title: Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine.
abstract: A balance between pro- and anti-inflammatory signals from milk and microbiota controls intestinal homeostasis just after birth, and an optimal balance is particularly important for preterm neonates that are sensitive to necrotizing enterocolitis (NEC). We suggest that the intestinal cytokine IL-8 plays an important role and hypothesize that transforming growth factor-β2 (TGF-β2) acts in synergy with bacterial lipopolysaccharide (LPS) to control IL-8 levels, thereby supporting intestinal homeostasis. Preterm pigs were fed colostrum (containing TGF-β2) or infant formula (IF) with or without antibiotics (COLOS, n = 27; ANTI, n = 11; IF, n = 40). Intestinal IL-8 levels and NEC incidence were much higher in IF than in COLOS and ANTI pigs (P < 0.001), but IL-8 levels did not correlate with NEC severity. Intestinal TGF-β2 levels were high in COLOS but low in IF and ANTI pigs. Based on these observations, the interplay among IL-8, TGF-β2, and LPS was investigated in a porcine intestinal epithelial cell line. TGF-β2 attenuated LPS-induced IL-6, IL-1β, and TNF-α release by reducing early ERK activation, whereas IL-8 secretion was synergistically induced by LPS and TGF-β2 via NF-κB. The TGF-β2/LPS-induced IL-8 levels stimulated cell proliferation and migration following epithelial injury, without continuous NF-κB activation and cyclooxygenase-2 expression. We suggest that a combined TGF-β2-LPS induction of IL-8 stimulates epithelial repair just after birth when the intestine is first exposed to colonizing bacteria and TGF-β2-containing milk. Moderate IL-8 levels may act to control intestinal inflammation, whereas excessive IL-8 production may enhance the damaging proinflammatory cascade leading to NEC.
authors.affiliation: Faculty of Science, Department of Food Science, University of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Duc Ninh
authors.initials: DN
authors.lastname: Nguyen
authors.affiliation: Faculty of Science, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Per T
authors.initials: PT
authors.lastname: Sangild
authors.affiliation: Faculty of Science, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette V
authors.initials: MV
authors.lastname: Ostergaard
authors.affiliation: Faculty of Science, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stine B
authors.initials: SB
authors.lastname: Bering
authors.affiliation: Faculty of Science, Department of Food Science, University of Copenhagen, Copenhagen, Denmark; and Faculty of Science, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark dcha@food.ku.dk.
authors.forename: Dereck E W
authors.initials: DE
authors.lastname: Chatterton
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D003126:Colostrum; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005865:Gestational Age; D006706:Homeostasis; D006801:Humans; D041943:Infant Formula; D007231:Infant, Newborn; D016209:Interleukin-8 / Q000378:metabolism* / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000254:growth & development / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D047928:Premature Birth; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013997:Time Factors; D053781:Transforming Growth Factor beta2 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053781:Transforming Growth Factor beta2; C433788:lipopolysaccharide, E. coli O26-B6; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: lipopolysaccharide; necrotizing enterocolitis; nuclear factor-κB; preterm infants