共查询到20条相似文献,搜索用时 33 毫秒
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Huang Z Richmond TD Muntean AG Barber DL Weiss MJ Crispino JD 《The Journal of clinical investigation》2007,117(12):3890-3899
Thrombocytosis is associated with inflammation, and certain inflammatory cytokines, including IFN-gamma, stimulate megakaryocyte and platelet production. However, the roles of IFN-gamma and its downstream effector STAT1 in megakaryocyte development are poorly understood. We previously reported that STAT1 expression was significantly downregulated in Gata1-knockdown murine megakaryocytes, which also have impaired terminal maturation. Here, we show that ectopic expression of STAT1, or its target effector IRF-1, rescued multiple defects in Gata1-deficient megakaryopoiesis in mice, inducing polyploidization and expression of a subset of platelet-expressing genes. Enforced expression of STAT1, IRF-1, or GATA-1 enhanced phosphorylation of STAT1, STAT3, and STAT5 in cultured Gata1-deficient murine megakaryocytes, with concomitant megakaryocyte maturation. In contrast, enhanced thrombopoietin signaling, conferred by enforced expression of constitutively active JAK2 or c-MPL, induced phosphorylation of STAT3 and STAT5, but not STAT1, and failed to rescue megakaryocyte maturation. Finally, megakaryocytes from Stat1(-/-) mice were defective in polyploidization. Together, these findings reveal a unique role for STAT1 in megakaryopoiesis and provide new insights into how GATA-1 regulates this process. Our studies elucidate potential mechanisms by which various inflammatory disorders can cause elevated platelet counts. 相似文献
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Interferon Enhances Tumor Necrosis Factor–induced Vascular Cell Adhesion Molecule 1 (CD106) Expression in Human Endothelial Cells by an Interferon-related Factor 1–dependent Pathway
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Sonja Lechleitner Jens Gille David R. Johnson Peter Petzelbauer 《The Journal of experimental medicine》1998,187(12):2023-2030
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Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1 总被引:2,自引:0,他引:2
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Kinjyo I Inoue H Hamano S Fukuyama S Yoshimura T Koga K Takaki H Himeno K Takaesu G Kobayashi T Yoshimura A 《The Journal of experimental medicine》2006,203(4):1021-1031
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IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice 总被引:1,自引:0,他引:1
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Thibault DL Chu AD Graham KL Balboni I Lee LY Kohlmoos C Landrigan A Higgins JP Tibshirani R Utz PJ 《The Journal of clinical investigation》2008,118(4):1417-1426
A hallmark of SLE is the production of high-titer, high-affinity, isotype-switched IgG autoantibodies directed against nucleic acid-associated antigens. Several studies have established a role for both type I IFN (IFN-I) and the activation of TLRs by nucleic acid-associated autoantigens in the pathogenesis of this disease. Here, we demonstrate that 2 IFN-I signaling molecules, IFN regulatory factor 9 (IRF9) and STAT1, were required for the production of IgG autoantibodies in the pristane-induced mouse model of SLE. In addition, levels of IgM autoantibodies were increased in pristane-treated Irf9 -/- mice, suggesting that IRF9 plays a role in isotype switching in response to self antigens. Upregulation of TLR7 by IFN-alpha was greatly reduced in Irf9 -/- and Stat1 -/- B cells. Irf9 -/- B cells were incapable of being activated through TLR7, and Stat1 -/- B cells were impaired in activation through both TLR7 and TLR9. These data may reveal a novel role for IFN-I signaling molecules in both TLR-specific B cell responses and production of IgG autoantibodies directed against nucleic acid-associated autoantigens. Our results suggest that IFN-I is upstream of TLR signaling in the activation of autoreactive B cells in SLE. 相似文献
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