Regulation of interleukin-2 induced soluble Fas ligand release from human peripheral blood mononuclear cells

Adjuvant interleukin (IL)-2 immunotherapy has been used in the treatment of different malignant dieseases. However, clinical results have been rather disappointing. Therefore, further investigations on IL-2-induced mediators of cytotoxicity seem to be necessary in order to possibly create cytokine cocktails which could enhance the IL-2-induced cytotoxicity. We therefore investigated the regulation of IL-2-induced release of soluble Fas Ligand (sFasL), since this factor is known to possess anti-tumor activities. In CD3-stimulated peripheral blood mononuclear cells IL-2 induced sFasL in a dose-dependent fashion. Maximum sFasL concentrations were obtained after stimulation of MNC for 120 hrs. Inhibition of endogenous IL-12 production significantly reduced IL-2-mediated sFasL release by about 25%. In contrast, addition of IL-12 enhanced the IL-2-induced sFasL about 1,5-fold. IL-10 and IL-4 reduced the IL-2-stimulated sFasL by about 30%. Interestingly, these suppressive effects could be antagonized by the addition of IL-12. Not only exogenous IL-10 but also endogenously produced IL-10 decreased the sFasL release to that extent which had been stimulated by IL-12. Since IL-12 and IL-10 only marginally influenced the IL-2-mediated cell proliferation as well as the IL-2-induced cell death, the IL-12- and IL-10-controlled sFasL release seems to be based on an enhanced production per cell. However, the increase in cell numbers as well as the decrease of viability during cell culture might additionally contribute to the IL-2-induced increase of sFasL release. This secondary effect might explain why IL-2-mediated sFasL production is only partially controlled by regulatory cytokines such as IL-4, IL-10 or IL-12. In conclusion, addition of IL-12 might increase the efficacy of IL-2 immunotherapy by inhibition of the IL-10-mediated negative feed-back loop on IL-2-mediated sFasL release.