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Cytokines as Mediators in the Pathogenesis of Septic Shock

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 216))

Abstract

During septic shock the host produces several proinflammatory cytokines which have been implicated as playing a critical role in the pathogenesis of the disease. The production of these cytokines is initiated by the organisms themselves (phagocytosis) or by soluble products of the organisms. For example, the lipopolysaccharide endotoxins (LPS) of gram-negative bacteria, the protein exotoxins of gram-positive bacteria, and the cell-wall glycopeptides such as teichoic acids and muramyl peptides. Of course, LPS is by far the most potent soluble product of bacteria which induces cytokine production, and therefore most information about cytokine induction is derived from studies using LPS in vitro and in vivo. However, it is important to recognize that the cytokine production in septic shock is neither specific nor unique. The cytokines which contribute to pathological changes in septic shock are not unique to infection. Multiple trauma, ischemia-reperfusion injury, acute transplant rejection, antigen-specific immune responses, and various acute inflammatory states (acute hepatitis and pancreatitis) initiate the same cytokine cascade and result in both systemic and local inflammatory processes.

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References

  • Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Allred R, Pennington JE, Wherry JC (1995) Efficacy and safety of monoclonal antibody to human tumor necrosis factor-α in patients with sepsis syndrome. JAMA 273: 934–941.

    Article  PubMed  CAS  Google Scholar 

  • Aderka D, Le JM, Vilcek J (1989) IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells, and in mice. J Immunol 143: 3517–3523.

    PubMed  CAS  Google Scholar 

  • Aderka D, Engelmann H, Hornik V, Skorick Y, Levo Y, Wallach D, Kushtai G (1991) Increased serum levels of soluble receptors for tumor necrosis in cancer patients. Cancer Res 51: 5602–5607.

    PubMed  CAS  Google Scholar 

  • Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D (1992) stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 175: 323–329.

    Article  PubMed  CAS  Google Scholar 

  • Aiura K, Gelfand JA, Wakabayashi G, Burke JF, Thompson RC, Dinarello CA (1993) lnterleukin-1 (IL-1) receptor antagonist prevents Staphylococcus epidermidis-induced hypotension and reduces circulating levels of tumor necrosis factor and IL-1β in rabbits. Infect Immun 61: 3342–3350.

    PubMed  CAS  Google Scholar 

  • Arend WP (1993) lnterleukin-1 receptor antagonist. Adv Immunol 54: 167–227.

    Article  PubMed  CAS  Google Scholar 

  • Arend WP, Malyak M, Smith MF, Whisenand TD, Slack JL, Sims JE, Giri JG, Dower SK (1994) Binding of IL-1 α, IL-1 β, and IL-1 receptor antagonist by soluble IL-1 receptors and levels of soluble IL-1 receptors in synovial fluids. J Immunol 153: 4766–4774.

    PubMed  CAS  Google Scholar 

  • Baggiolini M, Dewald B, Moser B (1994) lnterleukin-8 and related chemotactic cytokines-CXC and CC chemokines. Adv Immunol 55: 97–179.

    Article  PubMed  CAS  Google Scholar 

  • Bargetzi MJ, Lantz M, Smith CG, Torti FM, Olsson I, Eisenberg SP, Starnes HF (1993) lnterleukin-1 beta induces interleukin-1 receptor antagonist and tumor necrosis factor binding proteins. Cancer Res 53: 4010–4013.

    PubMed  CAS  Google Scholar 

  • Beasley D, McGuiggin M (1995) lnterleuin-1 induces prostacyclin-dependent increases in cyclic AMP production and does not affect cyclic GMP production in human vascular smooth muscle cells. Cytokine (in press).

    Google Scholar 

  • Beasley D, Schwartz JH, Brenner BM (1991) Interleukin 1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest 87: 602–608.

    Article  PubMed  CAS  Google Scholar 

  • Bertini R, Delgado R, Faggioni R, Gascon MP, Ythier A, Ghezzi P (1993) Urinary TNF-binding protein (TNF soluble receptor) protects mice against the lethal effect of TNF and endotoxic shock. Eur Cytokine Netw 4: 39–42.

    PubMed  CAS  Google Scholar 

  • Beutler B, Milsark IW, Cerami A (1985) Passive immunization against cachetin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229: 869–871.

    Article  PubMed  CAS  Google Scholar 

  • Billiau A, Vandekerckhove F (1991) Cytokines and their interactions with other inflammatory mediators in the pathogenesis of sepsis and septic shock. Eup J Clin Invest 21: 559–573.

    Article  CAS  Google Scholar 

  • Brakebusch C, Varfolomeev EE, Batkin M, Wallach D (1994) Structural requirements for inducible shedding of the p55 tumor necrosis factor receptor. J Biol Chem 269: 32488–32496.

    PubMed  CAS  Google Scholar 

  • Casey LC, Balk RA, Bone RC (1993) Plasma cytokines and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 119: 771–778.

    PubMed  CAS  Google Scholar 

  • Chantry D, Turner M, Abney E, Feldmann M (1989) Modulation of cytokine production by transforming growth factor-beta. J Immunol 142: 4295–4300.

    PubMed  CAS  Google Scholar 

  • Chapman PB, Lester TJ, Casper ES, Gabrilove JL, Wong GY, Kempin SJ, Gold PJ, Welt S, Warren RS, Starnes HF (1987) Clinical pharmacology of recombinant human tumor necrosis factor in patients with advanced cancer. J Clin Oncol 5: 1942–1951.

