Transforming growth factor-β1 inhibits non-pathogenic Gram-negative bacteria-induced NF-κB recruitment to the interleukin-6 gene promoter in intestinal epithelial cells through modulation of histone acetylation

Dirk Haller, Lisa Holt, Sandra C. Kim, Robert F. Schwabe, R. Balfour Sartor, Christian Jobin

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

Abstract

We have shown that non-pathogenic enteric Gram-negative Bacteroides vulgatus induces RelA phosphorylation, NF-κB 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-κB and transforming growth factor-β1 (TGF-β1) signaling are induced in vivo following bacterial colonization. Interestingly, TGF-β1 inhibited B. vulgatus- and lipopolysaccharide (LPS)-induced NF-κB transcriptional activity as well as interleukin-6 (IL-6) mRNA accumulation and protein secretion in IEC. The inhibitory effect of TGF-β1 is mediated independently of B. vulgatus/LPS-induced IκBα, Akt, and RelA phosphorylation as well as NF-κB 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-β1-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-β1 treatment. Adenoviral delivery of Smad7 and dominant negative Smad3 (SmadΔ3) reversed the TGF-β1-mediated inhibition of NF-κB transcriptional activity and NF-κB recruitment to the IL-6 promoter. In addition, TGF-β1 and Ad5Smad3/4 prevent B. vulgatus/LPS-induced CBP/p300 and p65 nuclear co-association. We concluded that the TGF-β1/ Smad signaling pathway helps maintain normal intestinal homeostasis to commensal luminal enteric bacteria by regulating NF-κB signaling in IEC through altered histone acetylation.

Original languageEnglish
Pages (from-to)23851-23860
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number26
DOIs
StatePublished - 27 Jul 2003

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