Secretory Leukocyte Protease Inhibitor: A Macrophage Product Induced by and Antagonistic to Bacterial Lipopolysaccharide

TLDR

The ability of interferon‑γ to restore LPS responsiveness is a hallmark of the LPS‑hyporesponsive phenotype. To explore regulation of potentially lethal responses to bacterial lipopolysaccharide, we used differential display under LPS‑free conditions to compare macrophage cell lines from two strains of mice congenic for a locus affecting LPS sensitivity. We used differential display under LPS‑free conditions to compare macrophage cell lines from two strains of mice congenic for a locus affecting LPS sensitivity. SLPI is produced by LPS‑hyporesponsive cells and primary macrophages, and its expression suppresses LPS‑induced NF‑κB activation, nitric oxide, and TNFα production, while IFNγ down‑regulates SLPI and restores LPS responsiveness, showing that SLPI is an IFNγ‑suppressible phagocyte product that antagonizes LPS responses.

Abstract

To explore regulation of potentially lethal responses to bacterial lipopolysaccharide (LPS), we used differential display under LPS-free conditions to compare macrophage cell lines from two strains of mice congenic for a locus affecting LPS sensitivity. LPS- hyporesponsive cells, primary macrophages, and polymorphonuclear leukocytes transcribed secretory leukocyte protease inhibitor (SLPI), a known epithelial cell-derived inhibitor of leukocyte serine proteases. Transfection of macrophages with SLPI suppressed LPS-induced activation of NF-κB and production of nitric oxide and TNFα. The ability of interferon-γ (IFNγ) to restore LPS responsiveness is a hallmark of the LPS-hyporesponsive phenotype. IFNγ suppressed expression of SLPI and restored LPS responsiveness to SLPI-producing cells. Thus, SLPI is an LPS-induced IFNγ-suppressible phagocyte product that serves to inhibit LPS responses.