    PubMed  CAS  Google Scholar 

  • Chensue SW, Bienkowski M, Eessalu TE, Warmington KS, Hershey SD, Lukas NW, Kunkel SL (1993) Endogenous IL-1 receptor antagonist protein (IRAP) regulates schistosome egg granuloma formation and the regional lymphoid response. J Immunol 151: 3654–3662.

    PubMed  CAS  Google Scholar 

  • Chernoff AE, Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB, Kennedy JS, Rabson AR, Wolff SM, Dinarello CA (1995) A randomized, controlled trial of interleukin-10 in humans: inhibition of inflammatory cytokine production and immune responses. J Immunol (in press).

    Google Scholar 

  • Chikanza IC, Roux-Lombard P, Dayer JM, Panayi GS (1993) Tumour necrosis factor soluble receptors behave as acute phase reactants following surgery in patients with rheumatoid arthritis, chronic osteomyelitis and osteorthritis. Clin Exp Immunol 92: 19–22.

    Article  PubMed  CAS  Google Scholar 

  • Chin J, Kostura MJ (1993) Dissociation of IL-1 b synthesis and secretion in human blood monocytes stimulated with bacterial cell waste products. J Immunol 151: 5574–5585.

    PubMed  CAS  Google Scholar 

  • Clark MA, Özgür LE, Conway TM, Dispoto J, Crooke ST, Bomalaski JS (1991) Cloning of a phospholipase A2-activating protein. Proc Natl Acad Sci USA 88: 5418–5422.

    Article  PubMed  CAS  Google Scholar 

  • Cooper AL, Gibbons L, Horan MA, Little RA, Rothwell NJ (1993) Effect of dietary fish oil supplementation on fever and cytokine production in human volunteers. Clin Nutr 12: 321–328.

    Article  PubMed  CAS  Google Scholar 

  • Crown J, Jakubowski A, Kemeny N, Gordon M, Gasparetto C, Wong G, Toner G, Meisenberg B, Botet J, Applewhite J, Sinha S, Moore M, Kelsen D, Buhles W, Gabrilove J (1991) A phase I trial of recombinant human interleukin-1 β alone and in combination with myelosuppressive doses of 5-fluoruracil in patients with gastrointestinal cancer. Blood 78: 1420–1427.

    PubMed  CAS  Google Scholar 

  • Dejana E, Breviario F, Erroi A, Bussolino F, Mussoni L, Gramse M, Pintucci G, Casali B, Dinarello CA, Van Damme J, Mantovani A (1987) Modulation of endothelial cell functions by different molecular species of interleukin 1. Blood 69: 695–699.

    PubMed  CAS  Google Scholar 

  • Dinarello CA, Cannon JG, Mancilla J, Bishai I, Lees J, Coceani F (1991) lnterleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheal blood mononuclear cells. Brain Res 562: 199–206.

    Article  PubMed  CAS  Google Scholar 

  • Dinarello CA, Zhang XX, Wen HD, Wolff SM, Ikejima T (1992) The effect of interleukin-1 receptor antagonist on IL-1, LPS, Staphylococcus epidermidis and tumor necrosis factor fever. In: Bartfai T, Ottoson D (eds) Neuro-immunology of fever. Pergamon Oxford, pp11–18.

    Google Scholar 

  • Dower SK, Fanslow W, Jacobs C, Waugh S, Sims JE, Widmer MB (1994) Interleukin-1 antagonists. Ther Immunol 1: 113–122.

    PubMed  CAS  Google Scholar 

  • Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP (1991) Effect of IL-1ra on IL-1 signal transduction. J Biol Chem 266: 10331–10336.

    PubMed  CAS  Google Scholar 

  • Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC (1990) Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature 343: 341–346.

    Article  PubMed  CAS  Google Scholar 

  • Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Long-Fox A, Charles P, Bijl H, Woody JN (1994) Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344: 1105–1110.

    Article  PubMed  CAS  Google Scholar 

  • Endres S, Cannon JG, Ghorbani R, Dempsey RA, Sisson SD, Lonnemann G, van der Meer JWM, Wolff SM, Dinarello CA (1989a) In vitro production of IL-1 β, IL-1 α, TNF, and IL-2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation Eur J Immunol 19: 2327–2333.

    Article  PubMed  CAS  Google Scholar 

  • Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Wolff SM, Dinarello CA (1989b) The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 320: 265–271.

    Article  PubMed  CAS  Google Scholar 

  • Endres S, Fuelle H-J, Sinha B, Stoll D, Dinarello CA, Gerzer R, Weber PC (1991) Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-α and interleukin-1 β by human mononuclear cells. Immunology 72: 56–60.

    PubMed  CAS  Google Scholar 

  • Engelmann H, Aderka D, Rubinstein M, Rotman D, Wallach D (1989) A tumor necrosis factor-binding protein purified to homogeneity from human urine protects cells from tumor necrosis factor toxicity. J Biol Chem 264: 11974–11980.

    PubMed  CAS  Google Scholar 

  • Engelmann H, Holtmann H, Brakebusch C, Avni YS, Sarov I, Nophar Y, Hadas E, Leitner O, Wallach D (1990a) Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem 265: 14497–14504.

    PubMed  CAS  Google Scholar 

  • Engelmann H, Novick D, Wallach D (1990b) Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem 265: 1531–1536.

    PubMed  CAS  Google Scholar 

  • Fanslow WC, Sims JE, Sassenfeld H, Morrissey PJ, Gillis S, Dower SK, Widmer MB (1990) Regulation of alloreactivity in vivo by a soluble form of the interleukin-1 receptor. Science 248: 739–742.

