The L-selectin adhesion molecule is rapidly downregulated from the surface of activated leukocytes by an undefined protease This regulated cleavage occurs at a membrane-proximal site of L-selectin and is resistant to a broad panel of common protease inhibitors. Here we report that a peptide hydroxamic acid-based metalloprotease inhibitor (KD-IX-73-4) is a potent inhibitor of L-selectin shedding from PMA-activated lymphocytes and fMLP- and PMA-activated neutrophils. KD-IX-73-4 inhibits L-selectin shedding in a dose-dependent manner and does not affect general cell activation. Analysis of L-selectin cleavage products confirmed that KD-IX-73-4 inhibits the proteolysis of L-selectin. Lymphocyte L-selectin was not downregulated when co-cultured with fMLP-stimulated neutrophils, suggesting that the putative secretase acts in cis with the membrane-bound L-selectin. These results suggest that the L-selectin secretase activity may involve a cell surface metalloprotease -although L-selectin shedding is not affected by EDTA - and may be related to the recently described activity involved in processing of membrane-bound TNF.
|Original language||English (US)|
|State||Published - Dec 1 1996|