Membrane-type 1-matrix metalloproteinase regulates intracellular adhesion molecule-1 (ICAM-1)-mediated monocyte transmigration

We examined the mechanism regulating intercellular cell adhesion molecule-1 ( ICAM-1)-dependent monocyte transendothelial migration. Monocyte migration through endothelial cells expressing ICAM- 1 alone was comparable to that of tumor necrosis factor- alpha- treated cells. Transmigration was reduced in ICAM- 1 lacking the cytoplasmic tail and in tyrosine to alanine substitutions at Tyr- 485 and Tyr- 474. Tissue inhibitors of matrix metalloproteinases ( TIMPs) - 2 and - 3 blocked transmigration, whereas TIMP- 1 was ineffective. This profile suggested a role for membrane-type matrix metalloproteinases ( MT-MMPs) in transmigration. Inhibitory antibodies and small interference RNA directed against MT1- MMP blocked transmigration, whereas overexpression of MT1- MMP in endothelial cells or monocytes promoted transmigration. MT1- MMP mediated the ectodomain cleavage of ICAM- 1 that was blocked by TIMP- 2 and - 3. Overexpression of MT1- MM Prescued function in ICAM-1Y485A, and to a lesser extent in the cytoplasmic tail-deleted ICAM- 1. In a binding assay, wild-type ICAM- 1 bound to purified MT1- MMP while ICAM- 1 mutants bound poorly. MT1- MMP co-localized with ICAM- 1 at distinct structures in endothelial cells. MT1- MMP localization with cells expressing ICAM- 1 mutations was reduced and diffused. These results indicate that the cytoplasmic tail of ICAM- 1 regulates leukocyte transmigration through MT1- MMP interaction.