    Article  PubMed  CAS  Google Scholar 

  • Fantuzzi G, Ghezzi P (1993) Glucocorticoids as cytokine inhibitors: role in neuroendocrine therapy of inflammatory diseases. Mediator Inflamm 2: 263–270.

    Article  CAS  Google Scholar 

  • Fattori E, Cappelletti M, Cost P, Sellitto C, Cantoni L, Carelli M, Faggioni R, Fantuzzi G, Ghezzi P, Poli V (1994) Defective inflammatory response in interleukin 6-deficient mice. J Exp Med 180: 1243–1250.

    Article  PubMed  CAS  Google Scholar 

  • Ferretti M, Casini-Raggi V, Pizarro TT, Eisenberg SP, Nast CC, Cominelli F (1994) Neutralization of endogenous IL-1 receptor antagonist exacerbates and prolongs inflammation in rabbit immune colitis. J Clin Invest 94: 449–453.

    Article  PubMed  CAS  Google Scholar 

  • Fischer E, Marano MA, Barber AE, Hudson AA, Lee K, Rock CS, Hawes AS, Thompson RC, Hayes TV, Benjamin WR, Lowry SF, Moldawer LL (1991) A comparison between the effects of interleukin-1 α administration and sublethal endotoxemia in primates. Am J Physiol 261: R442–R449.

    PubMed  CAS  Google Scholar 

  • Fischer E, van Zee KJ, Marano MA, Rock CS, Kenney JS, Poutsiaka DD, Dinarello CA, Lowry SF, Moldawer LL (1992) Interleukin-1 receptor antagonist circulates in experimental inflammation and in human disease. Blood 79: 2196–2200.

    PubMed  CAS  Google Scholar 

  • Fisher CJJ, Opal SM, Dhainaut J-F, Stephens S, Zimmerman JL, Nightingale P, Harris SJ, Schein RMH, Panacek EA, Vincent J-L, Foulke GE, Warren EL (1993) Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. Crit Care Med 21: 318–327.

    Article  PubMed  Google Scholar 

  • Fisher CJJ, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL (1994a) Recombinant human interleukin-1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double blind, placebo-controlled trial. JAMA 271: 1836–1843.

    Article  PubMed  Google Scholar 

  • Fisher CJJ, Slotman GJ, Opal SM, Pribble J, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MA (1994b) Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 22: 12–21.

    PubMed  Google Scholar 

  • Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney JS, Lee AT, Kuo GC, Allison AC, Lowry SF, Cerami A (1989) Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 β and interleukin 6 appearance during lethal bacteremia. J Exp Med 170: 1627–1633.

    Article  PubMed  CAS  Google Scholar 

  • Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J (1994) Interleukin-1 activates a novel protein cascade that results in the phosphorylation of hsp27. Cell 78: 1039–1049.

    Article  PubMed  CAS  Google Scholar 

  • Friedman B, Mure A, Brathwaite C, Quinn J, Shapiro E, Melhorn L, Slotman G (1994) The effects of human recombinant interleukin-1 receptor antagonist (IL-1 ra) on plasma levels of protaglandins and leukotrienes in septic patients. Crit Care Med 22: A193.

    Article  Google Scholar 

  • Galcheva-Gargova Z, Dèrijard B, Wu I-H, Davis RJ (1994) An osmosensing signal transduction pathway in mammalian cells. Science 265: 806–809.

    Article  PubMed  CAS  Google Scholar 

  • Gearing AJH, Beckett P, Christodoulous M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon JL, Leber TM, Mangian M, Miller K, Nayee P, Owen K, Patel S, Thomas W, Wells G, Wood LM, Woodley K (1994) Processing of tumour necrosis factor-a precursor by metalloproteinases. Nature 370: 555–567.

    Article  PubMed  CAS  Google Scholar 

  • Gershenwald JE, Fong YM, Fahey TJ, Calvano SE, Chizzonite R, Kilian PL, Lowry SF, Moldawer LL (1990) Interleukin 1 receptor blockade attenuates the host inflammatory response. Proc Natl Acad Sci USA 87: 4966–4970.

    Article  PubMed  CAS  Google Scholar 

  • Ghezzi P, Dinarello CA (1988) IL-1 induces IL-1. III. Specific inhibition of IL-1 production by IFN-y. J Immunol 140: 4238–4244.

    PubMed  CAS  Google Scholar 

  • Girardin E, Roux-Lombard P, Grau GE, Suter P, Gallati H, Group JS, Dayer JM (1994) Imbalance between tumor necrosis factor α and soluble TNF receptor concentrations in severe meningococcemia. Immunology (in press).

    Google Scholar 

  • Giri JG, Wells J, Dower SK, McCall CE, Guzman RN, Slack J, Bird TA, Shanebeck K, Grabstein KH, Sims JE, Alderson MR (1994) Elevated levels of shed type II IL-1 receptor in sepsis. J Immunol 153:5802–5813.

    PubMed  CAS  Google Scholar 

  • Granowitz EV, Santos A, Poutsiaka DD, Cannon JG, Wilmore DA, Wolff SM, Dinarello CA (1991) Circulating interieukin-1 receptor antagonist levels during experimental endotoxemia in humans. Lancet 338: 1423–1424.

    Article  PubMed  CAS  Google Scholar 

  • Granowitz EV, Clark BD, Vannier E, Callahan MV, Dinarello CA (1992a) Effect of interleukin-1 (IL-1) blockade on cytokine synthesis. I. IL-1 receptor antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of IL-1 to its type II receptor on human monocytes. Blood 79: 2356–2363.

