Abstract
The present study establishes that tumor necrosis factor‐α (TNF‐α) induction of sympathetic substance P (SP) requires sequential induction of both interleukin (IL‐1) and leukemia inhibitory factor (LIF). TNF‐α dose‐dependently induces SP, an induction that is secondory to an increase in the SP precursor, preprotachykinin (PPT), mRNA. Since TNF‐α conditioned medium (CM) mimics the effect of TNF‐α by raising SP, actions that are not antagonized by a neutralizing TNF‐α antibody, TNF‐α induction of SP is mediated by a soluble intermediate or intermediates. The blockade of TNF‐α action by a specific IL‐1 receptor antagonist and the induction of IL‐1 mRNA by TNF‐α suggest that IL‐1 is one of the intermediates. Moreover, because immunoprecipitation with LIF antibodies decreases SP‐inducing activity of TNF‐α CM, and because LIF mRNA is also induced by TNF‐α, LIF is a second intermediate. Furthermore, TNF‐α‐induced LIF mRNA is blocked by the IL1 receptor antagonist, whereas IL‐1‐induced LIF mRNA is not affected by TNF‐α antibodies, suggesting that TNF‐α first induces IL‐1, and IL‐1 subsequently induces LIF. These data suggest that TNF‐α induces SP in sympathetic ganglia through the sequential inductions of IL1 and LIF. © 1995 John Wiley & Sons, Inc.