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

Abstract

A Shwartzman-like reaction was elicited in rabbits by preparing the skin with intradermal injections of recombinant human tumor necrosis factor .alpha. (TNF.alpha.) and recombinant human interleukin-1 (IL-1.alpha. or .beta.). The animals were challenged intravenously with endotoxin or by intravascular activation of complement with immune complexes or zymosan 18 hours later and were sacrificed after another 2 hours. Animals challenged with saline did not develop Shwartzman-like reactions. The sites prepared with endotoxin or with either form of IL-1 plus TNF.alpha. developed visible hemorrhage, whereas sites injected with either IL-1 or TNF.alpha. alone did not. Hemorrhage and microthrombosis were quantitated with 59Fe-labeled erythrocytes and 111In-platelets for 2 hours after the intravenous challenge, and the findings confirmed the observations made on gross inspection. Dermal sites prepared with the cytokines and challenged intravenously with endotoxin, immune complexes, or zymosan exhibited some diffuse hemorrhage and an intense erythrocyte extravasation around distended vessels, along skin appendages, and the panniculus carnosus muscle. The lumens of many large and postcapillary venules contained aggregates of platelets and leukocytes. These changes were superimposed on those seen at prepared sites (leukocyte infiltration). By electron microscopy fibrin was demonstrable in association with the formed elements of the blood. Histologic examination of the 18-hour-old preparative lesions or 20-hour-old lesions of saline-"challenged" animals revealed accumulation of leukocytes in the dermis, predominantly neutrophils. This accumulation was sparse at sites treated with only IL-1 or TNF.alpha., but very intense at sites treated with both IL-1 and TNF.alpha. or with endotoxin. These observations were confirmed quantitatively by measuring the accumulation of 51Cr-labeled neutrophils for 2 hours after injection. The potency of IL-1.alpha. was comparable to that in our earlier report, and TNF.alpha. was about three log times less potent. Sites treated with both IL-1.alpha. and TNF.alpha. resulted in 69% greater neutrophil emigration than the additive response elicited by each cytokine. The reported finding implicate a synergism between IL-1 and TNF.alpha. in the induction of both the inflammatory reaction (preceding the Shwartzman reaction) and the thrombohemorrhagic component of the Shwartzman reaction proper.