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Lipopolysaccharide-Induced Desensitization of junB Gene Expression in a Mouse Macrophage-Like Cell Line, P388D1

Mitsuhiro Fujihara^1,*, Kenji Ikebuchi^*, Takami L. Maekawa², Shinobu Wakamoto^*, Chikayo Ogiso^*, Takatoshi Ito^*, Tsuneo A. Takahashi³, Tsuneo Suzuki and Sadayoshi Sekiguchi^*

^* Japanese Red Cross, Hokkaido Red Cross Blood Center, Yamanote, Nishi-ku, Sapporo, Japan; and Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS 66160

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.

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