NF-kappaB-mediated expression of MAPK phosphatase-1 is an early step in desensitization to TLR ligands in enterocytes.
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)-kappaB, but not of MAPK. Small interfering RNA knockdown of IkBalpha prolongs the expression of MKP-1. Rat MKP-1 promoter contains two NF-kappaB-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-kappaB-dependent expression of MKP-1 may contribute, by desensitization of p38, to the rapid establishment of unresponsiveness to several TLR ligands in enterocytes.
Wang
J
J
Division of Pediatric Surgery, Childrens Hospital Los Angeles, Los Angeles, California, USA.
Ford
H R
HR
Grishin
A V
AV
D000818:Animals; D018938:Caco-2 Cells; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020895:Enterocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance; D007113:Immunity, Innate; D007422:Intestines / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016328:NF-kappa B; D010455:Peptides; D034741:RNA, Small Interfering; C118258:SN50 peptide; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1