1999 Fiscal Year Final Research Report Summary
Analysis of signal transduction of OX40/gp34 and its role in pathogenesis of hematologic diseases
| Project/Area Number |
10307023
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
UCHIYAMA Takashi Kyoto, University, graduate School of Medicine, Professor, 医学研究科, 教授 (80151900)
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| Co-Investigator(Kenkyū-buntansha) |
HIRO Toshiyuki Kyoto University, graduate School of Medicine, Lecturer, 医学研究科, 講師 (70243102)
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| Project Period (FY) |
1998 – 1999
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| Keywords | OX40 / gp34 / TRAF / ATL / endothelial cell |
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| Research Abstract |
(1) Moleclar mechanism of OX40 signaling
We previously reported that OX40 signaling leads to NF-κB activation via TRAF2 and TRAF5. TRAF3 also binds to the cytoplasmic domain or OX40 but functions rather negatively to suppress NF-κB activation. In the present study we found that TRAF3 did not affect NIK-mediated NF-κB activation and that both N-terminus and C-terminus deletion mutants of TRAF3 have inhibitory effects. These results indicate that TRAF3 suppresses NF-κB activation at the pathway between TRAF2 and NIK, which is not necessarily due to competitive inhibition of binding between OX40 and TRAF2.
(2) Intracytoplasmic signaling of gp34
We exzmined expression induction of c-fos and c-jun mRNA in MMCE-gp34, a human gp34 stable transfectant line of a mouse epithelial cell line as well as human umbilical vein endothelial cells (HUVEC) when stimulated wth soluble OX40. Northern blot analysis showed that both c-fos and c-jun mRNA were induced in MMCE-gp34, and c-jun mRNA in HUVEC upon bin
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ding of soluble OX40. This indicates that signlaing of the OX40/gp34 system is bidirectional.
(3) Costimulation of T cells by endothelial cells via the OX40/gp34 system
Purified CD4^+ T cells responded with proliferation to immobilized anti-CD3 mAb in the presence of irradiated HUVEC.This proliferative response was shown to be mediated by IL-2 autocrine mechanism and inhibited by addition of anti-gp34 mAb. The inhibitory effect of anti-gp34 was stronger than that of anti-ICAM-1 or anti-LFA1, indicating that the OX40/gp34 system is one of the major pathways of costimulation by endothelial cells.
(4) Possible role of the OX40/gp34 in the leukemogenesis of ATL
We studied the relationship between OX40 signals and apoptosis of ATL cells. ATL constitutively express OX40 and became resistant to anti-Fas-induced apoptosis when cocultured MMCE-gp34 while coculture with MMCE-mock had no effects. This acquisition of resistance to apoptosis was accompanied by expression induction of XIAP, an anti-apoptotic protein. It is suggested that ATL cells receive favoraous sigals for survival through the OX40/gp34 system. Less
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Research Products
(14 results)
