Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients

This study shows that subcutaneous administration of increasing doses of IL -12, once a week, in 21 cancer patients increased the expression of cytokin e genes (interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-al pha), IP-10, MIG, IL-10, IL-4) in peripheral blood mononuclear cells even a t very low doses (30 ng/kg). Surprisingly, no circulating TNF-alpha or IL-4 could be detected in the plasma of patients treated with IL-12. However, a marked increase of soluble IL-4 receptor was demonstrated in the plasma of five of the six patients studied, which may represent an additional mechan ism by which IL-12 inhibits the development of the Th2 response in vivo. A marked decline of IFN-gamma and IP10 induction was recorded after repeated cycles of IL-12. In contrast, in most patients IL-12 increased IL-10 expres sion with no subsequent decrease during the course of therapy, and even an earlier peak of IL-10 induction at the 6th cycle. In addition, a constant u p-regulation of serum soluble IFN-gamma receptor levels was observed after each cycle of IL-12 treatment with a delayed peak compared with the IFN-gam ma peak. The constant rise of IL-10 and soluble IFN-gamma receptor during I L-12 therapy may therefore contribute to the inhibition of IFN-gamma activi ty detected after repeated cycles of IL-12. Lastly, a marked heterogeneity of cytokine induction was observed from one patient to another, which appea red to be independent of the dose of IL-12 administered. These data may lea d to a better understanding of the biological activity of IL-12 and the in vivo mechanisms of its regulation.