    PubMed  CAS  Google Scholar 

  • Granowitz EV, Porat R, Mier JW, Pribble JP, Stiles DM, Bloedow DC, Catalano MA, Wolff SM, Dinarello CA (1992b) Pharmacokinetics, safety, and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine 4: 353–360.

    Article  PubMed  CAS  Google Scholar 

  • Granowitz EV, Vannier E, Poutsiaka DD, Dinarello CA (1992c) Effect of interleukin-1 (IL-1) blockade on cytokine synthesis. II. Interleukin-1 receptor antagonist inhibits lipopolysaccharide-induced cytokine synthesis by human monocytes. Blood 79: 2364–2369.

    PubMed  CAS  Google Scholar 

  • Granowitz EV, Porat R, Mier JW, Orencole SF, Callahan MV, Cannon JG, Lynch EA, Ye K, Poutsiaka DD, Vannier E, Shapiro L, Pribble JP, Stiles DM, Catalano MA, Wolff SM, Dinarello CA (1993) Hematological and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans. Blood 82: 2985–2990.

    PubMed  CAS  Google Scholar 

  • Gronich J, Konieczkowski M, Gelb MH, Nemenoff RA, Sedor JR (1994) Interleukin-1 a causes a rapid activation of cytosolic phospholipase A2 by phosphorylation in rat mesangial cells. J Clin Invest 93:1224–1233.

    Article  PubMed  CAS  Google Scholar 

  • Guesdon F, Freshney N, Waller RJ, Rawlinson L, Saklatvala J (1993) Interleukin 1 and tumor necrosis factor stimulate two novel protein kinases that phosphorylate the heat shock protein hsp27 and betacasein. J Biol Chem 268: 4236–4243.

    PubMed  CAS  Google Scholar 

  • Guesdon F, Waller RJ, Saklatvala J (1994) Specific activation of β-casein kinase by the inflammatory cytokines interleukin-1 and tumour necrosis factor. Biochem J 304: 761–768.

    PubMed  CAS  Google Scholar 

  • Han J, Lee J-D, Bibbs L, Ulevitch RJ (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808–811.

    Article  PubMed  CAS  Google Scholar 

  • Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343: 336–340.

    Article  PubMed  CAS  Google Scholar 

  • Hauptmann B, Van Damme J, Dayer JM (1991) Modulation of IL-1 inflammatory and immunomodulatory properties by IL-6. Eur Cytokine Netw 2: 39–46.

    PubMed  CAS  Google Scholar 

  • Henricson BE, Neta R, Vogel SN (1991) An interleukin-1 receptor antagonist blocks lipopolysaccharide-induced colony stimulating factor production and early endotoxin tolerance. Infect Immun 59:1188–1192.

    PubMed  CAS  Google Scholar 

  • Holtmann H, Wallach D (1987) Down regulation of the receptors for tumor necrosis factor by interleukin 1 and 4 beta-phorbol-12-myristate-13-acetate. J Immunol 139: 1161–1167.

    PubMed  CAS  Google Scholar 

  • Hyams JS, Fitzgerald JE, Wyzga N, Treem WR, Justinich CJ, Kreutzer DL (1994) Characterization of circulating interleukin-1 receptor antagonist expression in children with inflammatory bowel disease. Dig Dis Sci 39: 1893–1899.

    Article  PubMed  CAS  Google Scholar 

  • Jacobs CA, Baker PE, Roux ER, Picha KS, Toivola B, Waugh S, Kennedy MK (1991) Experimental autoimmune encephalomyelitis is exacerbated by IL-1 α and suppressed by soluble IL-1 receptor. J Immunol 146: 2983–2989.

    PubMed  CAS  Google Scholar 

  • Jansen J, van der Poll T, Levi M, van Deventer SJH (1995) Inhibition of the release of soluble tumor necrosis factor receptors in experimental endotoxemia by anti-tumor necrosis factor antibody. J Clin Immunol (in press).

    Google Scholar 

  • Kapas L, Shibaya M, Kimura M, Krueger JM (1994) Inhibition of nitric oxide synthesis suppresses sleep in rabbits. Am J Physiol 266: R151–R157.

    PubMed  CAS  Google Scholar 

  • Kaplanski G, Porat R, Aiura K, Erban JK, Gelfand JA, Dinarello CA (1993) Activated platelets induce endothelial secretion of interleukin-8 in normal vitro via an interleukin-1-mediated event. Blood 81:2492–2495.

    PubMed  CAS  Google Scholar 

  • Kaplanski G, Farnarier C, Kaplanski S, Porat R, Shapiro L, Bongrand P, Dinarello CA (1994) lnterleukin-1 induces interleukin-8 from endothelial cells by a juxacrine mechanism. Blood 84: 4242–4248.

    PubMed  CAS  Google Scholar 

  • Kester M, Siomonson MS, Mene P, Sedor JR (1989) lnterleukin-1 generate transmembrane signals from phospholipids through novel pathways in cultured rat mesangial cells. J Clin Invest 83: 718–723.

    Article  PubMed  CAS  Google Scholar 

  • Knaus WA, Harrell FE, Fisher CJ, Wagner DP, Opal SM, Sadoff JC, Draper EA, Walawander CA, Conboy K, Grasela TH (1993) The clinical evaluation of new drugs for sepsis. JAMA 270: 1233–1241.

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi Y, Yamamoto K, Saido T, Kawasaki H, Oppenheim JJ, Matsushima K (1990) Identification of calcium-activated neutral protease as a processing enzyme of human interleukin 1 alpha. Proc Natl Acad Sci USA 87: 5548–5552.

