IL-4 directly modulates function of a model human intestinal epithelium.
Intestinal epithelia are in intimate contact with subepithelial and intraepithelial lymphocytes. When stimulated, mucosal lymphocytes generate inflammatory cytokines such as IL-4 and IFN-gamma. We have shown that IFN-gamma directly regulates epithelial function. It is unknown whether IL-4 might influence epithelial function and, if so, whether such influences are similar to or differ from those exerted by IFN-gamma. In this study, we examine the effect of human IL-4 on barrier function, ion transport, and immune accessory ligand expression on T84 cells, a crypt-like epithelial cell line. Basolateral exposure of epithelial monolayers to IL-4 attenuated epithelial barrier function by greater than 65% in a dose (50% of effective dose = 1 U/ml)- and time (t1/2 = 24 h)-dependent fashion, and was inhibitable by neutralizing anti-IL-4 and anti-IL-4R Ab. Stimulated Cl- secretion, as measured by epithelial short circuit current, was diminished by as much as 70% by IL-4. Epithelial preexposure to IL-4 brought about a greater than twofold increase in beta 2 integrin-dependent neutrophil adhesion to epithelial, but retarded neutrophil migration into and across epithelial monolayers. ELISAs revealed that epithelial exposure to IL-4 had no effect on cell surface expression of MHC class I, MHC class II, or ICAM-1. These results indicate that IL-4, like IFN-gamma, may serve to regulate intestinal epithelial function, but that resulting phenotypes may be cytokine specific. We speculate from these data that activation of the basolateral receptor for IL-4 potentially provides a new strategy for damping the cellular component of active inflammation in the intestine.
Colgan
S P
SP
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Resnick
M B
MB
Parkos
C A
CA
Delp-Archer
C
C
McGuirk
D
D
Bacarra
A E
AE
Weller
P F
PF
Madara
J L
JL
D015815:Cell Adhesion Molecules / Q000378:metabolism; D016764:Cell Polarity; D002712:Chlorides / Q000378:metabolism; D004848:Epithelium / Q000276:immunology; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000502:physiology*; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000502:physiology
D015815:Cell Adhesion Molecules; D002712:Chlorides; D006680:HLA Antigens; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4; D007371:Interferon-gamma