Protein tyrosine kinase inhibitors decrease induction of nitric oxide synthase activity in lipopolysaccharide-responsive and lipopolysaccharide-nonresponsive murine macrophages.
We investigated tumoricidal activation and induction of nitric oxide synthase (NOS) activity in macrophages from LPS-responsive (C3H/HeN) and -unresponsive mice (C3H/HeJ). Macrophages were incubated in vitro with a synthetic lipopeptide or with LPS and IFN-gamma. LPS and IFN-gamma activated C3H/HeN but not C3H/HeJ macrophages to lyse B16 melanoma cells. In contrast, lipopeptide and IFN-gamma activated macrophages from both strains of mice. Genistein, a specific inhibitor of protein tyrosine kinase, significantly blocked tumoricidal activation of macrophages from both strains of mice. Genistein did not affect tumor cell binding but significantly inhibited the production of nitric oxide. Genistein, herbimycin A, and tyrphostin inhibited the induction of NOS activity in macrophages from both strains of mice. These data suggest that protein tyrosine kinase activity is involved in the signal transduction pathway of LPS and other synthetic bacterial-related immunomodulators at a point preceding triggering of macrophage tumoricidal activation and expression of inducible NOS activity.
Dong
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Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
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Xie
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Fidler
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D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D016227:Benzoquinones; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D019833:Genistein; D007371:Interferon-gamma / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D019001:Nitric Oxide Synthase; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D016227:Benzoquinones; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010446:Peptide Fragments; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D007371:Interferon-gamma; C068423:CGP 31362; D019833:Genistein; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011505:Protein-Tyrosine Kinases