TY - JOUR
T1 - NF-κB-mediated expression of MAPK phosphatase-1 is an early step in desensitization to TLR ligands in enterocytes
AU - Wang, J.
AU - Ford, H. R.
AU - Grishin, A. V.
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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)-B, but not of MAPK. Small interfering RNA knockdown of IkBα prolongs the expression of MKP-1. Rat MKP-1 promoter contains two NF-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-B-dependent expression of MKP-1 may contribute, by desensitization of p38, to the rapid establishment of unresponsiveness to several TLR ligands in enterocytes.
AB - 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)-B, but not of MAPK. Small interfering RNA knockdown of IkBα prolongs the expression of MKP-1. Rat MKP-1 promoter contains two NF-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-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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U2 - 10.1038/mi.2010.35
DO - 10.1038/mi.2010.35
M3 - Article
C2 - 20555314
AN - SCOPUS:77955909527
VL - 3
SP - 523
EP - 534
JO - Mucosal Immunology
JF - Mucosal Immunology
SN - 1933-0219
IS - 5
ER -