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi Y, Oppenheim JJ, Matsushima K (1991) Human pre-interleukin-1 a and 1β: structural features revealed by limited proteolysis. Chem Pharm Bull (Tokyo) 39: 1513–1517.

    CAS  Google Scholar 

  • Kracht M, Truong O, Totty NF, Shiroo M, Saklatvala J (1994) lnterleukin-1 a activates two forms of p54oα mitogen-activated protein kinase in rabbit liver. J Exp Med 180: 2017–2027.

    Article  PubMed  CAS  Google Scholar 

  • Kriegler M, Perez C, DeFay K, Albert I, Lu SD (1988) A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 53: 45–53.

    Article  PubMed  CAS  Google Scholar 

  • Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS-S, Flavell RA (1995) Altered cytokine export and apoptosis in mice deficient in interleukin-1 ; converting enzyme. Science (in press).

    Google Scholar 

  • Kunz D, Mühl H, Walker G, Pfeilschifter J (1994) Two distinct signaling pathways trigger the expression of inducible nitric oxide synthase in rat mesangial cells. Proc Natl Acad Sci USA 91: 5387–5391.

    Article  PubMed  CAS  Google Scholar 

  • Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, Strickler JE, McLaughlin MM, Siemens IR, Fisher SM, Livi GP, White JR, Adams JL, Young PR (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739–747.

    Article  PubMed  CAS  Google Scholar 

  • LeMay LG, Otterness IG, Vander AJ, Kluger MJ (1990) In vivo evidence that the rise in plasma IL-6 following injection of a fever-inducing dose of LPS is mediated by IL-1 beta. Cytokine 2: 199–204.

    Article  PubMed  CAS  Google Scholar 

  • Lesslauer W, Tabuchi H, Gentz M, Brockhaus M, Schlaeger EJ, Grau G, Piquet H, Pointaire P, Vassali P, Loetscher HR (1991a) Recombinant soluble TNF receptor proteins inhibit LPS-induced lethality in mice (Abstr). Cytokine 3: 497.

    Google Scholar 

  • Lesslauer W, Tabuchi H, Gentz R, Brockhaus M (1991b) Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. Eur J Immunol 21: 2883–2886.

    Article  PubMed  CAS  Google Scholar 

  • Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, McDowell J, Paskind M, Rodman L, Salfeld J, Towne E, Tracey D, Wardwell S, Wei F-Y, Wong W, Kamen R, Seshadri T (1995) Mice deficient in interleukin-1 converting enzyme (ICE) are defective in production of mature interleukin-1β and resistant to endotoxic shock. Cell 80: 401–411.

    Article  PubMed  CAS  Google Scholar 

  • Lin T-A, Kong X, Haystead TAJ, Pause A, Belsham G, Sononberg N, Lawrence JC (1994) PHAS-I as a link between mitogen activated protein kinase and translation initiation. Science 266: 653–655.

    Article  PubMed  CAS  Google Scholar 

  • Lonnemann G, Endres S, van der Meer JW, Cannon JG, Koch KM, Dinarello CA (1989) Differences in the synthesis and kinetics of release of interleukin 1 alpha, interleukin 1 beta and tumor necrosis factor from human mononuclear cells. Eur J Immunol 19: 1531–1536.

    Article  PubMed  CAS  Google Scholar 

  • Mandrup-Poulsen T, Wogensen L, Jensen M, Svensson P, Nilsson P, Emdal T, Mølvig J, Dinarello CA, Nerup J (1995) Circulating interleukin-1 receptor antagonist concentrations are increased in adult patients with thermal injury. Crit Care Med 23: 26–33.

    Article  PubMed  CAS  Google Scholar 

  • Markewitz A, Faist E, Lang S, Endres S, Fuchs B, Reichart B (1993) Successful restoration of cell-mediated immune response after cardiopulmonary bypass by immunomodulation. J Thorac Cardiovasc Surg 105: 15–24.

    PubMed  CAS  Google Scholar 

  • Mathias S, Younes A, Kan C-C, Orlow I, Joseph C, Kolesnick RN (1993) Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1 β. Science 259:519–522.

    Article  PubMed  CAS  Google Scholar 

  • Mathison JC, Wolfson E, Ulevitch RJ (1988) Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 81: 1925–1937.

    Article  PubMed  CAS  Google Scholar 

  • McGeehan GM, Becherer JD, Bast R Jr, Boyer CM, Champion B, Connolly KM, Conway JG, Furdon P, Karp S, Kidao S (1994) Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor. Nature 370: 558–561.

    Article  PubMed  CAS  Google Scholar 

  • Meydani SN, Dinarello CA (1993) Influence of dietary fatty acids on cytokine production and its clinical implications. Nutr Clin Pract 8: 65–72.

    Article  PubMed  CAS  Google Scholar 

  • Meydani SN, Endres S, Woods MM, Goldin BR, Soo C, Morrill-Labrode A, Dinarello CA, Gorbach SL (1990) Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women. J Nutr 121: 547–555.

    Google Scholar 

  • Meydani SN, Lichtenstein AH, Cornwall S, Meydani M, Goldin BR, Rasmussen H, Dinarello CA, Schaefer EJ (1993) Immunological effects of National Cholesterol Education Panel (NCEP) step-2 diets with and without fish-derived n-3 fatty acid enrichment. J Clin Invest 92: 105–113.

    Article  PubMed  CAS  Google Scholar 

  • Miller LC, Lynch EA, Isa S, Logan JW, Dinarello CA, Steere AC (1993) Balance of synovial fluid IL-1β and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet 341: 146–148.

