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Outside-to-Inside Signal Through the Membrane TNF- Induces E-Selectin (CD62E) Expression on Activated Human CD4⁺ T Cells¹

Shin-ichi Harashima^*, Takahiko Horiuchi^2,*, Nobuaki Hatta, Chika Morita^*, Masanori Higuchi^*, Takuya Sawabe^*, Hiroshi Tsukamoto^*, Tomoko Tahira, Kenshi Hayashi, Shigeru Fujita and Yoshiyuki Niho^*

^* First Department of Internal Medicine, Faculty of Medicine, and Institute of Genetic Information, Kyushu University, Fukuoka, Japan; and First Department of Internal Medicine, School of Medicine, Ehime University, Ehime, Japan

The membrane TNF- is known to serve as a precursor of the soluble form of TNF-. Although it has been reported the biological functions of the membrane TNF- as a ligand, the outside-to-inside (reverse) signal transmitted through membrane TNF- is poorly understood. Here we report a novel function mediated by outside-to-inside signal via membrane TNF- into the cells expressing membrane TNF-. Activation by anti-TNF- Ab against membrane TNF- on human T cell leukemia virus (HTLV) I-infected T cell line, MT-2, or PHA-activated normal human CD4⁺ T cells resulted in the induction of an adhesion molecule, E-selectin (CD62E), on the cells with the peak of 12–24 h, which completely disappeared by 48 h. When wild-type or mutant membrane TNF- (R78T/S79T) resistant to proteolytic cleavage was introduced into Jurkat or HeLa cells, E-selectin was induced by the treatment with anti-TNF- Ab with the similar kinetics. Membrane TNF--expressing Jurkat cells also up-regulated E-selectin when brought into cell-to-cell contact with TNF receptor-expressing HeLa cells. Northern blot analysis and RT-PCR analysis showed that the membrane TNF--mediated E-selectin expression was up-regulated at the level of transcription. These results not only confirmed our previous findings of reverse signaling through membrane TNF-, but also presented evidence that E-selectin was inducible in cell types different from endothelial cells. It is strongly suggested that membrane TNF- is a novel proinflammatory cell surface molecule that transmits bipolar signals in local inflammation.

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