期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1529-1534
DOI：10.1073/pnas.1417972112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAllergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsiveness and remodeling. However, the mechanisms by which DC promote Th2 differentiation remain unclear. Herein we demonstrate that low cAMP levels in DC induce Th2-biased responses in vitro and in vivo. Furthermore, mice with conditional deletion of Gnas in DC (Gnas{Delta}CD11c mice) develop spontaneous bronchial asthma that shares multiple similarities with human asthma. In contrast, increasing cAMP levels inhibit these responses. Thus, regulators of cAMP levels in DC such as G-protein-coupled receptors are non-pattern recognition receptors that play a significant role in CD4 T cell differentiation. The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gs, and Gi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gs in mouse CD11c+ cells (Gnas{Delta}CD11c mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by Gnas{Delta}CD11c DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gs and Gi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.
