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This version published online on April 15, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0129
A more recent version of this article appeared on July 1, 2004
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Submitted on April 10, 2003
Accepted on April 6, 2004

The Pro-inflammatory Cytokines TNF-{alpha} and IL-1 Stimulate Neuropeptide Gene Transcription and Secretion in Adrenochromaffin Cells Via Activation of ERK 1/2 and p38 Protein Kinases, and Activator Protein-1 Transcription Factors

DJIDA AIT-ALI, VALERIE TURQUIER, LUCA GRUMOLATO, LAURENT YON, MATTHIEU JOURDAIN, DAVID ALEXANDRE, LEE E. EIDEN, HUBERT VAUDRY*, and YOUSSEF ANOUAR

European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U413, UA CNRS, University of Rouen (D.A-A., V.T., L.G., L.Y., M. J., D.A., H.V., Y.A.), 76821 Mont-Saint-Aignan, France and Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health (L.E.E.), Bethesda, Maryland 20892, USA

* To whom correspondence should be addressed. 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 pro-inflammatory cytokines TNF-{alpha} and IL-1 on gene transcription and secretion of bioactive neuropeptides, in primary bovine adrenochromaffin cells. TNF-{alpha} 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-{alpha} on neuropeptide gene expression and release appeared to be mediated through the type 2 TNF-{alpha} receptor, and required activation of ERK 1/2 and p38, but not JNK, MAP kinases. In addition, TNF-{alpha} increased the binding activity of activator protein-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-{alpha} 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-{alpha} in a major class of neuroendocrine cells that, unlike TNF-{alpha} signaling in lymphoid cells, employs ERK and p38 rather than JNK and p38 to transmit gene-regulatory signals to the cell nucleus.
Key words: Pro-inflammatory cytokines • Neuropeptides • Chromaffin cells • ERK 1/2 MAP kinases • AP-1 • Gene expression




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