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The Proinflammatory Cytokines Tumor Necrosis Factor- and Interleukin-1 Stimulate Neuropeptide Gene Transcription and Secretion in Adrenochromaffin Cells via Activation of Extracellularly Regulated Kinase 1/2 and p38 Protein Kinases, and Activator Protein-1 Transcription Factors

Laboratory of Cellular and Molecular Neuroendocrinology (D.A.-A., V.T., L.G., L.Y., M. J., D.A., H.V., Y.A.), European Institute for Peptide Research (IFRMP 23), Institut National de la Santé et de la Recherche Médicale Unité 413, Unité Associée Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan, France; and Section on Molecular Neuroscience (L.E.E.), Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Hubert Vaudry, European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Médicale Unité 413, Unité Associée Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: hubert.vaudry{at}univ-rouen.fr.

Immune-autonomic interactions are known to occur at the level of the adrenal medulla, and to be important in immune and stress responses, but the molecular signaling pathways through which cytokines actually affect adrenal chromaffin cell function are unknown. Here, we studied the effects of the proinflammatory cytokines, TNF- and IL-1, on gene transcription and secretion of bioactive neuropeptides, in primary bovine adrenochromaffin cells. TNF- and IL-1 induced a time- and dose-dependent increase in galanin, vasoactive intestinal polypeptide, and secretogranin II mRNA levels. The two cytokines also stimulated the basal as well as depolarization-provoked release of enkephalin and secretoneurin from chromaffin cells. Stimulatory effects of TNF- on neuropeptide gene expression and release appeared to be mediated through the type 2 TNF- receptor, and required activation of ERK 1/2 and p38, but not Janus kinase, MAPKs. In addition, TNF- increased the binding activity of activator protein-1 (AP-1) and stimulated transcription of a reporter gene containing AP-1-responsive elements in chromaffin cells. The AP-1-responsive reporter gene could also be activated through the ERK pathway. These results suggest that neuropeptide biosynthesis in chromaffin cells is regulated by TNF- via an ERK-dependent activation of AP-1-responsive gene elements. Either locally produced or systemic cytokines might regulate biosynthesis and release of neuropeptides in chromaffin cells, integrating the adrenal medulla in the physiological response to inflammation. This study describes, for the first time, a signal transduction pathway activated by TNF- in a major class of neuroendocrine cells that, unlike TNF- signaling in lymphoid cells, employs ERK and p38 rather than Janus kinase and p38 to transmit gene-regulatory signals to the cell nucleus.

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