Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia.

Although studies with interleukin-1 receptor antagonist (IL-1ra) in animal models have shown that IL-1 contributes to mortality in sepsis, the mechanisms whereby IL-1 mediates lethal effects are not well established. A possible mechanism is that IL-1 enhances the activation and release of other inflammatory mediator systems such as coagulation, fibrinolysis, neutrophils, and secretory-type phospholipase A2 (sPLA2). We investigated this possibility by assessing the effect of intravenously injected recombinant human IL-1 alpha (rhIL-1 alpha) on these plasma parameters in baboons. In addition, we examined the course of these inflammatory parameters in baboons after a challenge with a lethal dose of Escherichia coli and while receiving a 24-hour constant infusion of IL-1ra or placebo. Intravenous administration of IL-1 alpha (10 micrograms/kg) induced the formation of thrombin, as evidenced by the appearance of thrombin-antithrombin III (TAT) complexes into the circulation (peak levels, 188 +/- 92 ng/mL at 2 hours), as well as the activation of fibrinolysis, assessed by circulating plasmin-alpha 2-antiplasmin complexes (PAP complexes; peak levels, 0.4% +/- 0.03% of fully activated plasma at 1 hour), the release of tissue-type plasminogen activator (t-PA; peak levels, 6 +/- 2 ng/mL at 2 hours), and its inhibitor, plasminogen activator inhibitor (PAI; peak levels, 724 +/- 246 ng/mL at 4 hours). Il-1 alpha administration also induced the release of sPLA2 (maximal levels, 336 +/- 185 ng/mL at 8 hours), but not degranulation of neutrophils. In the septic baboons, a significant reduction of the formation of thrombin (peak TAT levels decreased from 582 +/- 78 ng/mL to 219 +/- 106 ng/mL; P < .005), the release of t-PA (peak levels decreased from 37 +/- 11 ng/mL to 17 +/- 2 ng/mL; P < .001), and its inhibitor, PAI (peak levels decreased from 2,639 +/- 974 ng/mL to 1,110 +/- 153 ng/mL; P <.001), was observed in the group receiving IL-1ra compared to that receiving placebo. The release of neutrophilic elastase was also significantly attenuated in IL-1a-treated animals (peak levels, 1,024 +/- 393 and 655 +/- 104 ng/mL in control and treatment groups, respectively; P < .05). The difference between sPLA2 levels in both groups, although higher in the controls (maximal levels, 3,140 +/- 1,435 ng/mL in control v 2,217 +/- 1,375 ng/mL in IL-1ra-treated group), was not significant. Thus, IL-1 contributes to activation of various other mediator systems in severe sepsis in nonhuman primates. We propose that these effects may explain the lethal actions of IL-1 in this sepsis model and suggest a similar role for IL-1 in severe human sepsis.

[1]  M. Boermeester,et al.  Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. , 1995, Archives of surgery.

[2]  R. F. Johnston,et al.  Recombinant Human Interleukin 1 Receptor Antagonist in the Treatment of Patients With Sepsis Syndrome: Results From a Randomized, Double-blind, Placebo-Controlled Trial , 1994 .

[3]  C. Elbim,et al.  Differential priming effects of proinflammatory cytokines on human neutrophil oxidative burst in response to bacterial N-formyl peptides , 1994, Infection and immunity.

[4]  T. van der Poll,et al.  Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. , 1994, Blood.

[5]  L. Touqui,et al.  Increased synthesis and secretion of a 14-kDa phospholipase A2 by guinea pig alveolar macrophages. Dissociation from arachidonic acid liberation and modulation by dexamethasone. , 1993, Journal of immunology.

[6]  R. Bone,et al.  Plasma Cytokine and Endotoxin Levels Correlate with Survival in Patients with the Sepsis Syndrome , 1993, Annals of Internal Medicine.

[7]  H. Redl,et al.  Tumor necrosis factor is a mediator of phospholipase release during bacteremia in baboons. , 1993, The American journal of physiology.

[8]  M. Murakami,et al.  Molecular nature of phospholipases A2 involved in prostaglandin I2 synthesis in human umbilical vein endothelial cells. Possible participation of cytosolic and extracellular type II phospholipases A2. , 1993, The Journal of biological chemistry.

[9]  D. Remick,et al.  Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. , 1992, The Journal of clinical investigation.

