COX-1-derived thromboxane A2plays an essential role in early B-cell development via regulation of JAK/STAT5 signaling in mouse

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Abstract

Cyclooxygenases (COXs) and their prostanoid products play important roles in a diverse range of physiological processes, including in the immune system. Here, we provide evidence that COX-1 is an essential regulator in early stages of B-cell development. COX-1-deficient mice displayed systematic reduction in total B cells, which was attributed to the arrest of early B-cell development from pro-B to pre-B stage.Wefurther demonstrated that this defect was mediated through downregulation of the Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) signaling and its target genes, including Pax5, in COX-1-/-mice. Mechanistic studies revealed that COX-1-derived thromboxane A2(TxA2) could regulate JAK3/STAT5 signaling through the cyclic adenosine monophosphate-protein kinase A pathway, via binding with its receptor thromboxane A2 receptor (TP). Administration of the TP agonist could rescue the defective B-cell development and JAK/STAT5 signaling activity in COX-1-deficient mice. Moreover, administration of low-dose aspirin caused a significant reduction in total B cells in peripheral blood of healthy human volunteers, coincidentally with reduced TxA2production and downregulation of JAK/STAT5 signaling. Taken together, our results demonstrate that COX-1-derived TxA2plays a critical role in the stage transition of early B-cell development through regulation of JAK/STAT5 signaling and indicate a potential immune-suppressive effect of low-dose aspirin in humans.

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Yang, Q., Shi, M., Shen, Y., Cao, Y., Zuo, S., Zuo, C., … Zhou, J. (2014). COX-1-derived thromboxane A2plays an essential role in early B-cell development via regulation of JAK/STAT5 signaling in mouse. Blood, 124(10), 1610–1621. https://doi.org/10.1182/blood-2014-03-559658

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