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

To explore gene regulation by bacterial lipopolysaccharide (LPS), we compared mRNA profiles of macrophage cell lines from two strains of mice congenic for a locus markedly affecting their ability to respond to LPS. Differential display detected four differentially expressed transcripts. One transcript encoded the mouse homolog of human secretory leukocyte protease inhibitor (SLPI), which was expressed by LPS-hyporesponsive macrophage cells (Lps(d)) but not by LPS-normoresponsive cells (Lps(n)). Among five macrophage cell lines, secretion of SLPI was inversely correlated with ability to produce nitric oxide (NO) and tumor necrosis factor alpha in response to LPS. Stable transfection of LPS-responsive macrophages with SLPI suppressed LPS-induced responses. Interferon-gamma (IFN-gamma), which corrects the defective LPS response in Lps(d) macrophages, suppressed the LPS-induced expression of SLPI and restored LPS response to SLPI-overexpressing macrophages. Besides its role as a LPS response inhibitor, mouse SLPI is also a lipoteichoic acid response inhibitor. The expression of SLPI was strongly enhanced by interleukin-10 and -6. SLPI may be an important antiinflammatory molecule in host defense against gram-negative and gram-positive bacteria.