Molecular mechanisms of constitutive NF-kappa B/Rel activation in Hodgkin/Reed-Sternberg cells

A common characteristic of malignant cells derived from patients wifh Hodgk in's disease (HD) is a high level of constitutive nuclear NF-kappa B/Rel ac tivity, which stimulates proliferation and confers resistance to apoptosis, We have analysed the mechanisms that account for NF-kappa B activation in a panel of Hodgkin/Reed-Sternberg (H-RS) cell lines. Whereas two cell lines (L428 and KMH-2) expressed inactive I kappa B alpha, no significant change s in NF-kappa B or I kappa B expression were seen in other H-RS cells (L591 , L1236 and HDLM-2), Constitutive NF-kappa-B was susceptible to inhibition by recombinant I kappa B alpha, suggesting that neither mutations in the NF -KB genes nor posttranslational modifications of NF-kappa B were involved. Endogenous I kappa B alpha was bound to p65 and displayed a very short half -life. I kappa B alpha. degradation could be blocked by inhibitors of the N F-kappa B activating pathway. Proteasomal inhibition caused an accumulation of phosphorylated I kappa B alpha and a reduction of NF-kappa B activity i n HDLM-2 and L1236 cells. By in vitro kinase assays we demonstrate constitu tive I kappa B kinase (IKK) activity in H-RS cells, indicating ongoing sign al transduction, Furthermore, HRS cells secrete one or more factor(s) that were able to trigger NF-kappa B activation. We conclude that aberrant activ ation of IKK's, and in some cases defective I kappa Bs, lead to constitutiv e nuclear NF-kappa B activity, which in turn results in a growth advantage of Hodgkin's disease tumor cells.