Tumor necrosis factor (TNF)-alpha persistently activates nuclear factor-kappaB signaling through the type 2 TNF receptor in chromaffin cells: implications for long-term regulation of neuropeptide gene expression in inflammation.
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-alpha on neuropeptide secretion and biosynthesis in isolated bovine chromaffin cells. Here, we demonstrate that the type 2 TNF-alpha receptor (TNF-R2) mediates TNF-alpha signaling in chromaffin cells via activation of nuclear factor (NF)-kappaB. Microarray and suppression subtractive hybridization have been used to identify TNF-alpha target genes in addition to those encoding the neuropeptides galanin, vasoactive intestinal polypeptide, and secretogranin II in chromaffin cells. TNF-alpha, acting through the TNF-R2, causes an early up-regulation of NF-kappaB, long-lasting induction of the NF-kappaB target gene inhibitor kappaB (IkappaB), and persistent stimulation of other NF-kappaB-associated genes including mitogen-inducible gene-6 (MIG-6), which acts as an IkappaB signaling antagonist, and butyrate-induced transcript 1. Consistent with long-term activation of the NF-kappaB signaling pathway, delayed induction of neuropeptide gene transcription by TNF-alpha in chromaffin cells is blocked by an antagonist of NF-kappaB signaling. TNF-alpha-dependent signaling in neuroendocrine cells thus leads to a unique, persistent mode of NF-kappaB activation that features long-lasting transcription of both IkappaB and MIG-6, which may play a role in the long-lasting effects of TNF-alpha in regulating neuropeptide output from the adrenal, a potentially important feedback station for modulating long-term cytokine effects in inflammation.
Ait-Ali
Djida
D
Institut National de la Santé et de la Recherche Médicale Unité 413, University of Rouen, 76821 Mont-Saint-Aignan, France.
Turquier
Valérie
V
Tanguy
Yannick
Y
Thouënnon
Erwan
E
Ghzili
Hafida
H
Mounien
Lourdes
L
Derambure
Céline
C
Jégou
Sylvie
S
Salier
Jean-Philippe
JP
Vaudry
Hubert
H
Eiden
Lee E
LE
Anouar
Youssef
Y
D000311:Adrenal Glands / Q000166:cytology / Q000502:physiology; D000818:Animals; D002417:Cattle; D019439:Chromaffin Cells / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D017403:In Situ Hybridization; D007249:Inflammation / Q000503:physiopathology*; D016328:NF-kappa B / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D009479:Neuropeptides; D011994:Recombinant Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D012313:RNA