Published ahead of print on July 29, 2008, doi:10.1165/rcmb.2007-0102OC
© 2009 American Thoracic Society DOI: 10.1165/rcmb.2007-0102OC NFAT1 Transcription Factor Regulates Pulmonary Allergic Inflammation and Airway Responsiveness1 Division of Cellular Biology, National Cancer Institute (INCA); 2 Laboratory of Inflammation, Department of Physiology and Pharmacodynamics, Oswaldo Cruz Foundation (FIOCRUZ); and 3 Multidisciplinary Laboratory, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil Correspondence and requests for reprints should be addressed to João P.B. Viola, M.D., Ph.D., Divisão de Biologia Celular, Instituto Nacional de Câncer, Rua André Cavalcanti 37, Rio de Janeiro 20231-050, Brasil. E-mail: jpviola{at}inca.gov.br Allergic asthma is a chronic inflammatory disease of the lung whose incidence and morbidity continues to rise in developed nations. Despite being a hallmark of asthma, the molecular mechanisms that determine airway hyperresponsiveness (AHR) are not completely established. Transcription factors of the NFAT family are involved in the regulation of several asthma-related genes. It has been shown that the absence of NFAT1 leads to an increased pleural eosinophilic allergic response accompanied by an increased production of Th2 cytokines, suggesting a role for NFAT1 in the regulation of allergic diseases. Herein, we analyze NFAT1–/– mice to address the role of NFAT1 in a model of allergic airway inflammation and its influence in AHR. NFAT1–/– mice submitted to airway inflammation display a significant exacerbation of several features of the allergic disease, including lung inflammation, eosinophilia, and serum IgE levels, which were concomitant with elevated Th2 cytokine production. However, in spite of the increased allergic phenotype, NFAT1–/– mice failed to express AHR after methacholine aerosol. Refractoriness of NFAT1–/– mice to methacholine was confirmed in naïve mice, suggesting that this refractoriness occurs in an intrinsic way, independent of the lung inflammation. In addition, NFAT1–/– mice exhibit increased AHR in response to serotonin inhalation, suggesting a specific role for NFAT1 in the methacholine pathway of bronchoconstriction. Taken together, these data add support to the interpretation that NFAT1 acts as a counterregulatory mechanism to suppress allergic inflammation. Moreover, our findings suggest a novel role for NFAT1 protein in airway responsiveness mediated by the cholinergic pathway.
Key Words: allergic inflammation • asthma • NFAT • immune response • lung
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