Transfection of IL-10 expression vectors into endothelial cultures attenuates alpha4beta7-dependent lymphocyte adhesion mediated by MAdCAM-1.
BACKGROUND
Enhanced expression of MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is associated with the onset and progression of inflammatory bowel disease. The clinical significance of elevated MAdCAM-1 expression is supported by studies showing that immunoneutralization of MAdCAM-1, or its ligands reduce inflammation and mucosal damage in models of colitis. Interleukin-10 (IL-10) is an endogenous anti-inflammatory and immunomodulatory cytokine that has been shown to prevent inflammation and injury in several animal studies, however clinical IL-10 treatment remains insufficient because of difficulties in the route of IL-10 administration and its biological half-life. Here, we examined the ability of introducing an IL-10 expression vector into endothelial cultures to reduce responses to a proinflammatory cytokine, TNF-alpha


METHODS
A human IL-10 expression vector was transfected into high endothelial venular ('HEV') cells (SVEC4-10); we then examined TNF-alpha induced lymphocyte adhesion to lymphatic endothelial cells and TNF-alpha induced expression of MAdCAM-1 and compared these responses to control monolayers.


RESULTS
Transfection of the IL-10 vector into endothelial cultures significantly reduced TNF-alpha induced, MAdCAM-1 dependent lymphocyte adhesion (compared to non-transfected cells). IL-10 transfected endothelial cells expressed less than half (46 +/- 6.6%) of the MAdCAM-1 induced by TNF-alpha (set as 100%) in non-transfected (control) cells.


CONCLUSIONS
Our results suggest that gene therapy of the gut microvasculature with IL-10 vectors may be useful in the clinical treatment of IBD.
Sasaki
Makoto
M
Louisiana State University Health Sciences Center-Shreveport Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, LA, USA. msasak@lsuhsc.edu
Jordan
Paul
P
Houghton
Jeff
J
Meng
Xianmin
X
Itoh
Makoto
M
Joh
Takashi
T
Alexander
J Steven
JS
D000268:Adhesiveness; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000628:therapy; D039001:Integrin alpha Chains / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D009088:Mucoproteins / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039001:Integrin alpha Chains; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10