Cyclooxygenase-2 Inhibits T Helper Cell Type 9 Differentiation during Allergic Lung Inflammation via Down-regulation of IL-17RB

摘要

Rationale: HelperCD4~+ Tcell subsets, including IL-9-and IL-10-producing T helper cell type 9 (Th9) cells, exist under certain inflammatory conditions. Cyclooxygenase (COX)-1 and COX-2 play important roles in allergic lung inflammation and asthma. It is unknown whether COX-derived eicosanoids regulate Th9 cells during allergic lung inflammation. Objectives: To determine the role of COX metabolites in regulating Th9 cell differentiation and function during allergic lung inflammation. Methods: COX-1~(-/-), COX-2~(-/-), and wild-type (WT) mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th9 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time PCR, and immuno-blotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PCs), selective inhibitors, and siRNA knockdown. Measurements and Main Results: Experimental endpoints were not different between COX-1~(-/-) and WT mice; however, the percentage of IL-9~+ CD4~+ T cells was increased in lung, bronchoalveolar lavage fluid, lymph nodes, and blood of allergic COX-2~(-/-) mice relative to WT. Bronchoalveolar lavage fluid IL-9 and IL-10, serum IL-9, and lung IL-17RB levels were significantly increased in allergic COX-2~(-/-) mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression In vivo was inhibited by PCD_2 and PCE_2, which also reduced Th9 cell differentiation of murine and human naive CD4~+ T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4~+ T cells isolated from WT mice in vitro. Conclusions: COX-2-derived PCD_2 and PGE_2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism.