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TGF-β2 Induces Maturation of Immature Human Intestinal Epithelial Cells and Inhibits Inflammatory Cytokine Responses Induced Via the NF-κB Pathway

Rautava, Samuli; Lu, Lei; Nanthakumar, N. Nanda; Dubert-Ferrandon, Alix; Walker, W. Allan

Journal of Pediatric Gastroenterology & Nutrition: May 2012 - Volume 54 - Issue 5 - p 630–638
doi: 10.1097/MPG.0b013e31823e7c29
Original Articles: Gastroenterology

Objectives: Breast milk transforming growth factor (TGF)-β2 is associated with healthy immune maturation and reduced risk of immune-mediated disease in infants. We sought to investigate whether conditioning with TGF-β2 may result in a more mature immune responder phenotype in immature human intestinal epithelial cells (IECs).

Methods: Primary human fetal IECs (hFIECs) and the human fetal small intestinal epithelial cell line (H4 cells) were conditioned with breast milk levels of TGF-β2, and an inflammatory response was subsequently induced. Inflammatory cytokine secretion and mRNA expression were measured by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. Alterations in activation of inflammatory signaling pathways were detected from IECs by immunoblotting and immunofluorescence. The effects of TGF-β2 conditioning on gene expression patterns in hFIECs were assessed by cDNA microarray analysis and quantitative PCR.

Results: Conditioning with TGF-β2 significantly attenuated subsequent interleukin (IL)-1β-, TNF-α-, and poly I:C-induced IL-8 and IL-6 responses in immature human IECs. Conditioning with TGF-β2 inhibited IL-1β-induced IκB-α degradation and NF-κB p65 nuclear translocation, which may partially result from TGF-β2-induced changes in the expression of genes in the NF-κB signaling pathway detected by cDNA microarray and qPCR.

Conclusions: Conditioning with TGF-β2 attenuates the subsequent inflammatory cytokine response in immature human IECs by inhibiting signaling in the NF-κB pathway. The immunomodulatory potential of breast milk may in part be mediated by TGF-β2, which may provide a novel means of supporting intestinal immune maturation in neonates.

Division of Pediatric Gastroenterology, Developmental Gastroenterology Laboratory, Massachusetts General Hospital for Children, Charlestown, MA.

Address correspondence and reprint requests to Samuli Rautava, MD, PhD, Division of Pediatric Gastroenterology, Developmental Gastroenterology Laboratory, Massachusetts General Hospital for Children, 114 16th St (114-3503), Charlestown, MA 02192-4404 (e-mail: samrau@utu.fi).

Received 22 April, 2011

Accepted 21 October, 2011

The present study was supported by grants NIH R01-HD12437; R01-DK70260; P01-DK33506; P30-DK40561 (W.A.W.), and NIH R01-HD059126 (N. N.N.). S.R. is supported by the Academy of Finland, Finnish Society for Pediatric Research, Foundation for Medical Research in Finland, and the Helsingin Sanomat Foundation.

The authors report no conflicts of interest.

Copyright 2012 by ESPGHAN and NASPGHAN