Anti-inflammatory function of secretory leukocyte protease inhibitor

Macrophages respond to lipopolysaccharide (LPS) by producing a battery of a larm signals and defense molecules, a response that can be beneficial or de trimental 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-hyporespon sive mice (Lps(d)) but not in macrophages derived from congenic LPS-respons ive mice (Lps(n)). The cloned cDNA encodes a protein homologous to human se cretory leukocyte protease inhibitor (SLPI), previously regarded as an epit helial 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 S LPI expression in macrophages. Stable transfection with SLPI suppresses the LPS- and LTA-induced production of nitric oxide and TNF alpha by macrophag es. An anti-inflammatory role for macrophage-derived SLPI seems likely base d on the following: (i) the slowly increasing production of SLPI in respons e to constituents of Gram-negative and Gram-positive bacteria; (ii) its ind uction both as a direct response to LPS and as a response to anti-inflammat ory cytokines (IL-6 and IL-10) induced by LPS; and (iii) its ability to sup press the production of pro-inflammatory products by macrophages stimulated with constituents of both Gram-positive and Gram-negative bacteria.