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The Journal of Immunology, 2005, 174: 7665-7675.
Copyright © 2005 by The American Association of Immunologists

Human Mast Cells Express Corticotropin-Releasing Hormone (CRH) Receptors and CRH Leads to Selective Secretion of Vascular Endothelial Growth Factor1

Jing Cao*,{dagger}, Nikoletta Papadopoulou{dagger}, Duraisamy Kempuraj{dagger}, William S. Boucher{dagger}, Koreaki Sugimoto2,{dagger}, Curtis L. Cetrulo{ddagger} and Theoharis C. Theoharides3,*,{dagger},§

Departments of* Biochemistry and {dagger} Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, and Departments of {ddagger} Obstetrics and Gynecology and § Internal Medicine, Tufts-New England Medical Center, Boston, MA 02111

Mast cells are critical for allergic reactions, but also for innate or acquired immunity and inflammatory conditions that worsen by stress. Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells. We detected mRNA for CRH-R1{alpha}, 1{beta}, 1c, 1e, 1f isoforms, as well as CRH-R1 protein in both cell types. CRH-R2{alpha} (but not R2{beta} or R2{gamma}) mRNA and protein were present only in human cord blood-derived mast cells. CRH increased cAMP and induced secretion of vascular endothelial growth factor (VEGF) without tryptase, histamine, IL-6, IL-8, or TNF-{alpha} release. The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist astressin 2B. CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536. This is the first evidence that mast cells express functional CRH receptors and that CRH can induce VEGF secretion selectively. CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress.




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