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Transforming growth factor-beta 1 inhibits non-pathogenic Gram negative bacteria-induced NF-kappa B recruitment to the interleukin-6 gene promoter in intestinal epithelial cells through modulation of histone acetylation.

We have shown that non-pathogenic enteric Gram-negative Bacteroides vulgatus induces RelA phosphorylation, NF-kappaB activation, and proinflammatory gene expression in primary and intestinal epithelial cell (IEC) lines. We now demonstrate the transient induction of nuclear phospho-RelA (day 3) followed by persistent activation of phospho-Smad2 (days 3 and 7) in IEC from mucosal tissue sections of B. vulgatus-monoassociated rats, indicating that both NF-kappaB and transforming growth factor-beta1 (TGF-beta1) signaling are induced in vivo following bacterial colonization. Interestingly, TGF-beta1 inhibited B. vulgatus- and lipopolysaccharide (LPS)-induced NF-kappaB transcriptional activity as well as interleukin-6 (IL-6) mRNA accumulation and protein secretion in IEC. The inhibitory effect of TGF-beta1 is mediated independently of B. vulgatus/LPS-induced IkappaBalpha, Akt, and RelA phosphorylation as well as NF-kappaB DNA binding activity. Moreover, the specific histone deacetylase inhibitor trichostatin A blocked B. vulgatus/LPS-induced histone acetylation/phosphorylation (Lys-9/Ser-10) and reversed TGF-beta1-mediated inhibition of IL-6 gene expression. Chromatin immunoprecipitation analysis revealed that B. vulgatus/LPS-induced RelA recruitment to the IL-6 promoter is inhibited by TGF-beta1 treatment. Adenoviral delivery of Smad7 and dominant negative Smad3 (SmadDelta3) reversed the TGF-beta1-mediated inhibition of NF-kappaB transcriptional activity and NF-kappaB recruitment to the IL-6 promoter. In addition, TGF-beta1 and Ad5Smad3/4 prevent B. vulgatus/LPS-induced CBP/p300 and p65 nuclear co-association. We concluded that the TGF-beta1/Smad signaling pathway helps maintain normal intestinal homeostasis to commensal luminal enteric bacteria by regulating NF-kappaB signaling in IEC through altered histone acetylation.

Pubmed ID: 12672795

Authors

  • Haller D
  • Holt L
  • Kim SC
  • Schwabe RF
  • Sartor RB
  • Jobin C

Journal

The Journal of biological chemistry

Publication Data

June 27, 2003

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK40249
  • Agency: NIDDK NIH HHS, Id: DK47700
  • Agency: NIDDK NIH HHS, Id: P30 DK34987

Mesh Terms

  • Acetylation
  • Animals
  • Bacteroides
  • Bacteroides Infections
  • Cell Line
  • Gram-Negative Bacteria
  • Histones
  • Interleukin-6
  • Intestinal Mucosa
  • Lipopolysaccharides
  • Mice
  • NF-kappa B
  • Promoter Regions, Genetic
  • Rats
  • Rats, Inbred F344
  • Signal Transduction
  • Transcription, Genetic
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1