SECRETORY LEUKOCYTE PROTEASE INHIBITOR - A MACROPHAGE PRODUCT INDUCEDBY AND ANTAGONISTIC TO BACTERIAL LIPOPOLYSACCHARIDE

To explore regulation of potentially lethal responses to bacterial lip opolysaccharide (LPS), we used differential display under LPS-free con ditions to compare macrophage cell lines from two strains of mice cong enic for a locus affecting LPS sensitivity. LPS-hyporesponsive cells, primary macrophages, and polymorphonuclear leukocytes transcribed secr etory leukocyte protease inhibitor (SLPI), a known epithelial cell-der ived inhibitor of leukocyte serine proteases. Transfection of macropha ges with SLPI suppressed LPS-induced activation of NF-kappa B and prod uction of nitric oxide and TNF alpha. The ability of interferon-gamma (IFN gamma) to restore LPS responsiveness is a hallmark of the LPS-hyp oresponsive phenotype. IFN gamma suppressed expression of SLPI and res tored LPS responsiveness to SLPI-producing cells. Thus, SLPI is an LPS -induced IFN gamma-suppressible phagocyte product that serves to inhib it LPS responses.