IFN-β Partially Counteracts Inhibition of Natural Killer Activity Induced by Some Antitumor Agents

Abstract

We investigated whether recombinant human (rHu-IFN-β) (IFN-β) could counteract the inhibition of natural killer (NK) activity caused by antitumor agents. Peripheral blood lymphocytes (PBL) were incubated with different antitumor agents alone or in combination with IFN-β for 3 days and then tested in a cytotoxicity assay against the K562 cell line. The following drugs were used, all of which caused a dose-dependent inhibition of NK activity: etoposide, camptothecin, doxorubicin, cis-DDP, tallimustine, and L-PAM. Concomitant treatment with (1000 U/ml) IFN-β counteracted the inhibitory effect of etoposide and camptothecin but had no consistent effect on the inhibition mediated by the other drugs. Mean values of inhibition of NK activity at 1 μM camptothecin was 48% ± 3.4% and with IFN-β was 10% ± 4.9%. With 100 μM etoposide, mean value of inhibition was 78% ± 3.3%, and with IFN-β, it was 18% ± 1.5%. Cell viability, assessed by vital dye exclusion, and drug uptake, assessed with radiolabeled etoposide, were similar in cells treated with or without IFN-β. The protective effect of IFN-β on NK function was rather selective, as IFN-β did not counteract the drug-mediated inhibition of PBL proliferation when stimulated by phytohemagglutinin (PHA). Other cytokines, IFN-α, IFN-γ, and interleukin-2 (IL-2), had similar protective effect, although IFN-β was slightly more potent. On the other hand, IL-6, a cytokine sharing some properties with IFNs was ineffective. Camptothecin inhibited the expression of mRNA for granzyme B, a lytic protein involved in lymphoid-mediated cytotoxicity. Combined treatment with IFN-β restored—at least in part—the transcription of granzyme B mRNA. These results show that the immunosuppressive effect of some antitumor agents could be partly counteracted by treatment with IFN-β.