Tumor necrosis factor alpha enhances nicotinic receptor up-regulation via a p38MAPK-dependent pathway.

A response by key neuronal nicotinic acetylcholine receptors (nAChRs) to sustained nicotine exposure is up-regulation. Although this unusual receptor characteristic contributes to processes ranging from aging to addiction, the normal physiologic reason for this response is unknown. We find that up-regulation of [(3)H]epibatidine binding and function in HEK293 cells stably expressing alpha4beta2-nAChR is significantly enhanced by co-application of the proinflammatory cytokine, tumor necrosis factor alpha. The mechanism of tumor necrosis factor alpha-enhanced up-regulation requires transcription, new protein synthesis, and signaling through p38(MAPK) as demonstrated by complete inhibition using SB 202190. This finding extends the possibilities for nAChR-inflammatory interactions in normal physiological processes and offers novel insights into endogenous mechanisms that can modify up-regulation.