COX-1–derived thromboxane A2 plays an essential role in early B-cell development via regulation of JAK/STAT5 signaling in mouse

• Published in: Blood Vol. 124; no. 10; pp. 1610 - 1621
• Main Authors: Yang, Qiong, Shi, Maohua, Shen, Yujun, Cao, Yingjiao, Zuo, Shengkai, Zuo, Caojian, Zhang, Hui, Gabrilovich, Dmitry I., Yu, Ying, Zhou, Jie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.09.2014; American Society of Hematology
• Subjects: Animals; B-Lymphocytes - physiology; Cell Differentiation - genetics; Cells, Cultured; Cyclooxygenase 1 - genetics; Cyclooxygenase 1 - metabolism; Humans; Immunobiology; Janus Kinases - metabolism; Leukopoiesis - genetics; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction - genetics; STAT5 Transcription Factor - metabolism; Thromboxane A2 - metabolism; Thromboxane A2 - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-03-559658

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. We further 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 TxA2 production and downregulation of JAK/STAT5 signaling. Taken together, our results demonstrate that COX-1–derived TxA2 plays 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. •This study demonstrated an essential role of COX-1 in early B-cell development.•Low-dose aspirin may have a potential suppressive effect on B-cell development in humans.