MAPK signaling drives inflammation in LPS-stimulated cardiomyocytes: the route of crosstalk to G-protein-coupled receptors.
MAPK signaling drives inflammation in LPS-stimulated cardiomyocytes: the route of crosstalk to G-protein-coupled receptors.
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DOI：
10.1371/journal.pone.0050071
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Frazier WJ;Xue J;Luce WA;Liu Y
严重的心血管功能障碍是感染性休克死亡的重要原因。早期脓毒症炎症激增期间心脏功能障碍的分子基础尚不完全清楚。 MAPK 是介导炎症的重要信号转导器，而 G 蛋白信号通路则调节心脏对应激的反应。使用 H9c2 心肌细胞，我们研究了脓毒症模型中 MAPK 和 G 蛋白信号传导的相互作用，以检验心肌细胞炎症反应由 MAPK 通过 G 蛋白介导的事件控制的假设。我们发现，MAPK 负调节因子 Mkp-1 的 siRNA 敲低显着加剧了 LPS 刺激的促炎细胞因子的产生。当细胞用 p38 抑制剂处理时，细胞因子的产生减弱。通常由 G 蛋白偶联受体调节的两种重要细胞信号分子 cAMP 和 PKC 活性，也通过 Mkp-1 和 p38 调节的过程受到 LPS 和炎症细胞因子 TNF-α 和 IL-6 的刺激。有趣的是，针对 Gαs 和 Gαq 的中和抗体分别阻断了响应炎症刺激的细胞 cAMP 和 PKC 激活的增加，表明 G 蛋白偶联受体在此过程中发挥着关键作用。 LPS 刺激会增加 H9c2 细胞中的 COX-2，该细胞也表达前列腺素受体。 AH 23848 阻断 G 蛋白偶联 EP4 前列腺素受体可阻止 LPS 诱导的 cAMP 增加。这些数据表明 MAPK 和 G 蛋白参与心肌细胞对 LPS 的炎症反应以及 COX-2 生成的 PGE2 的串扰。这些数据增加了我们对感染性休克发病机制的理解，并有可能指导未来治疗方法的选择。
Profound cardiovascular dysfunction is an important cause of mortality from septic shock. The molecular underpinnings of cardiac dysfunction during the inflammatory surge of early sepsis are not fully understood. MAPKs are important signal transducers mediating inflammation whereas G-protein signaling pathways modulate the cardiac response to stress. Using H9c2 cardiomyocytes, we investigated the interaction of MAPK and G-protein signaling in a sepsis model to test the hypothesis that the cardiomyocyte inflammatory response is controlled by MAPKs via G-protein-mediated events. We found that LPS stimulated proinflammatory cytokine production was markedly exacerbated by siRNA knockdown of the MAPK negative regulator Mkp-1. Cytokine production was blunted when cells were treated with p38 inhibitor. Two important cellular signaling molecules typically regulated by G-protein-coupled receptors, cAMP and PKC activity, were also stimulated by LPS and inflammatory cytokines TNF-α and IL-6, through a process regulated by Mkp-1 and p38. Interestingly, neutralizing antibodies against Gαs and Gαq blocked the increase in cellular cAMP and PKC activation, respectively, in response to inflammatory stimuli, indicating a critical role of G-protein coupled receptors in this process. LPS stimulation increased COX-2 in H9c2 cells, which also express prostaglandin receptors. Blockade of G-protein-coupled EP4 prostaglandin receptor by AH 23848 prevented LPS-induced cAMP increase. These data implicate MAPKs and G-proteins in the cardiomyocyte inflammatory response to LPS as well as crosstalk via COX-2-generated PGE2. These data add to our understanding of the pathogenesis of septic shock and have the potential to guide the selection of future therapeutics.
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影响因子：
4.6
作者：
Aronoff DM
通讯作者：
Aronoff DM
DOI：
10.4049/jimmunol.0804343
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Frazier WJ;Wang X;Wancket LM;Li XA;Meng X;Nelin LD;Cato AC;Liu Y
通讯作者：
Liu Y
影响因子：
15.9
作者：
Braz, JC;Bueno, OF;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
4.4
作者：
Halpert, Matthew M.;Thomas, Kimberly A.;Justement, Louis B.
通讯作者：
Justement, Louis B.
影响因子：
8.3
作者：
Kacimi, R;Gerdes, AM
通讯作者：
Gerdes, AM