TY - JOUR

T1 - Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine.

AU - Nguyen, Duc Ninh

AU - Sangild, Per Torp

AU - Østergaard, Mette Viberg

AU - Bering, Stine Brandt

AU - Chatterton, Dereck Edward Winston

N1 - CURIS 2014 NEXS 272

PY - 2014

Y1 - 2014

N2 - A balance between pro- and anti-inflammatory signals from the milk and microbiota controls intestinal homeostasis just after birth, and an optimal balance is particularly important for preterm neonates that are sensitive to necrotizing enterocolis (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 LPS to control IL-8 levels, thereby supporting intestinal homeostasis. Preterm pigs were fed colostrum (containing TGF-β2) or infant formula 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 COX-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, while excessive IL-8 production may enhance the damaging pro-inflammatory cascade leading to NEC.

AB - A balance between pro- and anti-inflammatory signals from the milk and microbiota controls intestinal homeostasis just after birth, and an optimal balance is particularly important for preterm neonates that are sensitive to necrotizing enterocolis (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 LPS to control IL-8 levels, thereby supporting intestinal homeostasis. Preterm pigs were fed colostrum (containing TGF-β2) or infant formula 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 COX-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, while excessive IL-8 production may enhance the damaging pro-inflammatory cascade leading to NEC.

U2 - 10.1152/ajpgi.00193.2014

DO - 10.1152/ajpgi.00193.2014

M3 - Journal article

C2 - 25147235

VL - 307

SP - G689-G699

JO - American Journal of Physiology: Gastrointestinal and Liver Physiology

JF - American Journal of Physiology: Gastrointestinal and Liver Physiology

SN - 0193-1857

IS - 7

ER -