Anti-inflammatory function of secretory leukocyte protease inhibitor

Abstract

Macrophages respond to lipopolysaccharide (LPS) by producing a battery of alarm signals and defense molecules, a response that can be beneficial or detrimental to the host depending on its scale. To explore the regulation of LPS response, we compared cell lines from two strains of mice congenic for a locus markedly affecting LPS sensitivity. Differential display detected a transcript expressed in a macrophage cell line derived from LPS-hyporesponsive mice ( Lpsd) but not in macrophages derived from congenic LPS-responsive mice ( Lps n). The cloned cDNA encodes a protein homologous to human secretory leukocyte protease inhibitor (SLPI), previously regarded as an epithelial cell-derived inhibitor of leukocyte serine proteases. In macrophages, SLPI production correlates inversely with response to LPS. Phagocytes are important sources of SLPI. Besides LPS, taxol, lipoteichoic acid (LTA) and two anti-inflammatory cytokines, IL-10 and IL-6, are capable of inducing SLPI expression in macrophages. Stable transfection with SLPI suppresses the LPS- and LTA-induced production of nitric oxide and TNFα by macrophages. An anti-inflammatory role for macrophage-derived SLPI seems likely based on the following: (i) the slowly increasing production of SLPI in response to constituents of Gram-negative and Gram-positive bacteria; (ii) its induction both as a direct response to LPS and as a response to anti-inflammatory cytokines (IL-6 and IL-10) induced by LPS; and (iii) its ability to suppress the production of pro-inflammatory products by macrophages stimulated with constituents of both Gram-positive and Gram-negative bacteria.