HYDROXAMATE-BASED METALLOPROTEASE INHIBITOR BLOCKS SHEDDING OF L-SELECTIN ADHESION MOLECULE FROM LEUKOCYTES - FUNCTIONAL CONSEQUENCES FOR NEUTROPHIL AGGREGATION

L-selectin is an adhesion molecule that mediates the recruitment of ne utrophils to inflammatory sites and initiates the migration of lymphoc ytes into the peripheral lymph nodes. In response to cell activation, L-selectin is shed from the cell surface, and altered levels of functi onal soluble L-selectin are detected in the plasma of patients sufferi ng from numerous inflammatory diseases as well as AIDS. The mechanism that regulates L-selectin shedding is poorly understood, Here we show that a hydroxamate-based metalloprotease inhibitor, -methylpentano}-L- 3-(tert-butyl)-alanyl-L-alanine, 2-aminoethyl amide, which blocks leuk ocyte TNF, TNF receptor, and IL-6 receptor release, also inhibits L-se lectin shedding from neutrophils, eosinophils, and lymphocytes, Moreov er, we show that such inhibition of L-selectin shedding profoundly aff ects neutrophil aggregation and permits reaggregation in the presence of a heterologous stimulus.