 Sep 1;180(3):907–915. [PMC free article] [PubMed]
  • Mengozzi M, Fantuzzi G, Sironi M, Bianchi M, Fratelli M, Peri G, Bernasconi S, Ghezzi P. Early down-regulation of TNF production by LPS tolerance in human monocytes: comparison with IL-1 beta, IL-6, and IL-8. Lymphokine Cytokine Res. 1993 Aug;12(4):231–236. [PubMed]
  • Fahmi H, Chaby R. Selective refractoriness of macrophages to endotoxin-induced production of tumor necrosis factor, elicited by an autocrine mechanism. J Leukoc Biol. 1993 Jan;53(1):45–52. [PubMed]
  • Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. [PubMed]
  • Barton BE, Jackson JV. Protective role of interleukin 6 in the lipopolysaccharide-galactosamine septic shock model. Infect Immun. 1993 Apr;61(4):1496–1499. [PMC free article] [PubMed]
  • Labeta MO, Durieux JJ, Spagnoli G, Fernandez N, Wijdenes J, Herrmann R. CD14 and tolerance to lipopolysaccharide: biochemical and functional analysis. Immunology. 1993 Nov;80(3):415–423. [PMC free article] [PubMed]
  • Ziegler-Heitbrock HW, Wedel A, Schraut W, Ströbel M, Wendelgass P, Sternsdorf T, Bäuerle PA, Haas JG, Riethmüller G. Tolerance to lipopolysaccharide involves mobilization of nuclear factor kappa B with predominance of p50 homodimers. J Biol Chem. 1994 Jun 24;269(25):17001–17004. [PubMed]
  • Elsbach P, Weiss J. Bactericidal/permeability increasing protein and host defense against gram-negative bacteria and endotoxin. Curr Opin Immunol. 1993 Feb;5(1):103–107. [PubMed]
  • Cassatella MA, Meda L, Bonora S, Ceska M, Constantin G. Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. J Exp Med. 1993 Dec 1;178(6):2207–2211. [PMC free article] [PubMed]
  • de Waal Malefyt R, Yssel H, Roncarolo MG, Spits H, de Vries JE. Interleukin-10. Curr Opin Immunol. 1992 Jun;4(3):314–320. [PubMed]
  • Jenkins JK, Malyak M, Arend WP. The effects of interleukin-10 on interleukin-1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils. Lymphokine Cytokine Res. 1994 Feb;13(1):47–54. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...