Article

Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas.

The Burnham Institute, La Jolla, California 92037, USA.
Journal of Biological Chemistry (impact factor: 4.77). 08/2005; 280(30):27755-8. DOI:10.1074/jbc.M506016200
Source: PubMed

ABSTRACT We have discovered that clinically tested inhibitors of matrix metalloproteinases can control the functional activity of T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the onset of disease in a rodent model of type 1 diabetes in non-obese diabetic mice. We determined that MT1-MMP proteolysis of the T cell surface CD44 adhesion receptor affects the homing of T cells into the pancreas. We also determined that both the induction of the intrinsic T cell MT1-MMP activity and the shedding of cellular CD44 follow the adhesion of insulin-specific, CD8-positive, Kd-restricted T cells to the matrix. Conversely, inhibition of these events by AG3340 (a potent hydroxamate inhibitor that was widely used in clinical trials in cancer patents) impedes the transmigration of diabetogenic T cells into the pancreas and protects non-obese diabetic mice from diabetes onset. Overall, our studies have divulged a previously unknown function of MT1-MMP and identified a promising novel drug target in type I diabetes.

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Keywords

cancer patents
 
cellular CD44
 
diabetes onset
 
diabetogenic T cells
 
functional activity
 
inhibition
 
inhibitors
 
intrinsic T cell MT1-MMP activity
 
Kd-restricted T cells
 
matrix metalloproteinases
 
MT1-MMP
 
MT1-MMP proteolysis
 
non-obese diabetic mice
 
potent hydroxamate inhibitor
 
promising novel drug target
 
rodent model
 
T cell membrane type-1 matrix metalloproteinase
 
T cells
 
type 1 diabetes
 
unknown function