    Article  PubMed  CAS  Google Scholar 

  • Mizel SB (1990) Cyclic AMP and interleukin-1 signal transduction. Immunol Today 11: 390–391.

    Article  PubMed  CAS  Google Scholar 

  • Mohler KM, Sleath PR, Fitzner JN, Cerretti DP, Alderson M, Kerwar SS, Torrance DS, Otten-Evans C, Greenstreet T, Weerawama K, Kronhein SR, Petersen M, Gerhart M, Kozlosky CL, March CJ, Black RA (1994) Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature 370: 218–220.

    Article  PubMed  CAS  Google Scholar 

  • Molvig J, Pociot F, Svingen BA, Mandrup-Poulsen T, Nerup J (1991) Dietary supplementation with n-3 fatty acids decreases mononuclear proliferation and interleukin-1 ß content but not monokine secretions in insulin-dependent diabetic individuals. Scand J Immunol 34: 399–410.

    Article  PubMed  CAS  Google Scholar 

  • Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109–142.

    PubMed  CAS  Google Scholar 

  • Moore KW, O’Garra A, de Waal Malefyt R, Vieira P, Mosmann TR (1993) interleukin-10. annu Rev Immunol 11: 165–190.

    Article  PubMed  CAS  Google Scholar 

  • Movat HZ, Burrowes CE, Cybulsky Ml, Dinarello CA (1987) Acute inflammation and a Shwartzman-like reaction induced by interleukin-1 and tumor necrosis factor. Synergistic action of the cytokines in the induction of inflammation and microvascular injury. Am J Pathol 129: 463–476.

    PubMed  CAS  Google Scholar 

  • Munoz E, Beutner U, Zubiaga A, Huber BT (1990) IL-1 activates two separate signal transduction pathways in T helper type II cells. J Immunol 144: 964–969.

    PubMed  CAS  Google Scholar 

  • O’Neill LAJ, Bird TA, Saklatvala J (1990) Interleukin-1 signal transduction. Immunol Today 11: 392–394.

    Article  PubMed  Google Scholar 

  • Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA (1988) Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest 81: 1162–1172.

    Article  PubMed  CAS  Google Scholar 

  • Oliveira IC, Mukaida N, Matsushima K, Vilcek J (1994) Transcriptional inhibition of the interleukin-8 gene by interferon is mediated by the NFkB site. Mol Cell Biol 14: 5300–5308.

    PubMed  CAS  Google Scholar 

  • Olivera DL, Laydon JT, Hillegass L, Badger AM, Lee JC (1993) Effects of pyridinyl imidazole compounds on murine TNFα production. Agents Actions 39: C55–C57.

    Article  PubMed  CAS  Google Scholar 

  • Olsson I, Gatanaga T, Gullberg U, Lantz M, Granger GA (1993) Tumour necrosis factor (TNF) binding proteins (soluble TNF receptor forms) with possible roles in inflammation and malignancy. Eur Cytokine Netw 4: 169–180.

    PubMed  CAS  Google Scholar 

  • Opal SM (1996) Clinical trials of novel therapeutic agents: why did they fail? In: Vincent J-L (ed) Yearbook of intensive care and emergency medicine. Springer, Berlin, Heidelberg, New York, 425–436.

    Google Scholar 

  • Orencole SF, Vannier E, Dinarello CA (1994) Detection of soluble IL-1 receptor type li (IL-1sRII) in sera and plasma from healthy volunteers (Abstr). Cytokine 6: 554.

    Article  Google Scholar 

  • Palmer RM, Hickery MS, Charles IG, Moncada S, Bayless MT (1994) Induction of nitric oxide synthase in human chrondrocytes. Biochem Biophys Res commun 193: 398–405.

    Article  Google Scholar 

  • Porat R, Poutsiaka DD, Miller LC, Granowitz EV, Dinarello CA (1992) Interleukin-1 (IL-1) receptor blockade reduces endotoxin and Borrelia burgdorferi-stimulated IL-8 synthesis in human mononuclear cells. FASEB J 6: 2482–2486.

    PubMed  CAS  Google Scholar 

  • Porat R, Paddock HN, Schwaitzberg SD, Connolly RJ, Wilkens T, Dasch JR, Gascon M-P, Hutchison JS, Ythier A, Wallach D, Dinarello CA (1995) Glycosylated recombinant human TNF binding protein-1 reduces mortality, shock and production of TNF in rabbit Escherichia coli sepsis. Crit Care Med (in press).

    Google Scholar 

  • Reimers Jl, Bjerre U, Mandrup-Poulsen T, Nerup J (1994) Interleukin-1 β induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases. Cytokine 6: 512–520.

    Article  PubMed  CAS  Google Scholar 

  • Reinhart K, Wiegand-Löhnert C, Grimminger F, Kaul M, Withington D, Treatcher J, Eckart J, Willats S, Guerrero-Sanz J, Krausch D, Stockenhuber F, Eiselstein J, Kempeni J (1995) Treatment of severe sepsis with antiTNF monoclonal antibody MAK 195F: dose-dependent reduction of mortality in patients with elevated IL-6 serum levels (Abstr). Clin Intensive Care 6: 82.

    Google Scholar 

  • River C, Shen GH (1994) In the rat, endogenous nitric oxide modulates the response of the hypothalamic-pituitary-adrenal axis to interleukin-1 β, vasopressin and oxytocin. J Neurosci 14:1985–1993.

    Google Scholar 

  • Rock CS, Coyle SM, Keogh CV, Lazarus DD, Hawes AS, Leskiw M, Moldawer LL, Stein TP, Lowry SF (1992) Influence of hypercortisolemia on the acute-phase protein response to endotoxin in humans. Surgery 112: 467–74.

