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

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

Am J Respir Crit Care Med. 2013 Feb 28;

Authors: Li H, Edin ML, Bradbury JA, Graves JP, Degraff LM, Gruzdev A, Cheng J, Dackor RT, Wang PM, Bortner CD, Garantziotis S, Jetten AM, Zeldin DC

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 na�ve CD4+ T cells in vitro. Inhibition of PKA significantly increased Th9 cell differentiation of na�ve 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.

PMID: 23449692 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors