Subject(s)
Multiple Myeloma/pathology , Apoptosis , Cell Division , Cell Survival , Humans , In Vitro Techniques , Insulin-Like Growth Factor I/physiology , Interferon-alpha/physiology , Interferon-gamma/physiology , Interleukin-6/physiology , Models, Biological , Multiple Myeloma/genetics , Tumor Cells, Cultured , fas Receptor/physiologyABSTRACT
A poor response to Fas-induced apoptosis is evident in some multiple myeloma (MM) cell lines and primary cells. In this study, we have examined the possibility to increase the sensitivity to Fas-induced apoptosis by pretreatment of MM cells with interferon-gamma (IFN-gamma) or interferon-alpha (IFN-alpha). Both IFN-gamma and IFN-alpha markedly increased the Fas-induced apoptosis in all cell lines tested (U-266-1970, U-266-1984, and U-1958). In the U-266-1970 and U-1958 cell lines, pretreatment with either IFN-gamma or IFN-alpha also inhibited proliferation in a dose-dependent manner. In contrast, IFN-gamma activation of the Fas death pathway in the U-266-1984 cells was not accompanied by growth inhibition. Incubation with the IFNs increased the Fas antigen expression in one of three cell lines but did not alter the expression of Bcl-2 or Bax. The IFNs are important regulators of growth and survival in MM cells. Our results suggest that activation of Fas-mediated apoptosis is a novel mechanism by which the IFNs exert inhibitory effects on MM cells.
Subject(s)
Apoptosis/drug effects , Interferon-alpha/pharmacology , Interferon-gamma/pharmacology , Interleukin-6/pharmacology , Membrane Glycoproteins/physiology , Multiple Myeloma/pathology , fas Receptor/physiology , Dose-Response Relationship, Drug , Fas Ligand Protein , Gene Expression Regulation/drug effects , Humans , In Situ Nick-End Labeling , Multiple Myeloma/metabolism , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins c-bcl-2/genetics , Recombinant Proteins/pharmacology , Tumor Cells, Cultured , bcl-2-Associated X ProteinABSTRACT
Several studies have documented IL-6-dependent growth promotion of murine and human neoplastic plasma cells. However, it is well known that human multiple myeloma (MM) cells in vitro show a considerable degree of heterogeneity concerning growth and survival requirements. This heterogeneity, which probably reflects overlapping effects of feeder cells, interleukin 6 (IL-6) and components of fetal calf serum (FCS) as well as tumour heterogeneity in vivo, has hampered the elucidation of molecular mechanisms underlying the effects of IL-6. In an attempt to dissociate growth and survival promotion of IL-6, we have studied two pairs of human MM cell lines, HL407E/HL407L and U-266-1970/U-266-1984, selected to represent different stages of in vitro tumour progression and dependence of feeder cells and exogenous IL-6. We demonstrated that exogenous IL-6, in the presence of FCS, conveyed: (a) a strong growth stimulatory effect with weak or no survival promotion in HL407L and U-266-1970 cells; (b) promotion of survival with no effects on growth in HL407E cells; (c) no growth or survival promotion to U-266-1984. Moreover, our results suggested that IL-6 may enhance apoptosis in U-266-1970/U-266-1984 cells, and that FCS may interfere with IL-6 in its growth stimulatory effect. The relative dissociation of growth, survival and apoptotic effects of IL-6 leads to the conclusion that the HL407E/HL407L and U-266-1970/U-266-1984 pairs of cell lines provide a useful human model system to study molecular mechanisms underlying these separate events.
