LIPOPOLYSACCHARIDE-RELATED STIMULI INDUCE EXPRESSION OF THE SECRETORYLEUKOCYTE PROTEASE INHIBITOR, A MACROPHAGE-DERIVED LIPOPOLYSACCHARIDEINHIBITOR

Mouse secretory leukocyte protease inhibitor (SLPI) was recently chara cterized as a lipopolysaccharide (LPS)-induced product of macrophages that antagonizes their LPS-induced activation of NF-kappa B and produc tion of NO and tumor necrosis factor (TNF) (F, Y, Jin, C. Nathan, D., Radzioch, and A. Ding, Cell 88:417-426, 1997), To better understand th e role of SLPI in innate immune and inflammatory responses, we examine d the kinetics of SLPI expression in response to LPS, LPS-induced cyto kines, and LPS-mimetic compounds. SLPI mRNA was detectable in macropha ges by Northern blot analysis within 30 min of exposure to LPS but lev els peaked only at 24 to 36 h and remained elevated at 72 h, Despite t he slowly mounting and prolonged response, early expression of SLPI mR NA was cycloheximide resistant. Two LPS-induced proteins-interleukin-1 0 (IL-10) and IL-6-also induced SLPI, while TNF and IL-1 beta did not. The slow attainment of maximal induction of SLPI by LPS in vitro was mimicked by infection with Pseudomonas aeruginosa in vivo, where SLPI expression in the lung peaked at 3 days. Two LPS-mimetic molecules-tax ol from yew bark and lipoteichoic acid (LTA) from gram-positive bacter ial cell walls-also induced SLPI, Transfection of macrophages with SLP I inhibited their LTA-induced NO production, An anti-inflammatory role for macrophage-derived SLPI seems likely based on SLPI's slowly mount ing production in response to constituents of gram-negative and gram-p ositive bacteria, its induction both as a direct response to LPS and a s a response to anti-inflammatory cytokines induced by LPS, and its ab ility to suppress the production of proinflammatory products by macrop hages stimulated with constituents of both gram-positive and gram-nega tive bacteria.