Interleukin‐6‐mediated signaling in adrenal medullary chromaffin cells

The pro‐inflammatory cytokines, tumor necrosis factor‐α, and interleukin‐1β/α modulate catecholamine secretion, and long‐term gene regulation, in chromaffin cells of the adrenal medulla. Since interleukin‐6 (IL6) also plays a key integrative role during inflammation, we have examined its ability to affect both tyrosine hydroxylase activity and adrenomedullary gene transcription in cultured bovine chromaffin cells. IL6 caused acute tyrosine/threonine phosphorylation of extracellular signal‐regulated kinase 1/2 (ERK1/2), and serine/tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Consistent with ERK1/2 activation, IL6 rapidly increased tyrosine hydroxylase phosphorylation (serine‐31) and activity, as well as up‐regulated genes, encoding secreted proteins including galanin, vasoactive intestinal peptide, gastrin‐releasing peptide, and parathyroid hormone‐like hormone. The effects of IL6 on the entire bovine chromaffin cell transcriptome were compared to those generated by G‐protein‐coupled receptor (GPCR) agonists (histamine and pituitary adenylate cyclase‐activating polypeptide) and the cytokine receptor agonists (interferon‐α and tumor necrosis factor‐α). Of 90 genes up‐regulated by IL6, only 16 are known targets of IL6 in the immune system. Those remaining likely represent a combination of novel IL6/STAT3 targets, ERK1/2 targets and, potentially, IL6‐dependent genes activated by IL6‐induced transcription factors, such as hypoxia‐inducible factor 1α. Notably, genes induced by IL6 include both neuroendocrine‐specific genes activated by GPCR agonists, and transcripts also activated by the cytokines. These results suggest an integrative role for IL6 in the fine‐tuning of the chromaffin cell response to a wide range of physiological and paraphysiological stressors, particularly when immune and endocrine stimuli converge. The cytokine interleukin‐6 (IL6) plays a key integrative role during inflammation. While it was shown that other pro‐inflammatory cytokines modulate catecholamine secretion and long‐term gene regulation in chromaffin cells of the adrenal medulla the effect of IL6 in these cells remains elusive. We provide evidence that IL6 interacts directly with those cells to rapidly increase the phosphorylation and activity of the catecholamine‐synthesizing enzyme tyrosine hydroxylase. Prolonged exposure to IL6 increased the expression of a wide range of genes, including those for a number of biologically active neurope