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.
Beatrice and Sammuel A Seaver Laboratory, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
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D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D053481:Secretory Leukocyte Peptidase Inhibitor; D013682:Teichoic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014162:Transfection / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007378:Interleukins; D008070:Lipopolysaccharides; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D012333:RNA, Messenger; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C009900:lipoteichoic acid; D007371:Interferon-gamma