Abstract
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.
Highlights
Lial cells (IEC)1 by activating multiple signaling cascades, including the transcription factor NF-B [1, 2]
We demonstrate the transient induction of nuclear phospho-RelA followed by persistent activation of phospho-Smad2 in intestinal epithelial cell (IEC) from mucosal tissue sections of B. vulgatus-monoassociated rats, indicating that both NF-B and transforming growth factor-1 (TGF-1) signaling are induced in vivo following bacterial colonization
Chromatin immunoprecipitation analysis revealed that B. vulgatus/LPSinduced RelA recruitment to the IL-6 promoter is inhibited by TGF-1 treatment
Summary
Lial cells (IEC) by activating multiple signaling cascades, including the transcription factor NF-B [1, 2]. We have shown that the non-pathogenic commensal enteric bacterial species Bacteroides vulgatus activates ICAM-1 gene expression through a mechanism involving both NF-B nuclear translocation and RelA phosphorylation in primary and IEC lines [3]. IEC must adapt to a constant and constitutively changing luminal environment by processing different biological information through multiple signaling cascades that target a defined set of genes, which provide an adequate effector response [2] These extracellular cytoplasmic signals must be integrated with the action of various nuclear signal processes controlling access of transcription factors to the regulatory region of gene promoters. We report that TGF-1-activated Smad signaling mediates inhibition of B. vulgatus and LPS-induced NF-B recruitment to the IL-6 gene promoter through modulation of histone acetylation Activation of this inhibitory pathway may be important in down-regulating IEC responses to commensal bacteria
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