    PubMed  CAS  Google Scholar 

  • Rordorf-Adam C, Geiger T, Henn R, Arnold J, Solf I, Wiesenberg PG, Ferrini PG, Vosbeck K (1994) CGP 47969A: a novel inhibitor of the synthesis of inflammatory cytokines. Agents Actions 41: 29–35.

    Google Scholar 

  • Rosoff PM, Savage N, Dinarello CA (1988) lnterleukin-1 stimulates diacylglycerol production in T lymphocytes by a novel mechanism. Cell 54: 73–81.

    Article  PubMed  CAS  Google Scholar 

  • Rossi V, Breviario F, Ghezzi P, Dejana E, Mantovani A (1985) Prostacyclin synthesis induced in vascular cells by interleukin-1. Science 229: 174–176.

    Article  PubMed  CAS  Google Scholar 

  • Salvemi D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P (1993) Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci USA 90: 7240–7244.

    Article  Google Scholar 

  • Santos AA, Scheltinga MR, Lynch E, Brown EF, Lawton P, Chambers E, Browning J, Dinarello CA, Wolff SM, Wilmore DW (1993) Elaboration of interleukin-1 receptor antagonist is not attenuated by glucocorticoids after endotoxemia. Arch Surg 128: 138–144.

    Article  PubMed  CAS  Google Scholar 

  • Schade UF, Burmeister I, Engel R (1987) Increased 13-hydroxyoctadecadienoic acid content in lipopolysacharide stimulated macrophages. Biochem Biophys Res Commun 147: 695–700.

    Article  PubMed  CAS  Google Scholar 

  • Schindler R, Ghezzi P, Dinarello CA (1990a) IL-1 induces IL-1. IV. IFN-y suppresses IL-1 but not lipopolysaccharide-induced transcription of IL-1. J Immunol 144: 2216–2222.

    PubMed  CAS  Google Scholar 

  • Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA (1990b) Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75: 40–47.

    PubMed  CAS  Google Scholar 

  • Seckinger P, Lowenthal JW, Williamson K, Dayer JM, MacDonald HR (1987) A urine inhibitor of interleukin-1 activity that blocks ligand binding. J Immunol 139: 1546–1549.

    PubMed  CAS  Google Scholar 

  • Shapiro L, Clark BD, Orencole SF, Poutsiaka DD, Granowitz EV, Dinarello CA (1993) Detection of umor necrosis factor soluble receptor p55 in blood samples from healthy and endotoxemic humans. J Infect Dis 167: 1344–1350.

    Article  PubMed  CAS  Google Scholar 

  • Shapiro L, Panayotatos N, Meydani SN, Wu D, Dinarello CA (1994) Ciliary neurotrophic factor combined with soluble receptor inhibits synthesis of pro-inflammatory cytokines and prostaglandin-E2 in vitro. Exp Cell Res 215: 51–56.

    Article  PubMed  CAS  Google Scholar 

  • Singer II, Scott S, Chin J, Kostura MJ, Miller DK, Chapman K, Bayne EK (1993) Interleukin-1 β converting enzyme is localized on the external cell-surface membranes and in the cytoplasmic ground substance of activated human monocytes by immuno-electronmicroscopy (Abstr). Lymphokine Cytokine Res 12: 340.

    Google Scholar 

  • Sirko S, Schindler R, Doyle MJ, Weisman SM, Dinarello CA (1991) Transcription, translation and secretion of interleukin-1 and tumor necrosis factor: effects of tebufelone, a dual cyclooxygenase/ 5-lipoxygenase inhibitor. Eur J Immunol 21: 242–250.

    Article  Google Scholar 

  • Smith JW, Urba WJ, Curti BD, Elwood LJ, Steis RG, Janik JE, Sharfman WH, Miller LL, Fenton RG, Conlon KC, Rossio J, Kopp W, Shimuzut M, Oppenheim JJ, Longo D (1992) The toxic and hematologie effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies. J Clin Oncol 10: 1141–1152.

    PubMed  Google Scholar 

  • Spinas GA, Bloesch D, Keller U, Zimmerli W, Cammisuli S (1991) Pretreatment with ibuprofen augments circulating tumor necrosis factor, interleukin-6 and elastase during acute endotoxemia. J Infect Dis 163: 89–95.

    Article  PubMed  CAS  Google Scholar 

  • Stevenson FT, Bursten SL, Locksley RM, Lovett DH (1992a) Myristyl acylation of the tumor necrosis factor-a precursor on specific lysines. J Exp Med 176: 1053–1062.

    Article  PubMed  CAS  Google Scholar 

  • Stevenson FT, Torrano F, Locksley RM, Lovett DH (1992b) Interleukin-1: the patterns of translation and intracellular distribution support alternative secretory mechanisms. J Cell Physiol 152: 223–231.

    Article  PubMed  CAS  Google Scholar 

  • Stevenson FT, Bursten SL, Fanton C, Locksley RM, Lovett DH (1993) The 31-kDa precursor of interleukin-1 α is myristoylated on specific lysines within the 16-kDa N-terminal propiece. Proc Natl Acad Sci USA 90: 7245–7249.

    Article  PubMed  CAS  Google Scholar 

  • Szabo C, Wu C-C, Gross SS, Thiemermann C, Vane JR (1993) Interleukin-1 contributes to the induction of nitric oxide synthase by endotoxin in vivo. Eur J Pharmacol 150: 157–160.

