Interleukin 1-induced pathophysiology: induction of cytokines, development of histopathologic changes, and immunopharmacologic intervention

Abstract

In this report, we describe a murine system in which treatment with recombinant human interleukin 1 (IL-1) induced an acute lethal state with pathologic changes similar to septic shock at high doses and development of arthritic and other tissue changes following more prolonged treatment with lower doses. We have demonstrated that both recombinant human interleukin 1 alpha and recombinant human interleukin 1 beta could be administered to an endotoxin hyporesponsive strain, C3H/HeJ, and produce these pathologic changes. Induction of tumor necrosis factor (TNF) and colony-stimulating factor activity was noted. The ability to induce these changes was dose and time dependent. Histopathologic changes included lesions in the lung, heart, liver, adrenal glands, intestines, and joints. Neutrophil infiltration was a prominent feature in many organs. Drugs, immunotherapy, or other treatments which have been effective in delaying or preventing a lethal syndrome induced following high dose interleukin 2 therapy were not effective in preventing the interleukin 1-induced lethal syndrome. Interestingly, pretreatment with low nonlethal doses of IL-1 (but not lipopolysaccharides or TNF) could prevent deaths from an LD100 challenge dose of IL-1.