Enhancement of monocyte-mediated tumoricidal activity by multiple interferon-alpha species.
Twenty-one interferon (IFN)-alpha species were evaluated for their ability to enhance monocyte-mediated lysis of the human melanoma cell line, A375. A wide variation in the potency of the different species in inducing monocyte tumoricidal action was observed. In addition, many IFN-alpha species were found to induce as much or more tumoricidal activity than recombinant IFN-gamma. The degree of monocyte activation induced by the various species generally correlated with their antiviral activity. Those which were better at inducing monocyte tumoricidal action also gave the highest antiviral specific activities. Studies were conducted to determine if the relative potency of the IFN-alpha species could be changed by altering certain parameters of the cytotoxicity assay. All IFN-alpha species tested required only 30 min in culture with the monocytes to induce activation. There were no changes in the relative potency of the species when cytotoxicity was measured at different times, nor when the effector:target ratio was altered. Competitive binding studies revealed that those IFN-alpha species which induced little activity in the bioassays were also generally poor in their ability to bind the IFN-alpha receptor on human monocytes, while the IFN-alpha species which induced relatively more activity in the bioassays were better able to bind to the IFN-alpha receptor. These data indicate that there are dramatic differences in activities among the IFN-alpha species which may, in part, be explained by different binding affinities. In addition, the differences observed among the IFN-alpha species demonstrate the need for further functional and structural characterization of the individual IFN-alpha species which could lead to a more effective clinical application of IFN-alpha.
Webb
D S
DS
Food and Drug Administration, Division of Cytokine Biology, Bethesda, Maryland 20892.
Zur Nedden
D
D
Miller
D M
DM
Zoon
K C
KC
Gerrard
T L
TL
D000998:Antiviral Agents / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008545:Melanoma / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism; D017471:Receptors, Interferon; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D007370:Interferon Type I; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D007371:Interferon-gamma