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(American Journal of Pathology. 2000;156:1033-1039.)
© 2000 American Society for Investigative Pathology

Regular Articles

Anti-Inflammatory Effects of Mutant Forms of Secretory Leukocyte Protease Inhibitor

Michael S. Mulligan^*, Alex B. Lentsch, Markus Huber-Lang, Ren-Feng Guo, Vidya Sarma, Clifford D. Wright^§, Thomas R. Ulich^§ and Peter A. Ward

From the Departments of Surgery^*
and Pathology,
University of Michigan Medical School, Ann Arbor, Michigan; the Department of Surgery,
University of Louisville School of Medicine, Louisville, Kentucky; and Amgen, Inc.,^§
Thousand Oaks, California

The secretory leukocyte protease inhibitor (SLPI) is found in a variety of secreted fluids in mammals and is a known inhibitor of serine proteases. Wild-type (WT) SLPI has recently been shown to block nuclear factor B (NF-B) activation in rat lungs and to interfere with the ensuing inflammatory response and recruitment of neutrophils after an intrapulmonary deposition of IgG immune complexes. In this study, WT SLPI and SLPI mutants with various degrees of protease-inhibitory capacity (for trypsin, chymotrypsin, and elastase) were evaluated for their ability to suppress the lung-vascular leak, neutrophil accumulation, and NF-B activation in the lung inflammatory model. The SLPI mutant with Gly⁷² (replacing Leu⁷² ) lost its ability to block in vivo activation of NF-B, as well as its ability to suppress the lung vascular leak and neutrophil recruitment. The Phe⁷² and Gly²⁰ mutants were as effective as the WT SLPI in suppressing NF-B activation and neutrophil recruitment. The Lys⁷² mutant had the most suppressive effects of the lung vascular leak and for neutrophil recruitment into the lung. The in vivo suppressive effects of SLPI mutants on lung vascular permeability, neutrophil recruitment, and NF-B activation appear to be most closely related to their trypsin-inhibiting activity. These data suggest that the suppressive effects of SLPI on the intrapulmonary activation of NF-B and neutrophil recruitment into the lung may be linked to their antiprotease activity, directed, perhaps, at the intracellular proteases.

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