Role of TNFa in mice exposed to high dose radiation: its mechanisms for radioprotection

Exposure to high dose radiation leads to serious radiation injuries. Radiation stimulates the production of tumor necrosis factor a (TNFa) in various cells and tissues. TNFa is a pro-inflammatory cytokine and plays a critical role in inflammation; TNFa-targeted therapies are increasingly used for rheumatic and autoimmune diseases. Furthermore, TNFa induces apoptosis in cells, suggesting that its excess production may lead to damage of tissues and organs in radiation exposure. On the other hand, administration of TNFa has been reported to protect lethally irradiated mice. However, the mechanisms of TNFa for radioprotective effects are not fully understood. In the present study, the wild-type of TNFa (WT) and its knockout (K/O) balb/c mice were subjected to total body g radiation. The survival rates on day 35 (SRs) were 45 and 7% in WT and K/O mice irradiated with 6.5 Gy, respectively. Administration of TNFa increased the survival rate in K/O mice; the SRs were 86 and 43% in these mice administered before and after radiation, respectively. Since autopsy failed to find difference in causes of death between both groups of mice, we compared injuries of bone marrow and small intestine. There was no difference in numbers of white blood cells (WBC) or platelets following to radiation in both mice, whereas radiation markedly reduced these cell numbers. However, 15 days after exposure, numbers of red blood cells (RBC), levels of hemoglobin (Hb), and values of hematocrit (Ht) were significantly reduced in K/O mice with concomitant higher levels of serum iron and lower unsaturated iron binding capacity (UIBC) as compared to those in WT mice. Administration of TNFa significantly improved those in irradiated K/O mice. Assays for crypt microcolony in small intestine showed no difference between both irradiated groups and the similar results were obtained from studies of intestinal cell apoptosis. Interestingly, administration of either TNFa or lipopolysaccharide (LPS) significantly inhibited the apoptosis in WT but not in K/O mice. The serum levels of TNFa were increased following to TNFa challenge in both groups, but that in WT was higher than that in K/O mice. LPS increased the levels of TNFa in WT but not in K/O mice. LPS also increased the levels of interleukin-1a (IL-1a) and IL-1b in both groups of mice, and those levels in WT were higher than that in K/O mice. Administration of IL-1a inhibited radiation-induced apoptosis in small intestine of WT but not K/O mice. However, IL-1b inhibited the apoptosis in both mice. We also studied the expression of Bax and Bcl2 proteins in intestinal crypt cells. Radiation increased the Bax/Bcl2 ratio in both mice. However, administration of TNFa before radiation reduced the ratio in irradiated WT but not in K/O mice. Our results suggest that endogenously-produced TNFa plays important roles in radiation injury.ＡＡＣＲ 100th　Ａｎｎｕａｌ　Ｍｅｅｔｉｎｇ　200

The role of TNFa in mice exposed to radiation

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 a (TNFa) in various cells including monocytes/macrophages and granulocytes. TNFa is well known as a pro-inflammatory cytokine and this factor plays a critical role in the initiation and continuation of inflammation and immunity. The excess production of TNFa leads to damage of tissues and organs. Previous studies showed that pretreatment with TNFa protected lethally radiated mice from death. On the other hand, there also are repots that radiation induced apoptosis through TNFa production. Thus, the role(s) of TNFa is not fully understood in radiation exposure. In this study, we investigated the roles of TNFa in mice exposed to radiation. We compared the wild-type (TNFa +/+) and the knockout (TNFa-/-) BALB/c mice. Both mice were subjected to g-ray radiation at doses of 6 -10 Gy. The survival durations in TNFa+/+ mice were significantly longer than those in TNFa-/- mice. We compared numbers of blood cells, numbers of surviving intestinal crypts, apoptosis in crypt cells and activity of an antioxidant enzyme manganese superoxide dismutase (MnSOD) in various organs following radiation. There was no significant difference in numbers of white blood cells after exposure. Furthermore, there was also no significant difference in surviving intestinal crypts after exposure and apoptosis in crypt cells between TNFa+/+and TNFa -/- mice. On day 15 after exposure, however, numbers of red blood cells in TNFa+/+ mice was higher than those in TNFa-/- mice. Activities of MnSOD were lower in liver of TNFa-/- than that of TNFa+/+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 Bcl2 protein was constitutively expressed and its level was reduced by radiation in TNFa+/+ mice. In contrast, Bcl2 was not expressed in TNFa-/- mice and radiation did not induce Bcl2 expression. Since administration of TNFa prior to radiation has been shown to have radio-protective effect in mice, our results suggest that TNFa endogenously produced may play important roles in the radiation-induced injuries.ＡＡＣＲ　Ａｎｎｕａｌ　Ｍｅｅｔｉｎｇ　200

TokyoTech’s TRECVID2006 Notebook

In this notebook we describe our TRECVID 2006 experiments. We TokyoTech team participated in shot boundary detection and high-level feature extraction tasks. 1 Shot Boundary Detection Our approach to shot bondary detection uses SVMs with generic features. Using the radial kernel for SVMs, we ignore the difference among the types of gradual transitions (i.e. FOI, DIS, and OTH). We classify shot boundaries into the following three categories. • Cuts(CUT) • Gradual transitions with five frames or less (Short Gradual; SG) • Gradual transitions with more than five frames (Long Gradual; LG) We prepare a kernel function and a feature set for each of these categories. 1.1 Cut Detection Since shot boundaries with less than five frames are classified as “cuts ” in the TRECVID evaluation, the results for SG are added to the results in CUT, and are submitted as the results for “cuts”. For the cut detection, we use two linear kernel SVMs (one for CUT and the other for SG) with different feature sets. The features for a CUT-SVM are activity ratio (the ratio of “dynamic ” pixels to all pixels, wher