Identification of genes involved in innate responsiveness to bacterial products by differential display

To explore gene regulation by bacterial lipopolysaccharide (LPS), we compar ed mRNA profiles of macrophage cell lines from two strains of mice congenic for a locus markedly affecting their ability to respond to LPS. Differenti al display detected four differentially expressed transcripts. One transcri pt encoded the mouse homolog of human secretory leukocyte protease inhibito r (SLPI), which was expressed by LPS-hyporesponsive macrophage cells (Lps(d )) but not by LPS-normoresponsive cells (Lps(n)). Among five macrophage cel l lines, secretion of SLPI was inversely correlated with ability to produce nitric oxide (NO) and tumor necrosis factor a in response to LPS. Stable t ransfection of LPS-responsive macrophages with SLPI suppressed LPS-induced responses. Interferon-gamma (IFN-gamma), which corrects the defective LPS r esponse in Lpsd macrophages, suppressed the LPS-induced expression of SLPI and restored LPS response to SLPI-overexpressing macrophages. Besides its r ole as a LPS response inhibitor, mouse SLPI is also a lipoteichoic acid res ponse inhibitor. The expression of SLPI was strongly enhanced by interleuki n-10 and -6. SLPI may be an important antiinflammatory molecule in host def ense against gram-negative and gram-positive bacteria. (C) 1998 Academic Pr ess.