Analysis of signal transduction of OX40/gp34 and its role in pathogenesis of hematologic diseases

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(1) Moleclar mechanism of OX40 signalingWe 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 gp34We 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 … More 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 systemPurified 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 ATLWe 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