Apoptosis, proliferation and NF-kappa B 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 myel oma 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). T he proliferative effect of TNF on OH-2 cells was abrogated by CH11, but thi s was not caused by an inhibition of the translocation of NF-kappa B. On th e 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 lev el of NF-kappa B activation was also examined in three other myeloma cell l ines. 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 ac tivated NF-kappa B. This shows that NF kappa-B is either constitutively act ivated or inducible in myeloma cells. Modulation of Fas expression and inhi bition of NF-kappa B activation can potentially be of therapeutic importanc e in multiple myeloma.