title: COX-1-derived thromboxane A2 plays an essential role in early B-cell development via regulation of JAK/STAT5 signaling in mouse.
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. 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.
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China;
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China;
authors.forename: Maohua
authors.initials: M
authors.lastname: Shi
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China;
authors.forename: Yingjiao
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;
authors.forename: Shengkai
authors.initials: S
authors.lastname: Zuo
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;
authors.forename: Caojian
authors.initials: C
authors.lastname: Zuo
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, China; and.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Translational Tumor Immunology, The Wistar Institute, Philadelphia, PA.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, China; and.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D019891:Leukopoiesis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013928:Thromboxane A2 / Q000378:metabolism / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D050799:STAT5 Transcription Factor; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D053612:Janus Kinases