Inhibition of NF-kappaB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide.
Calcitonin gene-related peptide (CGRP) is a neuropeptide produced by the central and peripheral nervous systems and by endocrine cells. CGRP exerts diverse biological effects on the cardiovascular, gastrointestinal, respiratory, central nervous and immune systems. Little is known, however, about the molecular mechanisms that mediate CGRP effects. Using the NFkappaB-luciferase reporter transgenic mice, here we show that CGRP selectively inhibits NF-kappaB-mediated transcription in thymocytes in vitro and in vivo. In contrast, CGRP does not affect transcription mediated by the AP-1 and NFAT transcription factors. CGRP inhibits the accumulation of NF-kappaB complexes in the nucleus by preventing phosphorylation and degradation of the NF-kappaB inhibitor IkappaB. Inhibition of NF-kappaB activity is associated with the induction of apoptosis by CGRP in thymocytes. Together these results demonstrate for the first time the selective implication of the NF-kappaB signaling pathway in the regulatory function of the neuropeptide CGRP. Our study suggests a potential molecular mechanism by which CGRP can induce cell death in thymocytes.
Millet
I
I
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Phillips
R J
RJ
Sherwin
R S
RS
Ghosh
S
S
Voll
R E
RE
Flavell
R A
RA
Vignery
A
A
Rincón
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D008156:Luciferases; D015740:Calcitonin Gene-Related Peptide