Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg cells.
Overexpression of CD30 and constitutive NF-kappaB activation characterizes tumor cells of Hodgkin's disease (HD), Hodgkin and Reed-Sternberg (H-RS) cells. We report that in H-RS cells overexpression of CD30 leads to self-aggregation, recruitment of TRAF2 and TRAF5, and NF-kappaB activation, independent of CD30 ligand. CD30 and TRAF proteins co-localized in H-RS cell lines and in lymph nodes of HD. An adenovirus-vector carrying a decoy CD30 lacking the cytoplasmic region or a dominant negative IkappaBalpha mutant blocks NF-kappaB activation, down regulates IL-13 expression and induces apoptosis. Thus, in H-RS cells, ligand-independent activation of CD30 signaling drives NF-kappaB activation and this leads to constitutive cytokine expression, which provides a molecular basis for HD. Inhibition of NF-kappaB activation by adenovirus vector-mediated gene transfer may provide a novel strategy of cell- and target molecule-specific therapy for patients with HD.
Horie
Ryouichi
R
Division of Pathology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Watanabe
Takuro
T
Morishita
Yasuyuki
Y
Ito
Kinji
K
Ishida
Takaomi
T
Kanegae
Yumi
Y
Saito
Izumu
I
Higashihara
Masaaki
M
Mori
Shigeo
S
Kadin
Marshall E
ME
Watanabe
Toshiki
T
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D002460:Cell Line; D005822:Genetic Vectors; D006689:Hodgkin Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D017730:Ki-1 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D014162:Transfection; D014407:Tumor Cells, Cultured
D020672:I-kappa B Proteins; D017730:Ki-1 Antigen; D008024:Ligands; D016328:NF-kappa B; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5