QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.019539v1 mol.105.019539v2 69/3/998    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cao, J. Articles by Theoharides, T. C. Search for Related Content PubMed PubMed Citation Articles by Cao, J. Articles by Theoharides, T. C.

Corticotropin-Releasing Hormone Induces Vascular Endothelial Growth Factor Release from Human Mast Cells via the cAMP/Protein Kinase A/p38 Mitogen-Activated Protein Kinase Pathway

Departments of Biochemistry, Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (J.C., T.C.T.); and Departments of Internal Medicine (T.C.T.) and Obstetrics and Gynecology (C.L.C.), Tufts-New England Medical Center, Boston, Massachusetts

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 and human umbilical cord blood-derived mast cells to release newly synthesized vascular endothelial growth factor (VEGF) without release of either preformed mediators or cytokines. This effect was mediated through the 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 N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89) or the p38 mitogen-activated protein kinase (MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) but not by the specific inhibitor 2'-amino-3'-methoxyflavone (PD98059) of mitogen-activated protein kinase kinase, the upstream kinase of the extracellular signal-regulated protein kinase (ERK) or the c-Jun N-terminal kinase (JNK) inhibitor 1,9-pyrazoloanthrone anthra-(1,9-cd)pyrazol-6(2H)-one (SP600125). Furthermore, CRH significantly increased protein kinase A activity, which could be mimicked by the cell-permeable cAMP analog 8-bromo-cAMP, and was blocked by H89 or the adenylate cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (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.

Address correspondence to: Dr. T. C. Theoharides, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111. E-mail: theoharis.theoharides{at}tufts.edu

This article has been cited by other articles:

				A. L. Christy and M. A. Brown The Multitasking Mast Cell: Positive and Negative Roles in the Progression of Autoimmunity J. Immunol., September 1, 2007; 179(5): 2673 - 2679. [Abstract] [Full Text] [PDF]

				A. C Moss, P. Anton, T. Savidge, P. Newman, A. S Cheifetz, J. Gay, S. Paraschos, M. W. Winter, M. P Moyer, K. Karalis, et al. Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2{alpha} Gut, September 1, 2007; 56(9): 1210 - 1217. [Abstract] [Full Text] [PDF]

				M. Guilarte, J. Santos, I. de Torres, C. Alonso, M. Vicario, L. Ramos, C. Martinez, F. Casellas, E. Saperas, and J. R. Malagelada Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum Gut, February 1, 2007; 56(2): 203 - 209. [Abstract] [Full Text] [PDF]

				A. Punn, M. A. Levine, and D. K. Grammatopoulos Identification of Signaling Molecules Mediating Corticotropin-Releasing Hormone-R1{alpha}-Mitogen-Activated Protein Kinase (MAPK) Interactions: The Critical Role of Phosphatidylinositol 3-Kinase in Regulating ERK1/2 But Not p38 MAPK Activation Mol. Endocrinol., December 1, 2006; 20(12): 3179 - 3195. [Abstract] [Full Text] [PDF]