Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes
Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes
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DOI：
10.1161/01.cir.94.10.2626
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发表时间：
1996-11-15
期刊：
影响因子：
37.8
通讯作者：
Kishimoto, T
中科院分区：
文献类型：
--
作者：
Kunisada, K;Hirota, H;Kishimoto, T
背景白介素6相关细胞因子gp130是信号转导蛋白。在gp130下游，已经发现了两条信号转导途径，即Janus激酶-信号转导和转录激活因子(JAK-STAT)通路和RAS-丝裂原活化蛋白激酶(MAPK)通路。为了确定心肌细胞中是否存在这两条通过gp130的信号通路，我们利用IL-6细胞因子家族成员白血病抑制因子(LIF)来检测它们的激活情况。方法与结果用抗gp130、抗JAK1或抗STAT3抗体免疫沉淀乳鼠心肌细胞，并用抗磷酸酪氨酸抗体印迹。LIF刺激心肌细胞后，观察到gp130、JAK1和STAT3的酪氨酸磷酸化。LIF刺激后5min，MAPKs的活性最高。此外，抗gp130抗体显著抑制LIF诱导的JAK1、STAT3和MAPKs的激活。为了检查这些信号通路在体内是否也在成人心脏中被激活，将LIF静脉注射到一只6周大的小鼠体内，然后检查心脏。结论首次证实心肌细胞中存在JAK-STAT通路和MAPK通路，并且在体外和体内均能被LIF迅速激活。在心肌细胞中，gp130的激活构成了一条新的信号通路。
Background Interleukin (IL)-6-related cytokines share gp130 as the signal-transducing protein. Downstream of gp130, two signal-transducing pathways have been recognized, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and the Ras-mitogen-activated protein kinase (MAPK) pathway. To determine whether these two signaling pathways through gp130 are present in cardiac myocytes, we examined their activation by using leukemia inhibitory factor (LIF), which is a member of the IL-6 cytokine family.Methods and Results Lysates from neonatal rat cardiac myocytes were immunoprecipitated with anti-gp130, anti-JAK1, or anti-STAT3 antibody and blotted with anti-phosphotyrosine antibody. Tyrosine phosphorylation of gp130, JAK1, and STAT3 was observed after LIF stimulation in cardiac myocytes. MAPKs were maximally activated 5 minutes after LIF stimulation. Furthermore, anti-gp130 antibody significantly inhibited the LIF-induced activation of JAK1, STAT3, and MAPKs. To examine whether these signaling pathways were also activated in the adult heart in vivo, LIF was injected intravenously into a 6-week-old mouse, and the heart was examined subsequently. gp130, STAT3, and MAPKs were activated in the heart after LIF treatment.Conclusions These results demonstrate for the first time that a JAK-STAT pathway and a MAPK pathway are present downstream of gp130 in cardiac myocytes and are rapidly activated by LIF both in vitro and in vivo. Activation of gp130 constitutes a novel signaling pathway in cardiac myocytes.