Pre-administration of cytokines, in particular of IL 1 can protect mice from lethal doses of irradiation ranging can protect from lethal doses of irradiation ranging from 900 to 1,200 cGy. IL 1 when administered after irradiation can protect mice up to doses of 1,000 cGy. These radioprotective effects of the cytokines were based on the recovery of suppressed hematopoietic tissues. Administration of inhibitory anti-IL 1 receptor and anti-TNF antibodies both reduced the radioresistance of normal mice and completely blocked the radioprotective effect of endotoxin. We determined that transforming growth factor Beta (TGFBeta) also radiosensitized mice, perhaps in part by reducing IL 1 receptor expression on bone marrow and other cell types. Both, IL 1 and TNF are potent inducers of mitochondrial MnSOD. Cells transfected with the cDNA of this intracellular radical scavenger became more radioresistant, and also more resistant to agents that generate oxygen radicals such as adriamycin, mitomycin C as well as to TNF and IL 1 itself. Conversely cells transfected with antisense cDNA for MnSOD became more sensitive. Thus induction of MnSOD may contribute to the radioprotective effects of cytokines. The role of cytokines in oncogenesis was also investigated. JB6 is a nontumorigenic murine epidermal cell line which undergoes irreversible phenotypic modification when treated with tumor promoters, such as PMA. JB6 loses anchorage dependence, as measured by colony formation in soft agar, and becomes tumorigenic in nude mice. The induction of transformation by PMA is inhibited by the addition of antipromoters, such as retinoids. Of the cytokines e.g. IFNalpha, IL 6, IL 1 and TGFBeta with differentiative activities that were tested only TGFBeta synergized with retinoic acid in a dose-dependent manner in reducing the number of JB6 colonies induced by PMA. Conversely, TNFAlpha had the opposite effect and like PMA promoted colony formation by both JB6 and 3T3 cells. Thus cytokines may influence the development and growth of tumorigenic cells.
