INTERFERON-GAMMA OVERCOMES GLUCOCORTICOID SUPPRESSION OF CACHECTIN TUMOR-NECROSIS-FACTOR BIOSYNTHESIS BY MURINE MACROPHAGES

Glucocorticoids almost completely inhibit the synthesis by isolated macrophages of cachectin/tumor necrosis factor (TNF), a cytokine implicated as a major endogenous mediator of septic shock. Despite this in vitro effectiveness, the clinical use of glucocorticoids has failed to demonstrate any clear benefit in the treatment of septic shock. In an effort to understand what other mechanisms might play a role in the patient with sepsis, we examined the effect of interferon-γ (IFNγ) on the synthesis of cachectin/TNF. We show here that IFNγ, although unable by itself to induce cachectin/TNF synthesis, enhanced the endotoxin-induced production of cachectin/TNF in vitro. Furthermore, IFNγ overcame the inhibition of cachectin/TNF synthesis caused by the glucocorticoid, dexamethasone. These effects of IFNγ were accounted for by increased levels of cachectin/TNF mRNA. The in vivo implications of these studies are discussed with emphasis on their relevance in human sepsis.