p42/p44-MAPK and PI3K are sufficient for IL-6 family cytokines/gp130 to signal to hypertrophy and survival in cardiomyocytes in the absence of JAK/STAT activation.
p42/p44-MAPK and PI3K are sufficient for IL-6 family cytokines/gp130 to signal to hypertrophy and survival in cardiomyocytes in the absence of JAK/STAT activation.
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DOI：
10.1016/j.cellsig.2012.12.008
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发表时间：
2013-04
影响因子：
4.8
通讯作者：
Heads R
中科院分区：
文献类型：
--
作者：
Fahmi A;Smart N;Punn A;Jabr R;Marber M;Heads R
在新生大鼠心肌细胞中研究了 IL-6 和白血病抑制因子 (LIF) 的差异信号传导（通过 gp130 同二聚化或 LIFRβ/gp130 异二聚化发出信号）对存活和肥大的影响。 LIF 和 IL-6 [在不存在可溶性 IL-6 受体 (sIL-6Rα) 的情况下] 均激活 Erk1/2、JNK1/2、p38-MAPK 和 PI3K 信号传导，并在 20 分钟时达到峰值，并诱导针对模拟缺血再灌注损伤的细胞保护作用，这种保护作用可被 MEK1/2 抑制剂 PD98059 阻断，但不能被 p38-MAPK 抑制剂 SB203580 阻断。在没有 sIL-6R 的情况下，IL-6 不诱导 STAT1/3 磷酸化，而 IL-6/sIL-6R 和 LIF 诱导 STAT1 和 STAT3 磷酸化。此外，SB203580 增强了 IL-6/sIL-6R 诱导的 STAT1 Tyr701 和 STAT3 Tyr705 的磷酸化。 IL-6 和去氧肾上腺素 (PE)（而非 LIF）诱导心肌细胞 iNOS 表达和一氧化氮 (NO) 产生。 IL-6、LIF 和 PE 诱导心肌细胞肥大，但在 ANF 和 SERCA2 表达以及肌丝组织方面存在表型差异，其中 IL-6 比 LIF 更类似于 PE。用全长或截短的嵌合 gp130 胞质结构域/促红细胞生成素受体 (EpoR) 胞外结构域融合构建体转染心肌细胞表明，含有 gp130 区域的膜近端 Box 1 和 Box 2 区域对于 MAPK 和 PI3K 激活是必要且充分的；肥大;在没有 JAK/STAT 激活的情况下 SERCA2 表达和 iNOS/NO 诱导。总之，IL-6 可以在心肌细胞中发出独立于 sIL-6R 和 STAT1/3 的信号，此外，IL-6 激活 Erk1/2 和 PI3K 对于诱导心脏保护来说是必要且充分的。此外，p38-MAPK 可能充当心肌细胞中 JAK/STAT 激活的负反馈调节因子。 ► IL-6 信号独立于心肌细胞中的可溶性 IL-6 受体。 ► 在没有 JAK/STAT 激活的情况下，IL-6 激活 MAPK 和 PI-3 激酶。 ► 在没有 JAK/STAT 激活的情况下，IL-6 会诱导细胞肥大和细胞保护。 ► IL-6 诱导的 Erk-1 和 2 MAPK 激活对于细胞保护是必要且充分的。
The effect of differential signalling by IL-6 and leukaemia inhibitory factor (LIF) which signal by gp130 homodimerisation or LIFRβ/gp130 heterodimerisation on survival and hypertrophy was studied in neonatal rat cardiomyocytes. Both LIF and IL-6 [in the absence of soluble IL-6 receptor (sIL-6Rα)] activated Erk1/2, JNK1/2, p38-MAPK and PI3K signalling peaking at 20 min and induced cytoprotection against simulated ischemia-reperfusion injury which was blocked by the MEK1/2 inhibitor PD98059 but not the p38-MAPK inhibitor SB203580. In the absence of sIL-6R, IL-6 did not induce STAT1/3 phosphorylation, whereas IL-6/sIL-6R and LIF induced STAT1 and STAT3 phosphorylation. Furthermore, IL-6/sIL-6R induced phosphorylation of STAT1 Tyr701 and STAT3 Tyr705 were enhanced by SB203580. IL-6 and pheneylephrine (PE), but not LIF, induced cardiomyocyte iNOS expression and nitric oxide (NO) production. IL-6, LIF and PE induced cardiomyocyte hypertrophy, but with phenotypic differences in ANF and SERCA2 expression and myofilament organisation with IL-6 more resembling PE than LIF. Transfection of cardiomyocytes with full length or truncated chimaeric gp130 cytoplasmic domain/Erythropoietin receptor (EpoR) extracellular domain fusion constructs showed that the membrane proximal Box 1 and Box 2 containing region of gp130 was necessary and sufficient for MAPK and PI3K activation; hypertrophy; SERCA2 expression and iNOS/NO induction in the absence of JAK/STAT activation. In conclusion, IL-6 can signal in cardiomyocytes independent of sIL-6R and STAT1/3 and furthermore, that Erk1/2 and PI3K activation by IL-6 are both necessary and sufficient for induced cardioprotection. In addition, p38-MAPK may act as a negative feedback regulator of JAK/STAT activation in cardiomyocytes. ► IL-6 signals independently of soluble IL-6 receptor in cardiomyocytes. ► IL-6 activates MAPK and PI-3-kinase in the absence of JAK/STAT activation. ► IL-6 induces hypertrophy and cytoprotection in the absence of JAK/STAT activation. ► IL-6 induced Erk-1 and 2 MAPK activation is necessary and sufficient for cytoprotection.
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影响因子：
4.2
作者：
Hart, SL;Arancibia-Cárcamo, CV;Kinnon, C
通讯作者：
Kinnon, C
影响因子：
9.5
作者：
Boengler K;Hilfiker-Kleiner D;Heusch G;Schulz R
通讯作者：
Schulz R
DOI：
10.1016/s0735-1097(02)01791-6
发表时间：
2002-05-01
影响因子：
24
作者：
Plenz, G;Eschert, H;Deng, MC
通讯作者：
Deng, MC
影响因子：
3.1
作者：
Aoyagi T;Matsui T
通讯作者：
Matsui T
影响因子：
10.8
作者：
Obasanjo-Blackshire, Kofo;Mesquita, Rul;Heads, Richard J.
通讯作者：
Heads, Richard J.