IL-10 attenuates TNF-α-induced NFκB pathway activation and cardiomyocyte apoptosis
IL-10 attenuates TNF-α-induced NFκB pathway activation and cardiomyocyte apoptosis
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DOI：
10.1093/cvr/cvp040
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发表时间：
2009-04-01
影响因子：
10.8
通讯作者：
Singal, Pawan K.
中科院分区：
文献类型：
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作者：
Dhingra, Sanjiv;Sharma, Anita K.;Singal, Pawan K.
我们最近报道，肿瘤坏死因子-α通过上调p38丝裂原活化蛋白(MAP)激酶(MAPK)的磷酸化来增加心肌细胞的氧化应激和细胞凋亡。白介素10(IL-10)通过上调细胞外信号调节激酶1/2(ERK 1/2)MAPK的磷酸化来阻断肿瘤坏死因子-α的上述作用。然而，IL-10的确切作用部位尚不清楚，本研究对此进行了研究。成年SD大鼠分离的心肌细胞分别暴露于肿瘤坏死因子-α(10 ng/mL)、IL-10(10 ng/mL)和IL-10+肿瘤坏死因子-α(比例为1)4h，以过氧化氢和抗氧化剂trolox为阳性对照。暴露于肿瘤坏死因子-α后，细胞内活性氧产生增加，细胞凋亡率增加，caspase-3激活，多聚ADP核糖聚合酶(PARP)裂解增加。使用过氧化氢导致的氧化应激增加也会导致细胞凋亡。肿瘤坏死因子-α引起的改变与kappa B激酶(IKK)和核因子kappaB(NF Kappa B)磷酸化抑制因子增加有关。IL-10本身无作用，但可阻止上述由肿瘤坏死因子-α引起的改变。曲洛昔单抗肿瘤坏死因子-α引起的改变。预先将细胞暴露于IKK抑制剂(PS-1145)可阻止肿瘤坏死因子-α诱导的caspase-3和PARP的切割。用PD98059抑制ERK 1/2 MAPK可减弱IL-10对肿瘤坏死因子-α诱导的IKK和核因子-kappaB活化以及心肌细胞凋亡的保护作用。IL-10通过激活ERK 1/2 MAPK而抑制IKK的磷酸化，从而阻止由肿瘤坏死因子-α诱导的心肌细胞核因子-kappaB的激活和促凋亡的改变。
We have recently reported that tumour necrosis factor-alpha (TNF-alpha) increases oxidative stress and apoptosis in cardiomyocytes by upregulating p38 mitogen-activated protein (MAP) kinase (MAPK) phosphorylation. Interleukin-10 (IL-10) blocked these effects of TNF-alpha by upregulating extracellular signal-regulated kinase 1/2 (ERK 1/2) MAPK phosphorylation. However, the precise site of this IL-10 action is still unknown, and this is investigated in the present study.Cardiomyocytes isolated from adult Sprague-Dawley rats were exposed to TNF-alpha (10 ng/mL), IL-10 (10 ng/mL), and IL-10+TNF-alpha (ratio 1) for 4 h. Hydrogen peroxide and antioxidant trolox were used as positive controls. Exposure to TNF-alpha resulted in an increase in the production of reactive oxygen species, the number of apoptotic cells, caspase-3 activation, and poly-ADP ribose polymerase (PARP) cleavage. Increased oxidative stress by using hydrogen peroxide also caused apoptosis. The changes due to TNF-alpha were associated with an increase in the inhibitor of kappa B kinase (IKK) and nuclear factor kappa-B (NF kappa B) phosphorylation. IL-10 by itself had no effect, but it prevented the above mentioned TNF-alpha-induced changes. Trolox also mitigated TNF-alpha induced changes. Pre-exposure of cells to an IKK inhibitor (PS-1145) prevented TNF-alpha-induced caspase-3 and PARP cleavage. Inhibition of ERK 1/2 MAPK with PD98059 attenuated the protective role of IL-10 against TNF-alpha-induced activation of IKK and NF kappa B as well as cardiomyocyte apoptosis.The present study shows that TNF-alpha-induced activation of the NF kappa B pathway plays a critical role in cardiomyocyte apoptosis. IL-10 prevents TNF-alpha-induced NF kappa B activation and pro-apoptotic changes in cardiomyocytes by inhibiting IKK phosphorylation through the activation of ERK 1/2 MAPK.