Lipopolysaccharide-induced desensitization of junB gene expression in a mouse macrophage-like cell line, P388D1.
Treatment of a mouse macrophage cell line, P388D1, for 1 h with bacterial LPS caused a transient increase in the level of junB mRNA expression. These cells became refractory in terms of the junB gene response to exposure to a second round of LPS or lipid A, but not to PMA. The LPS-induced desensitized state was not due to the shortening of the half-life of junB mRNA, but was suggested, by nuclear run-on analysis, to be caused by reduction of junB gene transcription. Pretreating cells with herbimycin A, a tyrosine kinase inhibitor, substantially inhibited LPS-induced expression of junB mRNA and decreased tyrosine phosphorylation of 38- to 42-kDa proteins, which comigrated with p38 and p42 mitogen-activated protein (MAP) kinases. Parallel to down-regulation of junB mRNA expression, activation of the p38 MAP kinase was markedly reduced in LPS-tolerant cells, whereas activation of p42 MAP kinase was relatively constant. The specific p38 MAP kinase inhibitor, SB202190, potently inhibited LPS-induced junB mRNA expression. These results suggest that the LPS-induced desensitization of junB gene expression occurs at or upstream of the level of gene transcription and may be involved in a defective LPS-induced p38 MAP kinase pathway.
Japanese Red Cross, Hokkaido Red Cross Blood Center, Sapporo, Japan.
M
M
Fujihara
K
K
Ikebuchi
T L
TL
Maekawa
S
S
Wakamoto
C
C
Ogiso
T
T
Ito
T A
TA
Takahashi
T
T
Suzuki
S
S
Sekiguchi
D000818:Animals; D016227:Benzoquinones; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D016758:Genes, jun / Q000187:drug effects / Q000276:immunology*; D007093:Imidazoles / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D007941:Leukemia P388 / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D017828:Rifabutin / Q000031:analogs & derivatives; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D016227:Benzoquinones; D007093:Imidazoles; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D011809:Quinones; D012333:RNA, Messenger; D017828:Rifabutin; C020754:herbimycin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole