期刊
MOLECULAR NEUROBIOLOGY
卷 54, 期 9, 页码 6737-6749出版社
SPRINGER
DOI: 10.1007/s12035-016-0142-6
关键词
Lipopolysaccharide; Neuroinflammation; SBE/Tk-Luc mice; TGF beta; TGF beta 3; TUDCA
资金
- Spanish Ministry of Science and Innovation [SAF2009-11257]
- Spanish Ministry of Economics and Competitiveness [SAF2012-40126]
- FISCAM-Comunidad de Castilla-La Mancha [PI2008/19, PI2009/51]
The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in various animal models of neuropathologies. We have previously shown the anti-inflammatory properties of TUDCA in an animal model of acute neuroinflammation. Here, we present a new anti-inflammatory mechanism of TUDCA through the regulation of transforming growth factor beta (TGF beta) pathway. The bacterial lipopolysaccharide (LPS) was injected intravenously (iv) on TGF beta reporter mice (Smad-binding element (SBE)/Tk-Luc) to study in their brains the real-time activation profile of the TGF beta pathway in a non-invasive way. The activation of the TGF beta pathway in the brain of SBE/Tk-Luc mice increased 24 h after LPS injection, compared to control animals. This activation peak increased further in mice treated with both LPS and TUDCA than in mice treated with LPS only. The enhanced TGF beta activation in mice treated with LPS and TUDCA correlated with both an increase in TGF beta 3 transcript in mouse brain and an increase in TGF beta 3 immunoreactivity in microglia/macrophages, endothelial cells, and neurons. Inhibition of the TGF beta receptor with SB431542 drug reverted the effect of TUDCA on microglia/macrophages activation and on TGF beta 3 immunoreactivity. Under inflammatory conditions, treatment with TUDCA enhanced further the activation of TGF beta pathway in mouse brain and increased the expression of TGF beta 3. Therefore, the induction of TGF beta 3 by TUDCA might act as a positive feedback, increasing the initial activation of the TGF beta pathway by the inflammatory stimulus. Our findings provide proof-of-concept that TGF beta contributes to the anti-inflammatory effect of TUDCA under neuroinflammatory conditions.
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