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(Journal of Leukocyte Biology. 2000;68:267-276.)
© 2000 by Society for Leukocyte Biology

Lipopolysaccharide-triggered desensitization of TNF- mRNA expression involves lack of phosphorylation of IB in a murine macrophage-like cell line, P388D1

Mitsuhiro Fujihara^*, Shinobu Wakamoto^*, Takatoshi Ito^*, Masashi Muroi, Tsuneo Suzuki, Hisami Ikeda^* and Kenji Ikebuchi^*

^* Japanese Red Cross, Hokkaido Red Cross Blood Center, Sapporo;
Division of Microbiology, National Institutes of Health Sciences, Tokyo, Japan; and
Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City

Correspondence: Dr. Mitsuhiro Fujihara, Japanese Red Cross, Hokkaido Red Cross Blood Center, Yamanote 2-2, Nishi-ku, Sapporo 063-0002 Japan. E-mail: fujihara{at}hokkaido.bc.jrc.or.jp

Activation of nuclear factor B (NF-B) is thought to be required for cytokine production by lipopolysaccharide (LPS)-responsive cells. Here, we investigated the contribution of NF-B in preventing LPS-induced transcription of the tumor necrosis factor (TNF-) gene in a murine macrophage cell line, P388D1, when tolerance was induced in the cells with a short exposure to a higher dose of LPS. Electrophoretic mobility shift assays with the B elements of the murine TNF- promoter and enhancer revealed that nuclear mobilization of heterodimers of p65/p50, c-rel/p50 and p65/c-rel, and homodimers of p65 was markedly reduced in LPS-tolerant cells, whereas that of p50 homodimers was only slightly increased. Western blot analysis showed that the phosphorylation of Ser³² on IB and its transient degradation did not occur in LPS-tolerant cells. These results thus suggest that desensitization of TNF- gene expression in this LPS-tolerant state is closely associated with down-regulation of transactivating NF-B and may involve a defect in the LPS-induced IB kinase pathway.

Key Words: NF-B • signal transduction • Toll-like receptor 4

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