Transforming growth factor-beta 1 preserves epithelial barrier function: Identification of receptors, biochemical intermediates, and cytokine antagonists

Freshly isolated human mucosal T lymphocytes in vitro can markedly diminish an important property of intestinal epithelium-its barrier function. On th e other hand, cytokines and their cellular receptors, which maintain homeos tasis of epithelia, limit epithelial permeability, and preserve barrier fun ction, are not well characterized. Using a described human colonic epitheli al cell monolayer system, we found that transforming growth factor-beta 1 ( TCF-beta 1) preserved 75% or more of epithelial barrier function, quantitat ed electrophysiologically, even in the presence of cytokines generated by a high density of barrier-disruptive mucosa-derived mononuclear cells. In op posing the TGF-beta 1 effect, cytokines able to reduce barrier function wer e spontaneously secreted by mucosal T cells and were increased in their bar rier effect after T-lymphocyte activation. Further, neutralization of indiv idual cytokines with specific monoclonal antibodies abrogated the lymphocyt e-induced reduction in epithelial barrier function, and identified interfer on gamma (IFN-gamma), interleukin (IL)-4, and IL-10, but not IL-6, as the p rimary cytokines whose barrier effects were curtailed by TGF-beta 1. Recept ors (RI and RII) for TGF-beta 1 were found to be localized primarily to the apical and basal membranes of surface epithelium in colonic crypts. These findings provide the scientific basis for new strategies to pharmacological ly enhance the barrier function of epithelia in mucosal organs regularly ex posed to environmental antigens and to T-lymphocyte products. J. Cell. Phys iol. 181:55-66, 1999. (C) 1999 Wiley-Liss, Inc.