Regulation of nuclear factor-kappaB by corticotropin-releasing hormone in mouse thymocytes.
CRH, a major mediator of the stress response, has been shown to exert potent immunomodulatory effects in vivo, through mechanisms that have not been elucidated yet. To determine the molecular pathways mediating the proinflammatory effects of peripheral CRH, we studied its role in the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor crucial for the regulation of a variety of inflammatory mediator genes. Our studies demonstrate that, in mouse thymocytes, CRH induces the NF-kappaB DNA-binding activity in a time- and dose-dependent manner, with parallel degradation of its inhibitor protein inhibitor of NF-kappaB. The effect of CRH is not inhibited by dexamethasone and is mediated by the protein kinase A and protein kinase C signaling pathways. In vivo, we show that CRH-deficient mice respond to lipopolysaccharide administration by reduced activation of thymus NF-kappaB, despite their significantly elevated proinflammatory cytokine and their low corticosterone levels. These findings suggest a putative molecular pathway mediating the proinflammatory effects of peripheral CRH through induction of the NF-kappaB DNA binding activity.
Zhao
Jie
J
Division of Endocrinology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Karalis
Katia P
KP
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009838:Oligodeoxyribonucleotides; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C