COX-2 Inhibits Th9 Differentiation During Allergic Lung Inflammation Via Downregulation of IL-17RB.

LRB, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 11.04). 02/2013; DOI: 10.1164/rccm.201211-2073OC
Source: PubMed

ABSTRACT RATIONALE: Helper CD4+ T cell subsets, including interleukin (IL)-9- and IL-10-producing 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 cyclooxygenase (COX)-derived eicosanoids regulate Th9 cells during allergic lung inflammation. OBJECTIVE: 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 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 polymerase chain reaction, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown. Measurement and MAIN RESULTS: Experimental endpoints were not different between COX-1-/- and wild type (WT) mice; however, the percentage of IL-9+ CD4+ T cells was increased in lung, bronchoalveolar lavage fluid (BALF), lymph nodes and blood of allergic COX-2-/- mice relative to WT. BALF 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 prostaglandin PGD2 and PGE2, which also reduced Th9 cell differentiation of murine and human naïve CD4+ T cells in vitro. Inhibition of PKA significantly increased Th9 cell differentiation of naïve CD4+ T cells isolated from WT mice in vitro. CONCLUSION: COX-2-derived PGD2 and PGE2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a PKA-dependent mechanism.

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