2006 Fiscal Year Final Research Report Summary
Functional analyses for transmembrane TNF-alpha
| Project/Area Number |
17591048
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | KYUSHU UNIVERCITY |
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Principal Investigator |
HORIUCHI Takahiko Kyushu University, Hospital, Assistant Professor, 大学病院, 講師 (90219212)
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| Co-Investigator(Kenkyū-buntansha) |
HOSPITAL Hiroshi Kyushu University, Hospital, Research Associate, 大学病院, 助手 (70304772)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Cytokine / anti-TNF therapy / rheumatoid arthritis / apoptosis / cell-cycle arrest |
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| Research Abstract |
TNF-alpha antagonists are the center of attention for their dramatic clinical efficacy in active chronic inflammatory diseases. In rheumatoid arthritis, both infliximab (chimeric anti-TNF-alpha antibody), adalimumab (humanized anti-TNF-alpha antibody) and etanercept (p75 TNF-alpha receptor fusion protein) are highly effective, while in Crohn's disease, only infliximab and adalimumab can induce clinical remission. As the differential clinical efficacy was likely to be caused by biological effects other than mere neutralization of soluble TNF-alpha, we here investigated reverse signaling through transmembrane TNF-alpha. mTNF induced by infliximab was analysed by cDNA array in the assay system using mTNF-expressing Jurkat T cells.
Cytoplasmic serine residues at positions 2, 5 and 27 of mTNF were sequentially substituted to alanine by site-directed mutagenesis. Infliximab-induced apoptosis and cell cycle arrest were completely abrogated by substitution of all of these three cytoplasmic serine residues. In this study, we revealed that novel biological effects induced by infliximab and etanercept were mediated by reverse signaling of mTNF, which might explain the differential clinical efficacy of these anti-TNF-alpha. agents. We also clarified that cytoplasmic serine residues were critical for the signal transduction through mTNF.
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Research Products
(10 results)
