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Cell Microbiol. 2010 Nov;12(11):1648-65. doi: 10.1111/j.1462-5822.2010.01497.x. Epub 2010 Jul 20.

Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling.

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  • 1Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea.

Abstract

In human monocytes, Toll-like receptor (TLR) 2/1 activation leads to vitamin D3-dependent antimycobacterial activities, but the molecular mechanisms by which TLR2/1 stimulation induces antimicrobial activities against mycobacteria remain unclear. Here we show that TLR2/1/CD14 stimulation by mycobacterial lipoprotein LpqH can robustly activate antibacterial autophagy through vitamin D receptor signalling activation and cathelicidin induction. We found that CCAAT/enhancer-binding protein (C/EBP)-β-dependent induction of 25-hydroxycholecalciferol-1α-hydroxylase (Cyp27b1) hydroxylase was critical for LpqH-induced cathelicidin expression and autophagy. In addition, increases in intracellular calcium following AMP-activated protein kinase (AMPK) activation played a crucial role in LpqH-induced autophagy. Moreover, AMPK-dependent p38 mitogen-activated protein kinase (MAPK) activation was required for LpqH-induced Cyp27b1 expression and autophagy activation. Collectively, these data suggest that TLR2/1/CD14-Ca(2+) -AMPK-p38 MAPK pathways contribute to C/EBP-β-dependent expression of Cyp27b1 and cathelicidin, which played an essential role in LpqH-induced autophagy. Furthermore, these results establish a previously uncharacterized signalling pathway of antimycobacterial host defence through a functional link of TLR2/1/CD14-dependent sensing to the induction of autophagy.

© 2010 Blackwell Publishing Ltd.

PMID:
20560977
[PubMed - indexed for MEDLINE]
PMCID:
PMC2970753
Free PMC Article

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