Adiponectin induces interleukin-6 production and activates STAT3 in adult mouse cardiac fibroblasts
Adiponectin induces interleukin-6 production and activates STAT3 in adult mouse cardiac fibroblasts
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DOI：
10.1042/bc20080117
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发表时间：
2009-05-01
影响因子：
2.7
通讯作者：
Campell, William
中科院分区：
文献类型：
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作者：
Liao, Wenqiang;Yu, Changan;Campell, William
背景资料。脂联素(APN)是一种高度存在于血清中的脂肪细胞源性细胞因子，具有抗糖尿病、抗动脉粥样硬化和心脏保护作用，还可促进CFB(心脏成纤维细胞)的增殖，保护心脏纤维化。信号转导和转录激活因子3是gp130/JAK2(Janus Kinase2)/STATS信号通路中的一个重要中介，在心肌保护事件中起着关键作用。几乎三分之二的心肌细胞是CFB；然而，APN是否调控STAT3信号通路在CFB中尚不清楚。在本研究中，我们观察了重组球状APN对成年小鼠CFBS中STAT3活性的影响，并探讨了可能的信号转导机制。在培养的CFB中，APN(10µg/ml)可显著诱导STAT3 Tyr(705)的延迟磷酸化，最长可达60min，并介导STAT3从胞浆到胞核的转位。针对AdipoR1(APN受体1)的siRNA(小干扰RNA)，而不是AdipoR2，明显抑制APN诱导的STAT3 Tyr(705)的磷酸化，表明STAT3的磷酸化需要的是AdipoR1，而不是AdipoR2。用抗gp130中和抗体抑制gp130和用JAK2的特异性抑制剂AG490抑制JAK2都能抑制APN诱导的STAT3磷酸化和2xpAPRE-Luc(APRE报告基因)检测到的STAT3转录活性。此外，我们还发现，APN刺激CFBS后，培养上清液中IL-6水平显著升高，IL-6mRNA水平也显著升高，而AdipoR1的siRNA能逆转这一作用，而AdipoR2则不能。抗IL-6中和抗体能显著抑制APN诱导的STAT3 Tyr(705)的磷酸化。APN诱导成年小鼠CFB产生由AdipoR1而不是AdipoR2介导的IL-6，从而刺激gp130/JAK信号通路，从而导致STAT3激活。
Background information. APN (adiponectin), an adipocyte-derived cytokine highly presented in serum, which exerts antidiabetic, anti-atherosclerotic and cardioprotective actions, also enhances CFB (cardiac fibroblast) proliferation and protects against cardiac fibrosis. STAT3 (signal transducer and activator of transcription 3), a major mediator in the gp130/JAK2 (Janus kinase 2)/STATs signalling pathway, plays a critical role in cardioprotective events. Almost two-thirds of total myocardial cells are CFBs; however, whether APN regulates STAT3 signalling pathway has not been clarified yet in CFBs. In the present study, we investigated the effect of recombinant globular APN on the STAT3 activity in adult mouse CFBs and explored the possible signalling transduction mechanism.Results. In cultured CFBs, APN (10 mu g/ml) can significantly induce delayed STAT3 Tyr(705) phosphorylation time-dependently, up to 60 min, and mediate STAT3 translocation from cytoplasm to nucleus. Transfection of siRNA (small interfering RNA) specific for AdipoR1 (APN receptor 1), but not AdipoR2, obviously inhibited APN-induced STAT3 Tyr(705) phosphorylation, indicating that AdipoR1, not AdipoR2, is required for STAT3 phosphorylation. Both inhibition of gp130 by anti-gp130 neutralizing antibody and JAK2 by AG490 (a specific inhibitor for JAK2) can inhibit APN-induced STAT3 phosphorylation and STAT3 transcription activity detected using 2xpAPRE-Luc (APRE reporter) assay. Furthermore, we found that the IL (interleukin)-6 level in culture medium was significantly increased after stimulation with APN and the IL-6 mRNA level was also markedly increased in CFBs, which can be reversed by siRNA for AdipoR1, but not for AdipoR2, and that anti-IL-6 neutralizing antibody can significantly inhibit APN-induced STAT3 Tyr(705) phosphorylation.Conclusions. APN induces IL-6 production mediated by AdipoR1, not AdipoR2, in adult mouse CFBs, which leads to the stimulation of the gp130/JAK signalling pathway, and as a result causes STAT3 activation.