RESUMO
Calcitonin gene-related peptide (CGRP) has inflammatory and immunoregulatory properties. CGRP directly inhibits IL-7 induced proliferation in developing B cells and also induces soluble factors that inhibit IL-7 responses. We identified 2 cytokines, IL-6 and TNF-alpha, induced by CGRP, that inhibit IL-7 pre-B cell responses. CGRP induction of IL-6 and TNF-alpha mRNA in long-term bone marrow cultures is transient and IL-6 or TNF-alpha inhibit IL-7 induced colony formation by 60%. When added with CGRP, colony formation is completely inhibited. TNF-alpha directly inhibits IL-7 responses in B220(+)/IgM(-) cells whereas IL-6 inhibits only colony formation with whole bone marrow. This suggests that the effect of IL-6 is mediated by other cells in the bone marrow. These results suggest that the indirect effect of CGRP on IL-7 depends in part on induction of IL-6 and TNF-alpha.
Assuntos
Linfócitos B/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Interleucina-6/metabolismo , Interleucina-7/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/metabolismo , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Interleucina-6/imunologia , Interleucina-7/imunologia , Masculino , Camundongos , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/efeitos dos fármacos , Células-Tronco/imunologia , Células-Tronco/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide with regulatory influences on immune and inflammatory responses and early B lymphocyte differentiation. Little is known about its cellular mechanisms. These studies examined whether CGRP induces c-fos. CGRP induced a transient concentration-dependent increase in c-fos in a CGRP receptor expressing pre-B cell line, 70Z/3. CGRP did not induce c-jun, jun B or jun D. A protein kinase A (PKA) inhibitor blocked c-fos induction by CGRP, suggesting that the mechanism depends on cAMP induction of PKA. CGRP induced AP-1 binding activity in the nucleus, indicating that CGRP regulates expression of specific target genes. CGRP also induced c-fos in B220(+) enriched cells from bone marrow. These results suggest that regulatory influences of CGRP on early B cells and in other tissues can involve a cAMP/PKA, c-fos/AP-1-dependent pathway for regulation of specific genes.
