Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo
Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo
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DOI：
10.1161/hh0701.088512
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发表时间：
2001-04-13
影响因子：
20.1
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Hamanaka, I;Saito, Y;Nakao, K
CIS（细胞因子诱导的SH2蛋白）、SOCS（细胞因子信号传导抑制因子）或SSI（信号转导和转录激活因子[STAT]诱导的STAT抑制剂）蛋白是一类细胞因子诱导的通过Janus激酶(JAK)-STAT通路的细胞因子信号传导负调节因子。鉴于JAK-STAT通路在心血管系统中起着关键作用的证据，本研究的主要目的是评估CIS家族对大鼠心血管系统中JAK-STAT信号传导的影响。静脉注射20马克/千克体重的CT-1可诱导多种组织（包括心脏和肺）中STAT3激活的短暂显着增加。随后CIS家族的2个成员jak结合蛋白(JAB)/SOCS-1/SSI-1和CIS3/SOCS-3/SSI-3在同一组织中表达上调。还观察到CIS3在体内与JAK2直接相关。在第二次注射CT-1前60分钟用相同剂量的CT-1进行预处理，显著减弱了第二次注射CT-1诱导的STAT3激活。我们之前报道过静脉注射CT-1导致一氧化氮（NO）依赖性低血压，并伴有诱导NO合成酶mRNA的诱导。在CT-1预处理的大鼠中，未观察到随后注射CT-1诱导NO合成酶mRNA或低血压的现象。强制表达JAB或CIS3，而非其他CIS3，直接阻断了293细胞中ct -1诱导的STAT3激活。这些结果表明，JAB和CIS3是体内心血管系统中ct -1介导的JAK-STAT信号传导的内源性抑制剂。
CIS (cytokine-inducible SH2 protein), SOCS (suppressor of cytokine signaling), or SSI (signal transducers and activators of transcription [STAT]-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given the evidence that the JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study was to assess the effects of the CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokines, Intravenous injection of 20 mug/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues. It was also observed that CIS3 was directly associated with JAK2 in vivo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-I, We previously reported that intravenous injection of CT-1 results in the nitric oxide (NO)-dependent hypotension accompanied by the induction of inducible NO synthase mRNA. In rats pretreated with CT-1, the induction of inducible NO synthase mRNA or hypotension by subsequent CT-I injection was not observed. Forced expression of JAB or CIS3, but not other CISs, directly blocked CT-1-induced STAT3 activation in 293 cells. These results suggest that JAB and CIS3 serve as endogenous inhibitors of CT-1-mediated JAK-STAT signaling in the cardiovascular system in vivo.