A common characteristic of malignant cells derived from patients with Hodgkin's disease (HD) is a high level of constitutive nuclear NF-kB/Rel activity, which stimulates proliferation and confers resistance to apoptosis. We have analysed the mechanisms that account for NF-kB activation in a panel of Hodgkin/Reed-Sternberg (H-RS) cell lines. Whereas two cell lines (L428 and KMH-2) expressed inactive IkBa, no signi®cant changes in NF-kB or IkB expression were seen in other H-RS cells (L591, L1236 and HDLM-2). Constitutive NF-kB was susceptible to inhibition by recombinant IkBa, suggesting that neither mutations in the NF-kB genes nor posttranslational modi®cations of NF-kB were involved. Endogenous IkBa was bound to p65 and displayed a very short half-life. IkBa degradation could be blocked by inhibitors of the NF-kB activating pathway. Proteasomal inhibition caused an accumulation of phosphorylated IkBa and a reduction of NF-kB activity in HDLM-2 and L1236 cells. By in vitro kinase assays we demonstrate constitutive IkB kinase (IKK) activity in H-RS cells, indicating ongoing signal transduction. Furthermore, H-RS cells secrete one or more factor(s) that were able to trigger NF-kB activation. We conclude that aberrant activation of IKK's, and in some cases defective IkBs, lead to constitutive nuclear NF-kB activity, which in turn results in a growth advantage of Hodgkin's disease tumor cells.

Bcl10 is a critical regulator of NF-B activity in T and