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* Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599;
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; and
¶ Institut National de la Santé et de la Recherche Médicale Unité 773, Centre de Recherche Biomédicale Bichat Beaujon, Université Paris 7, Paris, France
TGF-β1 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-
B has been well-studied; however, the potential effects of TGF-β1 on other proinflammatory signaling pathways is less clear. In this study, using the well-established LPS and the 1-methyl-4-phenylpyridinium-mediated models of Parkinson’s disease, we demonstrate that TGF-β1 exerts significant neuroprotection in both models via its anti-inflammatory properties. The neuroprotective effects of TGF-β1 are mainly attributed to its ability to inhibit the production of reactive oxygen species from microglia during their activation or reactivation. Moreover, we demonstrate that TGF-β1 inhibited LPS-induced NADPH oxidase (PHOX) subunit p47phox translocation from the cytosol to the membrane in microglia within 10 min. Mechanistic studies show that TGF-β1 fails to protect dopaminergic neurons in cultures from PHOX knockout mice, and significantly reduced LPS-induced translocation of the PHOX cytosolic subunit p47phox to the cell membrane. In addition, LPS-induced ERK phosphorylation and subsequent Ser345 phosphorylation on p47phox were significantly inhibited by TGF-β1 pretreatment. Taken together, our results show that TGF-β1 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 1-methyl-4-phenylpyridinium. The molecular mechanisms of TGF-β1-mediated anti-inflammatory properties is through the inhibition of PHOX activity by preventing the ERK-dependent phosphorylation of Ser345 on p47phox in microglia to reduce oxidase activities induced by LPS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health (NIH) Grant DE-13079 from the National Institute for Dental and Craniofacial Research, and was also supported in part by the Intramural Research Program of the NIH/National Institute on Environmental Health Sciences.
2 Address correspondence and reprint requests to Dr. Patrick M. Flood, Comprehensive Center for Inflammatory Disorders, University of North Carolina, Chapel Hill, NC 27599-7455. E-mail address: pat_flood{at}dentistry.unc.edu
3 Abbreviations used in this paper: PD, Parkinson’s disease; DA, dopaminergic; PHOX, NADPH oxidase; ROS, reactive oxygen species; MPP+, 1-methyl-4-phenylpyridinium; DCFH-DA, dichlorodihydrofluorescein diacetate; TH-IR, tyrosine hydroxylase-immunoreactive; SOD, superoxide dismutase.
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