Protective Roles of Cytokines Against Radiation: Induction of Mitochondrial MnSOD

Oxidative stress such as radiation can trigger the production of cytokines including tumor necrosis factor (TNF) and lymphotoxin (LT). The increased cytokine levels may in turn induce the synthesis of protein(s) that protect against subsequent killing by oxidative stress. Indeed, pretreatment of animals with TNF or LT can protect them against lethal doses of radiation and the alopecia that results from anticancer drugs. TNF or LT can specifically and selectively induce the expression of manganous superoxide dismutase (MnSOD). MnSOD, identified as one of the protective proteins, is a mitochondrial enzyme that scavenges superoxide radicals (O2-). TNF-R1 but not TNF-R2 is responsible for TNF and LT's induction of MnSOD. Paradoxically, the TNF-R1 is also the receptor that mediates the production of oxygen free radicals and apoptosis. Overexpression of MnSOD but not CuZn-SOD or EC-SOD enhances cellular resistance to radiation. Conversely, overexpression of antisense MnSOD RNA diminishes resistance. Transfection of cells with MnSOD lacking the mitochondrial matrix signal does not provide protection against radiation. However, insertion of the mitochondrial signal sequence into CuZn-SOD or EC-SOD results in significant protection. TNF or LT does not induce MnSOD in tumor cells; nor do they protect these cells against radiation. Actually, TNF or LT pretreatment can sensitize tumor cells to killing by radiation.