Ligand-independent signaling by overexpressed CD30 drives NF-κB activation in Hodgkin–Reed-Sternberg cells

Overexpression of CD30 and constitutive NF-κB 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-κB 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 IκBα mutant blocks NF-κB activation, down regulates IL-13 expression and induces apoptosis. Thus, in H–RS cells, ligand-independent activation of CD30 signaling drives NF-κB activation and this leads to constitutive cytokine expression, which provides a molecular basis for HD. Inhibition of NF-κB activation by adenovirus vector-mediated gene transfer may provide a novel strategy of cell- and target molecule-specific therapy for patients with HD.