Modulation of interferon-γ-induced glial cell activation by transforming growth factor β1: a role for STAT1 and MAPK pathways.
Modulation of interferon-γ-induced glial cell activation by transforming growth factor β1: a role for STAT1 and MAPK pathways.
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DOI：
10.1111/j.1471-4159.2012.07887.x
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发表时间：
2012-10
影响因子：
4.7
通讯作者：
von Bernhardi R
中科院分区：
文献类型：
--
作者：
Herrera-Molina R;Flores B;Orellana JA;von Bernhardi R
过度活化的神经胶质细胞可以产生神经毒性氧化剂分子，如一氧化氮（NO·）和超氧阴离子（O2·−）。我们以前曾报道海马细胞释放的转化生长因子β1（TGFβ1）调节干扰素-γ（IFNγ）诱导的神经胶质细胞产生O2·−和NO·。然而，其潜在的分子机制尚未完全了解，因此，本工作的目的是研究TGFβ1对IFNγ诱导的信号通路的影响。我们发现，与TGFβ1的共刺激减少了IFNγ诱导的STAT 1和细胞外信号调节激酶（ERK）的磷酸化，这与混合和纯化胶质细胞培养物中O2·−和NO·产生的减少有关。此外，IFNγ可减少TGFβ1介导的P38磷酸化，而ERK和P38抑制剂预处理可减少IFNγ诱导的STAT 1丝氨酸727磷酸化和自由基种类的产生。这些结果表明TGFβ1对胶质细胞活化的调节是通过MAPKs失活介导的。值得注意的是，TGFβ1增加MAPK磷酸酶-1（MKP-1）的水平，其参与TGFβ1介导的调节，通过MKP-1 siRNA转染混合和纯化的胶质细胞培养物证实。我们的研究结果表明，IFNγ和TGFβ1之间的相互作用可能调节胶质细胞的活化，TGFβ1通过STAT 1、ERK和P38途径调节IFNγ诱导的神经毒性氧化分子的产生。
Over-activated glial cells can produce neurotoxic oxidant molecules such as nitric oxide (NO·) and superoxide anion (O2·−). We have previously reported that transforming growth factor β1 (TGFβ1) released by hippocampal cells modulates interferon-γ (IFNγ)-induced production of O2·− and NO· by glial cells. However, underlying molecular mechanisms are not completely understood, thereby, the aim of this work was to study the effect of TGFβ1 on IFNγ-induced signaling pathways. We found that co-stimulation with TGFβ1 decreased IFNγ-induced phosphorylation of STAT1 and extracellular signal-regulated kinase (ERK), which correlated with a reduced O2·− and NO· production in mixed and purified glial cultures. Moreover, IFNγ caused a decrease in TGFβ1-mediated phosphorylation of P38, whereas pretreatment with ERK and P38 inhibitors decreased IFNγ-induced phosphorylation of STAT1 on serine727 and production of radical species. These results suggested that modulation of glial activation by TGFβ1 is mediated by deactivation of MAPKs. Notably, TGFβ1 increased the levels of MAPK phosphatase-1 (MKP-1), whose participation in TGFβ1-mediated modulation was confirmed by MKP-1 siRNA transfection in mixed and purified glial cultures. Our results indicate that the cross-talk between IFNγ and TGFβ1 might regulate the activation of glial cells and that TGFβ1 modulated IFNγ-induced production of neurotoxic oxidant molecules through STAT1, ERK and P38 pathways.
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