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Received for publication October 18, 2005.
Revised November 18, 2005.
Accepted for publication December 5, 2005.
Mast cells are involved in allergic reactions, but also in innate immunity and inflammation. Corticotropin-releasing hormone (CRH), the key regulator of the hypothalamic-pituitary-adrenal axis, also has proinflammatory effects, apparently through mast cells. We showed recently that CRH selectively stimulates human leukemic mast cells (HMC-1) and human umbilical cord blood-derived mast cells (hCBMC) to release newly synthesized vascular endothelial growth factor (VEGF) without release of either preformed mediators or cytokines. This effect was mediated through activation of CRH receptor-1 and adenylate cyclase with increased intracellular cAMP. However, the precise mechanism by which CRH induces VEGF secretion has not yet been defined. Here, we show that CRH-induced VEGF release was dose-dependently inhibited by the specific protein kinase A inhibitor H89 or the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, but not by the specific inhibitor PD98059 of MEK, the upstream kinase of the extracellular signal-regulated protein kinase (ERK) or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Furthermore, CRH significantly increased protein kinase A activity, which could be mimicked by the cell-permeable cAMP analogue 8-bromo-cAMP, and was blocked by H89 or the adenylate cyclase inhibitor SQ22536. CRH also induced rapid phosphorylation of p38 MAPK, which was mimicked by 8-bromo-cAMP and was inhibited by H89 or SB203580. CRH did not stimulate ERK or JNK phosphorylation and did not increase intracellular calcium levels. These results indicate that CRH induces VEGF release in human mast cells via selective activation of the cAMP/protein kinase A/p38 MAPK signaling pathway, thereby providing further insight into the molecular mechanism of how CRH affects the release of a key proinflammatory mediator.
Key words:
CRF, Interleukins, Adenylyl cyclases, cAMP, Protein Kinase A, MAP Kinase, Jun Kinase, P38 MAP Kinase, Func. analysis receptor/ion channel mutants, Leukocytes/Mast cells
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