    Article  Google Scholar 

  • Tilg H, Vannier E, Vachino G, Dinarello CA, Mier JW (1993) Antiinflammatory properties of hepatic acute phase proteins: preferential induction of interleukin-1 (IL-1) receptor antagonist over interleukin-1 β synthesis by human peripheral blood mononuclear cells. J Exp Med 178:1629–1636.

    Article  PubMed  CAS  Google Scholar 

  • Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW (1994a) Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83: 113–118.

    PubMed  CAS  Google Scholar 

  • Tilg H, Trehu E, Shapiro L, Pape D, Atkins MB, Dinarello CA, Mier JW (1994b) Induction of circulating soluble tumour necrosis factor receptor and interleukin 1 receptor antagonist following interleukin1a infusion in humans. Cytokine 6: 215–219.

    Article  PubMed  CAS  Google Scholar 

  • Tracey K, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A (1987) Anticachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 330:662–664.

    Article  PubMed  CAS  Google Scholar 

  • Tredget EE, Yu YM, Zhong S, Burini R, Okusawa S, Gelfand JA, Dinarello CA, Young VR, Burke JF (1988) Role of interleukin 1 and tumor necrosis factor on energy metabolism in rabbits. Am J Physiol 255: E760–E768.

    PubMed  CAS  Google Scholar 

  • Ucla C, Roux-Lombard P, Fey S, Dayer J-M, Mach B (1990) Interferon gamma drastically modifies the regulation of interleukin 1 genes by endotoxin in U937 cells. J Clin Invest 85: 185–191.

    Article  PubMed  CAS  Google Scholar 

  • Van der Poll T, Bueller HR, ten Cate H, Wortel CH, Bauer KA, van Deventer SJH, Hack CE, Sauerwein HP, Rosenberg RD, ten Cate JW (1990) Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 322: 1622–1627.

    Article  PubMed  Google Scholar 

  • Van der Poll T, van Deventer SJH, Hack CE, Wolbink GJ, Aarden LA, Büller HR, ten Cate JW (1991) Effects of leukocytes following injection of tumor necrosis factor into healthy humans. Blood 79:693–698.

    Google Scholar 

  • Van der Poll T, van Deventer SJH, ten Cate H, Levi M, ten Cate JW (1994) Tumor necrosis factor is involved in the appearance of interleukin 1 receptor antagonist in endotoxemta. J Infect Dis 169:665–667.

    Article  PubMed  Google Scholar 

  • Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF (1992) Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor-α in vitro and in vivo. Proc Natl Acad Sci USA 89: 4845–4849.

    Article  PubMed  Google Scholar 

  • Vannier E, Dinarello CA (1993) Histamine enhances interleukin (IL)-1-induced IL-1 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells: comparison with IL-1 receptor antagonist. J Clin Invest 92: 281–287.

    Article  PubMed  CAS  Google Scholar 

  • Vannier E, Dinarello CA (1994) Histamine enhances interleukin (IL)-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells. J Biol Chem 269: 9952–9956.

    PubMed  CAS  Google Scholar 

  • Vannier E, Lefort J, Lellouch-Tubiana A, Terlain B, Vargaftig BB (1991a) Lipopolysaccharide from E. coli reduces antigen-induced bronchoconstriction in actively sensitized guinea pigs. J Clin Invest 87:1936–1944.

    Article  PubMed  CAS  Google Scholar 

  • Vannier E, Miller LC, Dinarello CA (1991b) Histamine suppresses gene expression and synthesis of tumor necrosis factor a via histamine H2 receptors. J Exp Med 174: 281–284.

    Article  PubMed  CAS  Google Scholar 

  • Vannier E, Miller LC, Dinarello CA (1992) Coordinated anti-inflammatory effect of IL-4: IL-4 down regulates IL-1 synthesis but up regulates IL-1 ra production. Proc Natl Acad Sci USA 89:4076–4080.

    Article  PubMed  CAS  Google Scholar 

  • Vincent J-L, Bakker J, Marècaux G, Schandene L, Kahn RJ, Dupont E (1992) Administration of anti-TNF antibody improves left ventricular function in septic shock patients. Chest 101: 810–815.

    Article  PubMed  CAS  Google Scholar 

  • Waring PM, Waring LJ, Billington T, Metcalf D (1995) Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice. Proc Natl Acad Sci USA 92: 1337–1341.

    Article  PubMed  CAS  Google Scholar 

  • Watanabe N, Kobayashi Y (1994) Selective release of a processed form of interleukin-loc. Cytokine 6:597–601.

    Article  PubMed  CAS  Google Scholar 

  • Young PR, McDonnell PC, Laydon JT, Gallagher TF, Green D, Blumenthal MJ, McNulty D, Strickler JE, Kumar S, Heys JR, Adams JL, Landvatter SW, Lee JC (1994) A novel MAP kinase regulates the production of IL-1 and TNF in LPS activated human monocytes. Cytokine 6: 564.

    Google Scholar 

  • Zheng H, Fletcher D, Kozak W, Jiang M, Hofmann K, Conn CC, Siszynski D, Grabiec C, Trumbauer MA, Shaw AR, Kostura MJ, Stevens K, Rosen H, North RJ, Chen HY, Tocci MJ, Kluger MJ, Van der Ploeg LHT (1995) Resistance to fever induction and impaired acute-phase response in interleukin-1β deficient mice. Immunity (in press).

    Google Scholar 

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Dinarello, C.A. (1996). Cytokines as Mediators in the Pathogenesis of Septic Shock. In: Rietschel, E.T., Wagner, H. (eds) Pathology of Septic Shock. Current Topics in Microbiology and Immunology, vol 216. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-80186-0_7

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