Transforming growth factor-beta1 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 the other hand, cytokines and their cellular receptors, which maintain homeostasis of epithelia, limit epithelial permeability, and preserve barrier function, are not well characterized. Using a described human colonic epithelial cell monolayer system, we found that transforming growth factor-beta1 (TGF-beta1) preserved 75% or more of epithelial barrier function, quantitated electrophysiologically, even in the presence of cytokines generated by a high density of barrier-disruptive mucosa-derived mononuclear cells. In opposing the TGF-beta1 effect, cytokines able to reduce barrier function were spontaneously secreted by mucosal T cells and were increased in their barrier effect after T-lymphocyte activation. Further, neutralization of individual cytokines with specific monoclonal antibodies abrogated the lymphocyte-induced reduction in epithelial barrier function, and identified interferon gamma (IFN-gamma), interleukin (IL)-4, and IL-10, but not IL-6, as the primary cytokines whose barrier effects were curtailed by TGF-beta1. Receptors (RI and RII) for TGF-beta1 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 pharmacologically enhance the barrier function of epithelia in mucosal organs regularly exposed to environmental antigens and to T-lymphocyte products.
Planchon
S
S
Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA.
Fiocchi
C
C
Takafuji
V
V
Roche
J K
JK
D000242:Cyclic AMP / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000737:chemistry / Q000187:drug effects*; D018655:Lymphocyte Count / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects*; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016207:Cytokines; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000242:Cyclic AMP