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Maternal milk regulation of cell infiltration and interleukin 18 in the intestine of suckling rat pups

¹ Child Health Research Institute, North Adelaide, South Australia, Australia, 5006
² Department of Paediatrics, University of Adelaide, Adelaide, Australia
³ CRC for Tissue Growth and Repair, North Adelaide, South Australia, Australia, 5006

Correspondence to:
Correspondence to:
Dr I Penttila
Child Health Research Institute, 72 King William Road, North Adelaide, SA 5006, Australia; irmeli.penttila{at}adelaide.edu.au

ABSTRACT
Background and aims: In neonates the gastrointestinal tract is exposed to food and bacterial antigens at a time when the gut mucosal immune system has not developed the ability to induce oral tolerance. This increases the risk for an inappropriate immune response to oral antigens. Transforming growth factor ß (TGF-ß) is an immunoregulatory cytokine present in high concentration in maternal milk. Interleukin 18 (IL-18) is a cytokine that mediates early immune events, and drives T cell development. We assessed the role of TGF-ß in mediating mucosal immune development and specifically the effect on endogenous IL-18.

Methods: Rat pups were randomly assigned to the following groups, naturally suckled, maternal milk via cannula, and formula fed with and without physiological levels of TGF-ß2. A comparison of the immune response profile was then carried out. Cytokine profiles, dendritic cell, intestinal mast cell, and eosinophil numbers were assessed.

Results: We show that feeding formula deficient in TGF-ß2 resulted in accumulated IL-18 protein release from intestinal epithelial cells and IL-18 mRNA up regulation. A proinflammatory cytokine profile resulted in the gut, along with increased numbers of activated dendritic cells, eosinophils, and mast cells. Supplementation of the formula with TGF-ß2 down regulated the proinflammatory cytokine mRNA as well as the number of activated lymphocytes, eosinophils, mast cells, CD80, and CD86 positive dendritic cells.

Conclusion: The data suggests an important role for maternal milk, in regulating immune responses after exposure to food antigens, which might otherwise induce deleterious immune responses in the intestine of suckling neonates. This regulation is potentially mediated by milk TGF-ß2, as well as endogenous IL-18.

Keywords: milk; TGF-ß; IL-18; immune development

Abbreviations: BSA, bovine serum albumin; Cy3, indocarbocyanine; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IFN-, interferon ; IL-18, interleukin 18; IL-1ra, interleukin 1 receptor antagonist; PBS, phosphate buffered saline; RMCP II, rat mast cell protease II; TGF-ß, transforming growth factor ß; Th1, T helper cell type 1; Th2, T helper cell type 2

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