[10]  R. Ward,et al.  Measurement of human phospholipase A2 in arthritis plasma using a newly developed sandwich ELISA. , 1992, British journal of rheumatology.

[11]  R. Colman,et al.  Plasma elastase alpha 1-antitrypsin and lactoferrin in sepsis: evidence for neutrophils as mediators in fatal sepsis. , 1992, The Journal of laboratory and clinical medicine.

[12]  T. J. Hayes,et al.  Comparison between effects of interleukin-1 alpha administration and sublethal endotoxemia in primates. , 1991, The American journal of physiology.

[13]  L. Moldawer,et al.  IL-8 in septic shock, endotoxemia, and after IL-1 administration. , 1991, Journal of immunology.

[14]  C. Dinarello.  Interleukin-1 and interleukin-1 antagonism. , 1991, Blood.

[15]  J. Norton,et al.  A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice , 1991, The Journal of experimental medicine.

[16]  C. Dinarello,et al.  A specific receptor antagonist for interleukin 1 prevents Escherichia coli‐induced shock in rabbits , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  H. Imura,et al.  Effects of interleukins on plasma arginine vasopressin and oxytocin levels in conscious, freely moving rats. , 1991, Biochemical and biophysical research communications.

[18]  C. Hack,et al.  PAI-1 Synthesis in the Human Hepatoma Cell Line Hep G2 Is Increased by Cytokines - Evidence that the Liver Contributes to Acute Phase Behaviour of PAI-1 , 1991, Thrombosis and Haemostasis.

[19]  Robert C. Thompson,et al.  Interleukin-1 receptor antagonist reduces mortality from endotoxin shock , 1990, Nature.

[20]  F. Sendo,et al.  Vascular hyperpermeability induced by tumor necrosis factor and its augmentation by IL-1 and IFN-gamma is inhibited by selective depletion of neutrophils with a monoclonal antibody. , 1990, Journal of immunology.

[21]  T. van der Poll,et al.  Activation of coagulation after administration of tumor necrosis factor to normal subjects. , 1990, The New England journal of medicine.

[22]  B. Dularay,et al.  Recombinant Human Interleukin‐1 Beta Primes Human Polymorphonuclear Leukocytes for Stimulus‐Induced Myeloperoxidase Release , 1990, Journal of Leukocyte Biology.

[23]  J. Parrillo,et al.  Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. , 1989, The New England journal of medicine.

[24]  G. Mandell,et al.  Both Recombinant Interleukin‐1 (Beta) and Purified Human Monocyte Interleukin‐1 Prime Human Neutrophils for Increased Oxidative Activity and Promote Neutrophil Spreading , 1989, Journal of leukocyte biology.

[25]  M. Gimbrone,et al.  Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. , 1988, The Journal of biological chemistry.

[26]  K. Tracey,et al.  Cytokine appearance in human endotoxemia and primate bacteremia. , 1988, Surgery, gynecology & obstetrics.

[27]  E. Dennis.  Regulation of Eicosanoid Production: Role of Phospholipases and Inhibitors , 1987, Bio/Technology.

[28]  J. Cajot,et al.  Mapping of Epitopes on Human Tissue-Type Plasminogen Activator with Recombinant Deletion Mutant Proteins , 1987, Thrombosis and Haemostasis.

[29]  W. Fiers,et al.  Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Stern,et al.  Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[31]  T. Kooistra,et al.  Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells , 1986, The Journal of experimental medicine.

[32]  M. Gilbert,et al.  Tissue plasminogen activator release in vivo in response to vasoactive agents. , 1985, Blood.

[33]  R. Cotran,et al.  Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells , 1984, The Journal of experimental medicine.

[34]  C. Hack,et al.  Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. , 1993, Circulatory shock.

[35]  C. Hack,et al.  The Orchestra of Mediators in the Pathogenesis of Septic Shock: A Review , 1991 .

[36]  E. Wijelath,et al.  Interleukin-one induced arachidonic acid turnover in macrophages. , 1990, Autoimmunity.

[37]  A. Kharazmi,et al.  Recombinant interleukin 1 alpha and beta prime human monocyte superoxide production but have no effect on chemotaxis and oxidative burst response of neutrophils. , 1988, Immunobiology.

[38]  A. Ferrante,et al.  Effects of tumour necrosis factor alpha and interleukin-1 alpha and beta on human neutrophil migration, respiratory burst and degranulation. , 1988, International archives of allergy and applied immunology.