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

Abstract

Rationale: HelperCD41 T cell subsets, includingIL-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., COX-2 2/2 , 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 immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown. Measurements and Main Results: Experimental endpoints were not different between COX-1 2/2 and WT mice; however, the percentage of IL-9 1 CD4 1 T cells was increased in lung, bronchoalveolar lavage fluid, lymph nodes, and blood of allergic COX-2 2/2 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 2/2 mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression in vivo was inhibited by PGD 2 and PGE 2 , which also reduced Th9 cell differentiation of murine and human naive CD4 1 T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4 1 T cells isolated from WT mice in vitro. Conclusions: COX-2-derived PGD 2 and PGE 2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism.

In vitro exposure to isoprene-derived secondary organic aerosol by direct deposition and its effects on <i>COX-2</i> and <i>IL-8</i> gene expression

“…COX-2 is the inducible form of the cyclooxygenase enzyme, regulated by cytokines and mitogens, and is responsible for prostaglandin synthesis associated with inflammation (FitzGerald, 2003). Consistent with the reports that IL-8 and COX-2 play important roles in lung inflammation (Nocker et al, 1996;Li et al, 2013), in vivo studies have shown that isoprene oxidation products cause airflow limitation and sensory irritation in mice (Rohr et al, 2003). In humans, the role of IL-8 and COX-2 in lung inflammation can be associated with diseases such as chronic obstructive pulmonary disease and asthma (Nocker et al, 1996;Peng et al, 2008;Fong et al, 2000).…”

MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells

“…MAG-EPA reduces airway hyperresponsiveness and lung inflammation in OVA-sensitized animals (5). COX-2-derived PGD2 and PGE2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism (6). COX-2-derived PGE (2) is a hallmark of allergic inflammation.…”

Reduced immune responses in chimeric mice engrafted with bone marrow cells from mice with airways inflammation

“…Further, chimeric mice engrafted with BM cells from mice implanted with PGE 2 -releasing pellets for 3 days have reduced DC-initiated immune responses [26]. Links between prostanoids, of which PGE 2 is the most abundant, and asthma are well recognized [27] and mechanistically, cyclooxygenase inhibition increases allergic inflammation in murine models of asthma [28,29].…”