Pertussis toxin-sensitive factor differentially regulates lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production in mouse peritoneal macrophages.
It has been established that LPS, the major constituent of the outer membrane of gram negative bacteria, stimulates macrophages to produce numerous inflammatory mediators, including TNF-alpha and nitric oxide (NO). Both TNF-alpha and NO are important in the macrophage-mediated cytotoxicity against invading microorganisms and tumor cells. Although many LPS-dependent immune responses have been well characterized phenomenologically, the precise signal transduction pathways in LPS-induced macrophage activation are not clear. We reported that 1) pretreatment of C3HeB/FeJ mouse peritoneal macrophages with pertussis toxin (PT) markedly enhanced LPS-induced TNF-alpha production but inhibited LPS-dependent NO production under the same conditions; 2) kinetics of the PT effects on these LPS-responses were correlated with PT-mediated ADP-ribosylation of a 41-kDa protein(s); and 3) PT pretreatment did not correct the refractory states of C3H/HeJ macrophages to wild type smooth-LPS. These results suggest that LPS stimulates TNF-alpha and NO production in mouse peritoneal macrophages through different biochemical pathways, and that the signal transduction for both pathways is regulated by a PT-sensitive factor. It is possible that this factor is a guanine nucleotide-binding regulatory protein(s). Finally our data indicate that it is unlikely that the defect of the C3H/HeJ macrophages in response to LPS is at the level of this PT-sensitive factor.
Zhang
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Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City 66160.
Morrison
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D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000378:metabolism*; D010529:Peritoneal Cavity / Q000166:cytology; D037342:Pertussis Toxin; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D009569:Nitric Oxide; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins