期刊
MUCOSAL IMMUNOLOGY
卷 3, 期 5, 页码 523-534出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2010.35
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- NIH [AI083612, AI014032, AI 049473]
Toll-like receptor (TLR) signaling in naive enterocytes is rapidly inhibited, leading to the establishment of tolerance. To gain insight into tolerance at the level of the proinflammatory mitogen-activated protein kinase (MAPK) p38, we characterized TLR-mediated induction of the p38-specific phosphatase MKP-1. In cultured enterocytes, ligands of TLR3, TLR4, TLR5, and TLR9, but not TLR2, induce MKP-1 at 30-60 min, coincident with dephosphorylation of p38 following the peak of TLR ligand-induced phosphorylation. Induction of MKP-1 is blocked by inhibitors of nuclear factor (NF)-kappa B, but not of MAPK. Small interfering RNA knockdown of IkB alpha prolongs the expression of MKP-1. Rat MKP-1 promoter contains two NF-kappa B-binding sites, mutations in which additively impair lipopolysaccharide-induced transcription from the MKP-1 promoter. In the intestine, MKP-1 is expressed in the crypts, the epithelial compartment that also displays bacteria-dependent activating phosphorylation of p38. Thus, NF-kappa B-dependent expression of MKP-1 may contribute, by desensitization of p38, to the rapid establishment of unresponsiveness to several TLR ligands in enterocytes.
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