Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia.
Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia.
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DOI：
10.4049/jimmunol.181.1.660
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发表时间：
2008-07-01
期刊：
影响因子：
--
通讯作者：
Flood PM
中科院分区：
文献类型：
--
作者：
Qian L;Wei SJ;Zhang D;Hu X;Xu Z;Wilson B;El-Benna J;Hong JS;Flood PM
TGFβ1 is one of the most potent endogenous immune modulators of inflammation. The molecular mechanism of its anti-inflammatory effect on the activation of the transcription factor NF-kB has been well studied, however, the potential effects of TGFβ1 on other pro-inflammatory signaling pathways is less clear. In this study, using the well-established lipopolysaccharide (LPS) and the 1-methyl-4-phenylpyridinium (MPP+)-mediated models of Parkinson’s disease (PD), we demonstrate TGFβ1 exerts significant neuroprotection in both models via its anti-inflammatory properties. The neuroprotective effects of TGFβ1 are mainly attributed to its ability to inhibit the production of reactive oxygen species (ROS) from microglia during their activation or reactivation. Moreover, we demonstrate that TGFβ1 inhibited LPS-induced NADPH oxidase (PHOX) subunit p47phox translocation from the cytosol to the membrane in microglia within 10 min. Mechanistic studies show that TGFβ1 fails to protect dopaminergic neurons in cultures from PHOX knockout mice, and significantly reduced LPS-induced translocation of the PHOX cytosolic subunits p47phox to the cell membrane. In addition, LPS-induced ERK phosphorylation and subsequent serine345 (Ser345) phosphorylation on p47phox were significantly inhibited by TGFβ1 pretreatment. Taken together, our results show that TGFβ1 exerted potent anti-inflammatory and neuroprotective properties, either through the prevention of the direct activation of microglia by LPS, or indirectly through the inhibition of reactive microgliosis elicited by MPP+. The molecular mechanisms of TGFβ1-mediated anti-inflammatory properties is through the inhibition of PHOX activity by preventing the ERK-dependent phosphorylation of Ser345 on p47phox in microlgia to reduce oxidase activities induced by LPS.
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影响因子：
82.9
作者：
Liu, Yawei;Teige, Ingrid;Issazadeh-Navikas, Shohreh
通讯作者：
Issazadeh-Navikas, Shohreh
DOI：
10.1042/bss0660085
发表时间：
1999-01-01
期刊：
MITOCHONDRIA AND CELL DEATH
影响因子：
--
作者：
Greenamyre, JT;MacKenzie, G;Stephans, SE
通讯作者：
Stephans, SE
影响因子：
3.7
作者：
Jackson-Lewis, V;Smeyne, RJ
通讯作者：
Smeyne, RJ
影响因子：
5.3
作者：
McGuire, SO;Ling, ZD;Carvey, PM
通讯作者：
Carvey, PM
DOI：
10.1073/pnas.91.26.12599
发表时间：
1994-12-20
影响因子：
11.1
作者：
PREHN, JHM;BINDOKAS, VP;MILLER, RJ
通讯作者：
MILLER, RJ