Tumor Necrosis Factor‐α Regulates Nicotinic Responses in Mixed Cultures of Sympathetic Neurons and Nonneuronal Cells

It is recognized that tumor necrosis factor‐α (TNF‐α), a pleiotropic cytokine, influences hormone secretion and transmitter release from central neurons. To examine the role of TNF‐α as a modulator of autonomic function of the PNS, we measured [ 3 H]norepinephrine ([ 3 H]NE) secretion evoked by 1,1‐dimethyl‐4‐phenylpiperazinium iodide (DMPP), a nicotinic agonist, in cultures from neonatal rat superior cervical ganglia (SCG). We found that (1) DMPP‐evoked [ 3 H]NE secretion was enhanced in SCG mixed cultures treated for 48 h with recombinant human TNF‐α (rhTNF‐α) plus rat interferon‐γ (IFN‐γ) but not in cultures treated with either cytokine alone; (2) an increase in [ 3 H]NE secretion was also observed in mixed cultures treated with recombinant murine TNF‐α (rmTNF‐α) alone; and (3) the presence of nonneuronal cells or soluble factors released by them was required for the effect of these cytokines on secretion. Electrophysiologic experiments revealed an increase in nicotinic receptor current density in neurons from mixed cultures treated with rhTNF‐α plus IFN‐γ or with rmTNF‐α when compared with control cultures. We conclude that prolonged exposure to rhTNF‐α plus IFN‐γ or rmTNF‐α regulates nicotinic responses in SCG cultures via a soluble factor or factors secreted by nonneuronal cells.