title: Interleukin-6-mediated signaling in adrenal medullary chromaffin cells.
abstract: 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.
authors: Department of Anatomy, Centre for Neuroendocrinology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors: Danielle E
authors: DE
authors: Jenkins
authors: Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.
authors: Dharshini
authors: D
authors: Sreenivasan
authors: Department of Anatomy, Centre for Neuroendocrinology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors: Fiona
authors: F
authors: Carman
authors: Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, MD, USA.
authors: Babru
authors: B
authors: Samal
authors: Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, MD, USA.
authors: Lee E
authors: LE
authors: Eiden
authors: Department of Anatomy, Centre for Neuroendocrinology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors: Stephen J
authors: SJ
authors: Bunn
mesh_terms: D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor
keywords: STAT3; chromaffin cell; cytokine; inflammation; interleukin-6; tyrosine hydroxylase