Interleukin‐12 Induces Sustained Activation of Multiple Host Inflammatory Mediator Systems in Chimpanzees

Fanny N. Lauw, Pascale E. P. Dekkers, Anje A. te Velde, Peter Speelman, Marcel Levi, Masashi Kurimoto, C. Erik Hack, Sander J. H. van Deventer, Tom van der Poll
1999 Journal of Infectious Diseases  
To determine in vivo effects of interleukin (IL)-12 on host inflammatory mediator systems, 4 healthy chimpanzees received recombinant human IL-12 (1 mg/kg) by intravenous injection. IL-12 induced increases in plasma concentrations of IL-15, IL-18, and interferon-g (IFN-g), plus a marked antiinflammatory cytokine response (IL-10, soluble tumor necrosis factor [TNF] receptors, IL-1 receptor antagonist) and secretion of a-chemokines (IL-8, IFN-g-inducible protein 10) and b-chemokines (monocyte
more » ... kines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1b). In addition, IL-12 elicited neutrophilic leukocytosis, neutrophil degranulation (elastase-a 1 -antitrypsin complexes), coagulation activation (F1 ϩ 2 prothrombin fragment, thrombin-antithrombin III complexes), and fibrinolytic activation (tissue-type plasminogen activator, plasmin-a 2 -antiplasmin complexes). IL-12-induced activation of multiple host mediator systems was found only after 8-24 h, remained detectable until the end of the 48-h observation period, and occurred in the absence of detectable TNF and IL-1b. These data may contribute to understanding the role of IL-12 in the pathogenesis of sepsis syndrome and the toxicity found after repeated injections of IL-12. Interleukin (IL)-12 is a heterodimeric proinflammatory cytokine formed by two covalently linked subunits of 35 kDa (p35) and 40 kDa (p40) [1]. Both chains, which are encoded by different and unrelated genes, have to be produced for the formation of the biologically active p70 heterodimer. The main producer cells of IL-12 are monocytes, macrophages, and other antigen-presenting cells. The most potent stimuli for IL-12 production are bacteria, bacterial products (e.g., endotoxin), and intracellular parasites. Most biologic effects of IL-12 involve activities on NK cells and T lymphocytes. IL-12 can induce the production of interferon-g (IFN-g) and other cytokines and enhances cytotoxic activities of NK and lymphokine-activated
doi:10.1086/314636 pmid:9952371 fatcat:6hesrs6bmfhj5csq6pbslzfpua