title: Interferon-gamma and tumor necrosis factor-alpha exert their antirickettsial effect via induction of synthesis of nitric oxide.
abstract: How the host defenses control rickettsiae in the cytosol of nonphagocytic host cells, where they are not exposed to antibodies or phagocytes, has posed a difficult question. Rickettsia conorii infection of a mouse fibroblast cell line was inhibited in a dose-dependent manner by nitrogen oxide synthesized by eukaryotic host cells stimulated by interferon-gamma or tumor necrosis factor-alpha. L-arginine was the source of the nitric oxide as demonstrated by competitive inhibition by NG-monomethyl-L-arginine. Nitric oxide synthesis required host cell protein synthesis and had an approximately 48-hour lag phase following cytokine stimulation. At low doses of interferon-gamma and tumor necrosis factor-alpha, which had no detectable response as single agents, dramatic synergistic nitric oxide synthesis and antirickettsial effects were observed.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston 77555-0609.
authors.forename: H M
authors.initials: HM
authors.lastname: Feng
authors.forename: D H
authors.initials: DH
authors.lastname: Walker
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004357:Drug Synergism; D005347:Fibroblasts / Q000378:metabolism / Q000382:microbiology; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009573:Nitrites / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D009994:Osmolar Concentration; D012281:Rickettsia / Q000187:drug effects* / Q000254:growth & development; D012282:Rickettsia Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019323:omega-N-Methylarginine
chemical_list: D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine; D003513:Cycloheximide