Anti-inflammatory effects of mutant forms of secretory leukocyte protease inhibitor

The secretory leukocyte protease inhibitor (SLPI) is found in a variety of secreted fluids in mammals and is a known inhibitor of serine proteases. Wi ld-type (WT) SLPI has recently been shown to block nuclear factor kappa B ( NF-kappa B) activation in rat lungs and to interfere with the ensuing infla mmatory response and recruitment of neutrophils after an intrapulmonary dep osition of IgG immune complexes. In this study, WT SLPI and SLPI mutants wi th various degrees of protease-inhibitory capacity (for trypsin, chymotryps in, and elastase) were evaluated for their ability to suppress the lung-vas cular leak, neutrophil accumulation, and NF-kappa B activation in the lung inflammatory model The SLPI mutant with Gly(72) (replacing Leu(72)) lost it s ability to block in vivo activation of NF-kappa B, as well as its ability to suppress the lung vascular leak and neutrophil recruitment. The Phe(72) and Gly(20) mutants were as effective as the WT SLPI in suppressing NF-kap pa B activation and neutrophil recruitment. The Lys(72) mutant had the most suppressive effects of the lung vascular leak and for neutrophil recruitme nt into the lung. The in vivo suppressive effects of SLPI mutants on lung v ascular permeability, neutrophil recruitment, and NF-kappa B activation app ear to be most closely related to their trypsin-inhibiting activity. These data suggest that the suppressive effects of SLPI on the intrapulmonary act ivation of NF-kappa B and neutrophil recruitment into the lung may be linke d to their antiprotease activity, directed, perhaps, at the intracellular p roteases.