TUMOR-NECROSIS-FACTOR-ALPHA INDUCES SUBSTANCE-P IN SYMPATHETIC-GANGLIA THROUGH SEQUENTIAL INDUCTION OF INTERLEUKIN-1 AND LEUKEMIA INHIBITORY FACTOR

The present study establishes that tumor necrosis factor-alpha (TNF-alpha) induction of sympathetic substance P (SP) requires sequential induction of both interleukin (IL-I) and leukemia inhibitory factor (LIF), TNF-alpha dose-dependently induces SP, an induction that is secondary to an increase in the SP precursor, preprotachykinin (PPT), mRNA, Since TNF-alpha conditioned medium (CM) mimics the effect of TNF-alpha by raising SP, actions that are not antagonized by a neutralizing TNF-alpha antibody, TNF-alpha induction of SP is mediated by a soluble intermediate or intermediates, The blockade of TNF-alpha action by a specific IL-1 receptor antagonist and the induction of IL-1 mRNA by TNF-alpha suggest that IL-1 is one of the intermediates, Moreover, because immunoprecipitation with LIF antibodies decreases SP-inducing activity of TNF-alpha CM, and because LIF mRNA is also induced by TNF-alpha, LIF is a second intermediate, Furthermore, TNF-alpha-induced LIF mRNA is blocked by the IL-1 receptor antagonist, whereas IL-1-induced LIF mRNA is not affected by TNF-alpha antibodies, suggesting that TNF-alpha first induces IL-1, and IL-1 subsequently induces LIF. These data suggest that TNF-alpha induces SP in sympathetic ganglia through the sequential inductions of IL-1 and LIF. (C) 1995 John Wiley & Sons, Inc.