NIH Research Festival
Thromboxane (TXA2) is implicated in asthma pathogenesis. TXA2 inhibits the interaction of dendritic cells (DCs) with T cells via thromboxane receptor (TP) signaling. T helper type 9 (Th9) cells, a subpopulation of CD4+ T cells, play an important role in asthma pathogenesis; however, it is unknown whether TXA2 regulates Th9 cell differentiation/function during allergic lung inflammation. We used an in vivo ovalbumin (OVA)-induced allergic inflammation model to study the role of TXA2 and its receptor in Th9 cell differentiation. Following OVA sensitization/exposure, the percentage of IL-9+/CD4+ T cells was decreased in lungs of mice treated with the stable TP receptor agonist cTXA2. Consistent with this observation, TP-/- mice had a significantly higher percentage of Th9 cells in lung after OVA sensitization/exposure compared to WT mice, and exhibited increased allergic lung inflammation. In vitro experiments showed that differentiation of naïve CD4+ T cells to Th9 cells was inhibited by cTXA2. Lung F4/80+ DCs had higher TXA2 secretion than F4/80- cells after LPS stimulation. CD4+ T cells did not produce TXA2, but expressed the TP receptor during Th9 cell differentiation. TXA2 activation of TP receptors increased cAMP production and enhanced phosphorylation of p38 MAPK, ERK and PI3K in CD4+ T cells during Th9 differentiation. These effects were attenuated in TP-/- cells. TXA2 signaling suppressed activation of the Il9 promoter via a mechanism that involved binding of PBX1 and NFE2 transcription factors to their corresponding response elements. Thus, TXA2 acts through TP receptors to suppress Il9 promoter activation and Th9 cell differentiation.
Scientific Focus Area: Institute, Center, and Scientific Directors
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