Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice |
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Authors: | Eda Yildirim Michelle A Carey Jeffrey W Card Alexander Dietrich Gordon P Flake Yingpei Zhang J Alyce Bradbury Yvette Rebolloso Dori R Germolec Daniel L Morgan Darryl C Zeldin Lutz Birnbaumer |
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Affiliation: | Laboratory of Neurobiology, National Institutes of Health, Dept. of Health and Human Services, 111 T. W. Alexander Dr., Research Triangle Park, NC 27709. birnbau1@niehs.nih.gov. |
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Abstract: | Transient receptor potential channels (TRPCs) are widely expressed and regulate Ca(2+) entry in the cells that participate in the pathophysiology of airway hyperreactivity, inflammation, and remodeling. In vitro studies point to a role for TRPC1-mediated Ca(2+) signaling in several of these cell types; however, physiological evidence is lacking. Here we identify TRPC1 signaling as proinflammatory and a regulator of lung hyperresponsiveness during allergen-induced pulmonary response. TRPC1-deficient (Trpc1(-/-)) mice are hyposensitive to methacholine challenge and have significantly reduced allergen-induced pulmonary leukocyte infiltration coupled with an attenuated T helper type 2 (Th2) cell response. Upon in vitro allergen exposure, Trpc1(-/-) splenocytes show impaired proliferation and T cell receptor-induced IL-2 production. A high number of germinal centers in spleens of Trpc1(-/-) mice and elevated levels of immunoglobulins in their serum are indicative of dysregulated B cell function and homeostasis. Thus we propose that TRPC1 signaling is necessary in lymphocyte biology and in regulation of allergen-induced lung hyperresponsiveness, making TRPC1 a potential target for treatment of immune diseases and asthma. |
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