Tumor necrosis factor and lymphotoxin: protection against oxidative stress through induction of MnSOD.

Abstract

Tumor necrosis factor (TNF) and lymphotoxin (LT) are related cytokines produced in response to infection or oxidative insults such as radiation. These cytokines bind to the same receptors and have pleiotropic effects on a variety of cell types. TNF or LT pretreatment, which can induce the synthesis of "protective" proteins such as mitochondrial manganese superoxide dismutase (MnSOD), protects animals from lethal doses of radiation or the chemotherapeutic drug doxorubicin. In contrast, TNF or LT pretreatment of tumor cells, which do not express MnSOD, results in sensitization to these insults. Therefore, radio- or chemoprotection of normal cells may act partially through enhanced expression of MnSOD. On the other hand, tumor sensitization may result from activation of "killing" proteins such as interleukin-1 beta converting enzyme (ICE) or other ICE-like proteases, possibly through TNF/LT-induced oxygen free radicals. In addition to their originally described anti-tumor activity, these cytokines may have new therapeutic indications in protecting normal cells while sensitizing tumor cells to radiation or chemotherapeutic drugs.