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Tumor Necrosis Factor (TNF)- Persistently Activates Nuclear Factor-B Signaling through the Type 2 TNF Receptor in Chromaffin Cells: Implications for Long-Term Regulation of Neuropeptide Gene Expression in Inflammation

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité (U) 413 (D.A.-A., V.T., Y.T., E.T., H.G., L.M., S.J., H.V., Y.A.), Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP23), University of Rouen, 76821 Mont-Saint-Aignan, France; INSERM U519 (C.D., J.-P.S.), European Institute for Peptide Research, Faculty of Medicine and Pharmacy, 76183 Rouen, France; and Section on Molecular Neuroscience (L.E.E., D.A.-A.), 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: Dr. Youssef Anouar, European Institute for Peptide Research (IFRM23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Médicale Unité 413, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: youssef.anouar{at}univ-rouen.fr.

Chromaffin cells of the adrenal medulla elaborate and secrete catecholamines and neuropeptides for hormonal and paracrine signaling in stress and during inflammation. We have recently documented the action of the cytokine TNF- on neuropeptide secretion and biosynthesis in isolated bovine chromaffin cells. Here, we demonstrate that the type 2 TNF- receptor (TNF-R2) mediates TNF- signaling in chromaffin cells via activation of nuclear factor (NF)-B. Microarray and suppression subtractive hybridization have been used to identify TNF- target genes in addition to those encoding the neuropeptides galanin, vasoactive intestinal polypeptide, and secretogranin II in chromaffin cells. TNF-, acting through the TNF-R2, causes an early up-regulation of NF-B, long-lasting induction of the NF-B target gene inhibitor B (IB), and persistent stimulation of other NF-B-associated genes including mitogen-inducible gene-6 (MIG-6), which acts as an IB signaling antagonist, and butyrate-induced transcript 1. Consistent with long-term activation of the NF-B signaling pathway, delayed induction of neuropeptide gene transcription by TNF- in chromaffin cells is blocked by an antagonist of NF-B signaling. TNF--dependent signaling in neuroendocrine cells thus leads to a unique, persistent mode of NF-B activation that features long-lasting transcription of both IB and MIG-6, which may play a role in the long-lasting effects of TNF- in regulating neuropeptide output from the adrenal, a potentially important feedback station for modulating long-term cytokine effects in inflammation.