DIFFERENTIAL INHIBITION OF MAST-CELL CHYMASES BY SECRETORY LEUKOCYTE PROTEASE INHIBITOR

The major physiological role of human secretory leukocyte protease inh ibitor (SLPI), a low molecular weight inhibitor present in mucus, is t he rapid formation of a tight-binding inhibitory complex with neutroph il elastase. It is also the most effective known inhibitor of human ma st cell chymase. The inhibitory efficacy of recombinant SLPI towards t hree other mast cell chymases was therefore investigated. Rat mast cel l proteinases-l and -2 (rMCP-1 and -2, respectively) and sheep mast ce ll proteinase-1 (sMCP-1), a chymase with additional tryptase-like prop erties, were treated with the inhibitor. SLPI inhibited rMCP-1 very ef ficiently in the absence of heparin, with a low dissociation constant, K-i = 3 x 10(-10) M and high second order association constant, k(ass ) = 8.0 x 10(6) M-1 s(-1), and inhibition was enhanced when heparin wa s present. rMCP-2 was not inhibited by SLPI in the presence or absence of heparin, and did not degrade SLPI on prolonged incubation. SLPI in hibited sMCP-1 very poorly in the absence of heparin (K-i = 9 x 10(-6) M). However, in the presence of heparin, the K-i for inhibition of sM CP-1 by SLPI was reduced to the nanomolar range. sMCP-1 was observed t o cleave SLPI with chymase-like specificity at Leu(72)-Met(73) on prol onged incubation in the absence of heparin, but increasing concentrati ons of heparin reduced the extent of cleavage. (C) 1998 Elsevier Scien ce B.V.