title: Pertussis toxin-sensitive factor differentially regulates lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production in mouse peritoneal macrophages.
abstract: 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.
authors.affiliation: Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City 66160.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: D C
authors.initials: DC
authors.lastname: Morrison
mesh_terms: 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*
chemical_list: 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