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首页> 外文期刊>American Journal of Physiology >Distinctive role of Stat3 and Erk-1/2 activation in mediating interferon-gamma inhibition of TGF-beta1 action.
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Distinctive role of Stat3 and Erk-1/2 activation in mediating interferon-gamma inhibition of TGF-beta1 action.

机译：Stat3和Erk-1 / 2激活在介导干扰素-γ抑制TGF-beta1作用中的独特作用。

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摘要

Interferon-gamma (IFN-gamma) is a multifunctional cytokine that elicits antifibrotic activity in a variety of organs. In this study, we investigated the potential role and mechanism of IFN-gamma in modulating the fibrogenic action of transforming growth factor (TGF)-beta(1) in tubular epithelial cells. Incubation of human proximal tubular epithelial (HKC) cells with IFN-gamma inhibited TGF-beta(1)-mediated alpha-smooth muscle actin (alpha-SMA) expression. IFN-gamma also abolished TGF-beta(1)-induced fibronectin and plasminogen activator inhibitor-1 (PAI-1) expression. To explore the mechanisms by which INF-gamma inhibits TGF-beta(1) action, the signaling pathways that are critical for mediating the antifibrotic activity of IFN-gamma were studied. Stimulation of HKC cells with IFN-gamma triggered a sustained activation of Erk-1/2 and signal transducer and activator of transcription-3 (Stat3). Blockade of Erk-1/2 activation with an Mek1 inhibitor abolished the inhibitory effect of IFN-gamma on alpha-SMA expression, whereas inhibition of Stat3 activation had no influence. Constitutive activation of Erk-1/2 by ectopic expression of activated Mek1 mimicked IFN-gamma and suppressed TGF-beta(1)-mediated alpha-SMA expression. Interestingly, inhibition of Stat3 activation abolished the ability of IFN-gamma to attenuate TGF-beta(1)-mediated PAI-1 and fibronectin expression in HKC cells. These findings indicate that IFN-gamma is capable of antagonizing the fibrogenic actions of TGF-beta(1) in renal tubular epithelial cells. The antifibrotic action of IFN-gamma appears to be mediated through a coordinated activation of both Erk-1/2 and Stat3 signal pathways in a mutually independent fashion.
机译：干扰素-γ（IFN-γ）是一种多功能的细胞因子，可在多种器官中引发抗纤维化活性。在这项研究中，我们调查了IFN-γ在调节肾小管上皮细胞中转化生长因子（TGF）-beta（1）的纤维化作用中的潜在作用和机制。人类近端肾小管上皮细胞（HKC）与IFN-γ的孵育抑制了TGF-beta（1）介导的α-平滑肌肌动蛋白（alpha-SMA）的表达。 IFN-γ还废除了TGF-beta（1）诱导的纤连蛋白和纤溶酶原激活物抑制剂1（PAI-1）的表达。为了探索INF-γ抑制TGF-β（1）作用的机制，研究了对介导IFN-γ的抗纤维化活性至关重要的信号通路。用IFN-γ刺激HKC细胞触发了Erk-1 / 2以及信号转导和转录激活因子3（Stat3）的持续活化。用Mek1抑制剂阻断Erk-1 / 2激活可消除IFN-γ对α-SMA表达的抑制作用，而抑制Stat3激活则没有影响。通过激活的Mek1的异位表达来组成性激活Erk-1 / 2模仿IFN-γ和抑制TGF-beta（1）介导的α-SMA表达。有趣的是，抑制Stat3激活消除了IFN-γ减弱HKC细胞中TGF-β（1）介导的PAI-1和纤连蛋白表达的能力。这些发现表明，IFN-γ能够拮抗TGF-β（1）在肾小管上皮细胞中的纤维化作用。 IFN-γ的抗纤维化作用似乎是通过以相互独立的方式协同激活Erk-1 / 2和Stat3信号通路来介导的。

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