title: Oral administration of transforming growth factor-β1 (TGF-β1) protects the immature gut from injury via Smad protein-dependent suppression of epithelial nuclear factor κB (NF-κB) signaling and proinflammatory cytokine production.
abstract: Inflammatory immune responses play an important role in mucosal homeostasis and gut diseases. Nuclear factor κB (NF-κB), central to the proinflammatory cascade, is activated in necrotizing enterocolitis (NEC), a devastating condition of intestinal injury with extensive inflammation in premature infants. TGF-β is a strong immune suppressor and a factor in breast milk, which has been shown to be protective against NEC. In an NEC animal model, oral administration of the isoform TGF-β1 activated the downstream effector Smad2 in intestine and significantly reduced NEC incidence. In addition, TGF-β1 suppressed NF-κB activation, maintained levels of the NF-κB inhibitor IκBα in the intestinal epithelium, and systemically decreased serum levels of IL-6 and IFN-γ. The immature human fetal intestinal epithelial cell line H4 was used as a reductionistic model of the immature enterocyte to investigate mechanism. TGF-β1 pretreatment inhibited the TNF-α-induced IκBα phosphorylation that targets the IκBα protein for degradation and inhibited NF-κB activation. Chromatin immunoprecipitation (ChIP) assays demonstrated decreased NF-κB binding to the promoters of IL-6, IL-8, and IκBα in response to TNF-α with TGF-β1 pretreatment. These TGF-β1 effects appear to be mediated through the canonical Smad pathway as silencing of the TGF-β central mediator Smad4 resulted in loss of the TGF-β1 effects. Thus, TGF-β1 is capable of eliciting anti-inflammatory effects by inhibiting NF-κB specifically in the intestinal epithelium as well as by decreasing systemic IL-6 and IFN-γ levels. Oral administration of TGF-β1 therefore can potentially be used to protect against gastrointestinal diseases.
authors.affiliation: From the Department of Pediatrics, Section of Neonatology, and.
authors.forename: Sheng-Ru
authors.initials: SR
authors.lastname: Shiou
authors.forename: Yueyue
authors.initials: Y
authors.lastname: Yu
authors.forename: Yuee
authors.initials: Y
authors.lastname: Guo
authors.forename: Maria
authors.initials: M
authors.lastname: Westerhoff
authors.forename: Lei
authors.initials: L
authors.lastname: Lu
authors.forename: Elaine O
authors.initials: EO
authors.lastname: Petrof
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Erika C
authors.initials: EC
authors.lastname: Claud
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D005767:Gastrointestinal Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8; D007413:Intestinal Mucosa / Q000293:injuries / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C497782:SMAD2 protein, human; D051785:Smad Proteins; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma
keywords: Chromatin Immunoprecipitation (ChIP); Inflammation; Innate Immunity; Intestinal Epithelium; NF-kappa B (NF-KB); SMAD Transcription Factor; Transforming Growth Factor Beta (TGFbeta)