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- Title
Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling.
- Authors
Dong-Min Shin; Jae-Min Yuk; Hye-Mi Lee; Sang-Hee Lee; Ji Woong Son; Harding, Clifford V.; Jin-Man Kim; Modlin, Robert L.; Eun-Kyeong Jo
- 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-Ca2+-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.
- Subjects
MONOCYTES; CELL receptors; ANTI-infective agents; VITAMIN D; CELL communication
- Publication
Cellular Microbiology, 2010, Vol 12, Issue 11, p1648
- ISSN
1462-5814
- Publication type
Article
- DOI
10.1111/j.1462-5822.2010.01497.x