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.
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ABSTRACT: Obesity is a chronic inflammatory state and adipocytes are capable of contributing to this inflammation by their production of inflammatory mediators. The present study used fibroblast-derived adipocytes and normal spleen cells as a model to determine if adipocytes can also serve as immune regulatory cells by modulating the functions of conventional immune cells. Media conditioned by the adipocytes stimulated release of the Th1-type cytokines IL-2, IFN-γ and GM-CSF from cultures of normal spleen cells. The adipocytes also stimulated spleen cell release of inhibitory cytokines, although to varying degrees. This included IL-10, IL-13 and, to a lesser extent, IL-4. Spleen cell production of the inflammatory cytokines IL-6, TNF-α and IL-9 was stimulated by adipocytes, although production of the Th17-derived cytokine, IL-17, was not stimulated. The adipocyte-conditioned medium did not stimulate production of predominantly monocytes-derived chemokines CXCL9, CCL2, CCL3, CCL4, but stimulated production of the predominantly T-cell-derived chemokine CCL5. In all cases where cytokine/chemokine production from spleen cells was stimulated by adipocytes, it was to a far greater level than was produced by the adipocytes themselves. Studies initiated to determine the identity of the adipocyte-derived mediators showed that the spleen cell modulation could not be attributed to solely adiponectin or leptin. Studies to determine the source of some of the cytokines whose production was stimulated by adipocytes showed that expression of the inflammatory cytokine IL-6 was not increased in either CD4(+) or CD8(+) T-cell. When the splenic T-cells were examined for IFN-γ, the adipocyte stimulation of IFN-γ was within CD8(+) T-cells, not CD4(+) T-cells. These studies show that adipocytes may be able to serve as immune regulatory cells to stimulate conventional immune cells to release a spectrum of immune mediators.International immunopharmacology 04/2013; 16(2). DOI:10.1016/j.intimp.2013.04.002 · 2.71 Impact Factor
- American Journal of Respiratory and Critical Care Medicine 04/2013; 187(8):785-6. DOI:10.1164/rccm.201302-0205ED · 11.99 Impact Factor
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ABSTRACT: Upon antigen-specific stimulation, naïve CD4(+) T cells have the potential to differentiate into various T helper (Th) cell subsets. Earlier models of Th cell differentiation focused on IFN-γ-producing Th1 cells and IL-4-secreting Th2 cells. The discovery of additional CD4(+) Th cell subsets has extended our understanding of Th cell differentiation beyond this dichotomy. Among these is the recently described Th9 cell subset, which preferentially produces interleukin (IL)-9. Here, we review the latest developments in Th9 cell development and differentiation, focusing on contributing environmental signals, and discuss potential physiological and pathophysiological functions of these cells. We describe the challenges inherent to unambiguously defining roles for Th9 cells using the available experimental animal models, and suggest new experimental models to address these concerns.Trends in Immunology 11/2013; 35(2). DOI:10.1016/j.it.2013.10.004 · 12.03 Impact Factor