Interferon-gamma and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function

Inflammatory bowel disease (IBD) is associated with Th1/th2 cytokine dysreg ulation, leukocyte extravasation, and tissue edema, but the mechanisms for cytokine-mediated vascular dysfunction are not understood. To investigate h ow cytokines might control edema in IBD, we determined vascular permeabilit y and IFN-gamma expression in two models of murine colitis: SCID mice recon stituted with CD45RB(high) T-lymphocytes (CD45RB(high)/ SCID mice), and int erleukin-10 gene deficient (IL-10(-/-)) mice. We also investigated the in v itro effects of IFN-gamma and IL-10 on human endothelial solute barrier and junction protein expression. Vascular permeability in CD45RB(high)/SCID an d IL-10(-/-) mice was quantified using tissue I-131-IgG accumulation. The I FN-gamma message was quantified using the ribonuclease protection assay. En dothelial barrier integrity in vitro was measured by transmonolayer electri cal resistance, and junctional proteins were examined by immunoblotting and fluorescence microscopy. Both CD45RB(high)/SCID and IL-10(-/-) mice exhibi t enhanced colonic microvascular leakage and IFN-gamma message levels compa red to their respective controls. In vitro, IFN-gamma also reduced endothel ial barrier (monolayer electrical resistance, increased albumin permeabilit y) and reduced tight junction (occludin) expression and staining. These eff ects were reversed by pretreatment of monolayers with IL-10. Therefore, in vivo IFN-gamma and IL-10 may modulate microvascular leakage in IBD partly b y controlling the expression of intestinal endothelial tight junctional pro teins, (C) 2001 Academic Press.