Apoptosis, proliferation and NF-κB activation induced by agonistic Fas antibodies in the human myeloma cell line OH-2:: amplification of Fas-mediated apoptosis by tumor necrosis factor

Tumor necrosis factor (TNF) is known to be a growth factor for several myeloma cell lines. However, in the presence of the agonistic Fas antibody CH11, TNF enhanced the level of apoptosis in cultures of the human myeloma cell line OH-2. This pro-apoptotic effect of TNF was explained at least in part by a TNF-mediated enhancement of Fas expression. TNF induces proliferation of OH-2 by activating nuclear transcription factor kappa-B (NF-kappa B). The proliferative effect of TNF on OH-2 cells was abrogated by CH11, but this was not caused by an inhibition of the translocation of NF-kappa B. On the contrary, CH11 could by itself activate NF-kappa B in OH-2 cells, and in the presence of an inhibitor of caspase-1 induce proliferation of the cells. The relationship between stimulation of TNF receptors and Fas and the level of NF-kappa B activation was also examined in three other myeloma cell lines. RPMI-8226 cells showed NF-kappa B activation by TNF, but contrary to OH-2, not by CH11. Unstimulated U-266 and JJN-3 cells had high levels of activated NF-kappa B. This shows that NF kappa-B is either constitutively activated or inducible in myeloma cells. Modulation of Fas expression and inhibition of NF-kappa B activation can potentially be of therapeutic importance in multiple myeloma.