Paradoxical preservation of a lipopolysaccharide response in C3H/HeJ macrophages: induction of matrix metalloproteinase-9.
C3H/HeJ mice carry a mutant allele (Lpsd) of a recently identified gene whose normal allele (Lpsn) confers responsiveness to bacterial LPS in C3H/HeN and most other mouse strains. Recently we reported differential display analysis of matched macrophage-derived cell lines from C3H/HeJ and C3H/HeN mice under LPS-free conditions. Of the approximately 12,000 transcripts evaluated, 4 were differentially expressed. One transcript represented secretory leukocyte protease inhibitor. In this study, we report another differentially expressed transcript, mouse matrix metalloprotease-9 (MMP-9). Like secretory leukocyte protease inhibitor, MMP-9 was expressed constitutively in the Lpsd macrophage cell line and not in the Lpsn cell line. Similarly, two additional macrophage cell lines that respond readily to LPS by producing nitric oxide and TNF expressed no MMP-9 under LPS-free conditions. However, in all four cell lines, LPS induced MMP-9 or augmented its expression. In primary macrophages, concentrations of LPS in the ng/ml range augmented the expression of MMP-9 mRNA. Paradoxically, macrophages from Lpsd mice expressed more MMP-9 transcripts than macrophages from Lpsn mice. In contrast, the induction of TNF in response to LPS was much more pronounced in Lpsn macrophages. The present findings with MMP-9 suggest that homozygosity at Lpsd does not so much prevent a response to LPS as dysregulate it, resulting in the suppression of some LPS signaling pathways and the preservation of others.
Jin
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Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York 10021, USA.
Nathan
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CF
Ding
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D000483:Alleles; D000818:Animals; D002460:Cell Line; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D004790:Enzyme Induction / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008809:Mice, Inbred C3H; D013864:Thioglycolates / Q000008:administration & dosage; D014158:Transcription, Genetic / Q000276:immunology
D008070:Lipopolysaccharides; D013864:Thioglycolates; D017364:Collagenases; D020780:Matrix Metalloproteinase 9