Sm. Planchon et al., REGULATION OF INTESTINAL EPITHELIAL BARRIER FUNCTION BY TGF-BETA-1 - EVIDENCE FOR ITS ROLE IN ABROGATING THE EFFECT OF A T-CELL CYTOKINE, The Journal of immunology, 153(12), 1994, pp. 5730-5739
Maintenance of the integrity of the single-cell-thick intestinal epith
elium as an in vivo barrier between environmental Ags and mucosal immu
nocytes is pivotal for health. The T cell cytokine IFN-gamma consisten
tly disrupts this epithelial barrier in vitro, but the substances in m
ucosa that may be responsible for sustaining or enhancing barrier func
tion have not been clearly identified. Therefore, we characterized the
effect on the epithelial barrier of TGF-beta 1 and three prominent ne
uropeptides (VIP, substance P, somatostatin) by using a model system i
n which barrier function of a mature polar human colonic epithelial (T
84) cell monolayer is reflected in 1) the electrical potential differe
nce across the apical to basolateral surface of each cell, 2) the tran
smonolayer permeability to macromolecules such as horseradish peroxida
se, and 3) lactate dehydrogenase release into the medium indicating ep
ithelial cell cytolysis. Whereas T84 monolayers exposed to TGF-beta 1
alone demonstrated a modest increase in electrical resistance and barr
ier integrity, TGF-beta 1 showed a striking ability to reduce the capa
city of IFN-gamma to disrupt epithelial barrier function. Characteriza
tion studies demonstrated that this TGF-beta 1 effect was prolonged (e
.g., days) after a single exposure, progressive over the dose range 0.
1 to 2.5 ng/ml, reversible with increased concentrations of IFN-gamma,
and more pronounced when TGF-beta 1 exposure was to basolateral rathe
r than to apical epithelial membranes. Macromolecular (horseradish per
oxidase) penetration of epithelium was not simultaneously altered by T
GF-beta 1 and epithelial cellular injury was minimal as gauged by lact
ate dehydrogenase release. Additional studies using a human pathogen d
emonstrated that TGF-beta 1 delayed and decreased the barrier disrupti
on caused by exposure to Cryptosporidium parvum. TGF-beta 1 may be the
first of a new class of cytokines that maintains and/or enhances barr
ier function of human enterocytes, in part by countering the effect of
a T cell cytokine.