The role of TNFα in mice exposed to radiation

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Exposure to high dose radiation results in radiation injury which is a serious problem in accidental exposure and also in radiation therapy. There are many reports that radiation activates the production of tumor necrosis factor α (TNFα) in various cells including monocytes/macrophages and granulocytes. TNFα is known to be a pro-inflammatory cytokine and this factor plays a critical role in the initiation and continuation of inflammation and immunity. The excess production of TNFα leads to damage of tissues and organs. TNFα is an important cytokine in radiation exposure, because it is produced upon radiation in various tissues. Previous studies showed that pretreatment with TNFα protected lethally radiated mice from death. On the other hand, there are repots that radiation induced apoptosis through TNFα production. However, the role(s) of TNFα is not fully understood in radiation exposure. In this study, we investigated the roles of TNFα in mice exposed to radiation. We compared the wild-type (TNFα ^+/+) and the knockout (TNFα^-/-) BALB/c mice. Both mice were subjected to γ-ray radiation at a dose of 5-10 Gy. The survival durations in TNFα^-/- mice were significantly longer than those in TNFα^+/+ mice. We compared the numbers of blood cells, numbers of surviving intestinal crypts, apoptosis in crypt cells and activity of an antioxidant enzyme manganese superoxide dismutase (MnSOD) following radiation. However, there was no significant difference in blood cell numbers 7 days after exposure or surviving intestinal crypts 3.5 days after exposure between TNFα^+/+and TNFα^-/- mice. Activities of MnSOD were lower in liver of TNFα^-/- than that of TNFα^+/+mice. We also studied the expression of apoptosis-related proteins in mouse intestinal epithelial cells along the crypt-villus axis after radiation. Epithelial cells were sequentially isolated cells from the villus tip to the crypts of mouse small intestine by the modified Weiser method. The expression of Bcl2 was constitutively expressed and its level was reduced by radiation in TNFα^+/+ mice. On the other hand, Bcl2 was not expressed in TNFα^-/- mice and radiation did not affect these levels. Since administration of TNFα prior to radiation has been shown to have radio-protective effect in mice, our results suggest that TNFα endogenously produced may play important roles in the radiation-induced injuries. Further studies are in progress.