INTERLEUKIN-6 AND RENAL-CELL CANCER - PRODUCTION, REGULATION, AND GROWTH EFFECTS

Interleukin-6 (IL-6) is a recently characterized pleiotropic cytokine with antitumor activity. We investigated the production of IL-6 by renal cell cancer (RCC) and the growth effects of IL-6 on RCC. Using immunoperoxidase staining, cytoplasmic IL-6 was detected in four of four renal tumor lines and in tumor cells from freshly nephrectomized RCC. We found that IL-6 mRNA was expressed at basal culture conditions by seven of ten RCC tumor lines tested. Biologically active IL-6, as measured by the B9 assay, was produced by all ten RCC tumor lines. The addition of tumor necrosis factor-alpha (TNF-alpha) significantly augmented the expression of IL-6 mRNA in five RCC tumor lines (P < 0.05). The combination of interferon gamma-IFN-gamma and TNF-alpha further enhanced the augmented IL-6 mRNA accumulation seen with TNF-alpha alone (P < 0.05). TNF-alpha also significantly stimulated the production of biologically active IL-6 (P < 0.01). Furthermore, IFN-gamma and TNF-alpha were found to enhance IL-6 bioactivity synergistically (P < 0.05). The growth effects of IL-6 on RCC were also investigated in two experimental systems: IL-6 was found to stimulate proliferative responses in six of six RCC tumor lines as measured by thymidine-uptake assays; however, only one of six tumor lines displayed an increase in proliferative response of greater than 21% (113%). The growth effect of IL-6 was further tested in clonogenic assays. One of the tumor lines tested displayed an enhanced growth response of up to 200%. We conclude that IL-6 is produced by RCC; this production is enhanced by TNF-alpha with synergistic effects seen with IFN-gamma at both mRNA and protein levels. In turn, IL-6 may have a modest stimulatory growth effect on certain RCC tumor lines.