COX-2 Inhibits Th9 Differentiation During Allergic Lung Inflammation Via Downregulation of IL-17RB.
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.
Article: Update in asthma 2013.American Journal of Respiratory and Critical Care Medicine 06/2014; 189(12):1487-93. · 11.99 Impact Factor
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ABSTRACT: IL-10 is a multifunctional cytokine secreted by a variety of cells. It not only inhibits activation of monocyte/macrophage system and synthesis of monocyte cytokine and inflammatory cytokine but also promotes the proliferation and maturation of non-monocyte-dependent T cell, stimulating proliferation of antigen-specific B cell. Increasing evidence indicates that IL-10 plays an important role in both the onset and development of auto-immune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS), multiple sclerosis (MS), Crohn's disease (CD), and psoriasis. However, the exact mechanisms of IL-10 in auto-immune diseases remain unclear. In the present review, we will summarize the biological effects of IL-10, as well as its role and therapeutic potential in auto-immune diseases.Cell biochemistry and biophysics 03/2014; · 3.34 Impact Factor
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ABSTRACT: Despite the fact that cyclooxygenase and its products, prostaglandins, have been traditionally associated with the development of inflammation, PGE2 was implicated early on as potentially beneficial in asthma. During the 1970s and 1980s, several studies reported the bronchodilator effect of PGE2 in asthma patients. In parallel, it was being shown to exert an inhibitory effect on mast cells in vitro. In spite of this, data supporting the beneficial role for PGE2 in asthma were scarce and sometimes controversial. Many years later, in vitro and in vivo studies suggested a range of biological activities attributable to PGE2, others than the ability to relax smooth muscle, that potentially explained some of the observed positive effects in asthma. The identification and cloning of the four PGE2 receptors made available new tools with which to fine-tune investigation of the anti-inflammatory, pro-inflammatory, immunoregulatory, and bronchodilation mechanisms of PGE2. Among these, several suggested involvement of mast cells, a cell population known to play a fundamental role in acute and chronic asthma. Indeed, it has been shown that PGE2 prevents human and murine MC activity in vitro through activation of the EP2 receptor, and also that both exogenously administered and endogenous PGE2 inhibit airway MC activity in vivo in mouse models of asthma (likely through an EP2-mediated mechanism as well). In the last few years, we have furthered into the functional connection between PGE2-induced mast cells inhibition and attenuated damage, in asthma and allergy models. The validity of the findings supporting a beneficial effect of PGE2 in different asthma phases, the direct effect of PGE2 on mast cells populations, and the functional implications of the PGE2–MC interaction on airway function are some of the topics addressed in this review, under the assumption that increased understanding of the PGE2–EP2–mast cell axis will likely lead to the discovery of novel antiasthma targets.Molecular Immunology 01/2014; · 3.00 Impact Factor