Regulation of Toll-like receptor 4-associated MD-2 in intestinal epithelial cells: a comprehensive analysis.
Innate Immun
; 16(2): 93-103, 2010 Apr.
Article
en En
| MEDLINE
| ID: mdl-19710105
ABSTRACT
The intestinal epithelium maintains a state of controlled inflammation despite continuous contact with Gram-negative commensal bacteria and lipopolysaccharide (LPS) on its luminal surface. Recognition of LPS by the Toll-like receptor (TLR) 4/MD-2 complex results in pro-inflammatory gene expression and cytokine secretion in intestinal epithelial cells (IECs). We have shown that IECs express low levels of MD-2 and TLR4 and are poorly responsive to LPS. In this study, we did a comprehensive analysis to understand the immune-mediated and epigenetic mechanisms by which IECs down-regulate MD-2 expression. Expression of MD-2 and TLR4 mRNA was examined in human inflammatory bowel disease and intestinal epithelial cell lines (T84, HT-29, Caco-2). Nuclear factor-kappaB transcriptional activation was used as a measure of LPS responsiveness. Intestinal epithelial cells in patients with inflammatory bowel disease exhibited increased expression of MD-2 and TLR4 mRNA. Lipopolysaccharide responsiveness in IECs was polarized to the basolateral membrane. Bisulfite sequencing of the MD-2 promoter demonstrated methylation of CpG dinucleotides. Inhibition of methylation by 5-azacytidine and histone de-actylation by trichostatin A, two forms of epigenetic silencing, resulted in increased mRNA expression of MD-2 in IECs. These results demonstrate various molecular mechanisms by which IECs down-regulate MD-2 and, thereby, protect against dysregulated inflammation to commensal bacteria in the intestinal lumen.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Enfermedades Inflamatorias del Intestino
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FN-kappa B
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Antígeno 96 de los Linfocitos
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Receptor Toll-Like 4
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Mucosa Intestinal
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Innate Immun
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
BACTERIOLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos