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(PP222) Radioprotection of the murine gastrointestine by IL-1 involves downregulation of apoptotic caspases.
Johnke, Roberta*,1, Smith, Elizabeth1, Kovacs, Charles1, Evans, Mark1, Cariveau, Mickael1, Allison, Ron1, 1 Department of Radiation Oncology, Greenville, NC, USA
ABSTRACT- Introduction and Objectives - While interleukin 1- (IL-1) is known to radioprotect the gastrointestine, the mechanism by which this protection occurs has yet to be established. Of several possible mechanisms, IL-1's radioprotective potential may be linked to its ability to reduce apoptotic activity in the crypt cells. To investigate this idea more fully, studies were designed to establish whether IL-1 interferes with the induction of apoptosis by downregulating members of the apoptotic caspase cascade. Methods - IL-1 (7.5 x 105 U/mouse) was administered to C57Bl/6 mice 24 hours prior to the animals receiving 8.0 Gy of regional abdominal x-irradiation (xRT). At designated times following IL-1 and/or xRT, groups of 4-5 mice were sacrificed, jejunal and colon tissue sections removed, embedded in paraffin, and sectioned onto slides for later morphometric analysis of apoptotic indices using the Schiff reaction and Fast Green FCF staining and determination of caspase 3, 8 and 9 levels using immunohistochemistry (IHC) techniques. Results - Data demonstrate that a marked increase in the apoptotic index is seen in both the jejunum and colon following irradiation, but pretreatment with IL-1 results in a significant decrease in this observed apoptotic response. Additionally, concomitant with this IL-related reduction in radiation-induced apoptosis, both caspases 3 and 9, which were highly expressed after radiation alone, were seen to be significantly less expressed after IL-1 + xRT. In contrast, however, treatment of IL-1 prior to radiation did not seem to affect the level of caspase 8 expression observed. Finally, the data illustrate that IL-1's modulation of caspase activity following radiation appears to demonstrate cell type specificity, being most pronounced within the goblet cells of the gastrointestine. Conclusions - Collectively, the results outlined herein suggest that the radioprotection observed in the gastrointestine following IL-1 pretreatment is mediated, at least in part, through a significant reduction in the apoptotic response. Furthermore, this reduced apoptosis appears to display cell type specificity and to occur in a manner which appears to involve downregulation of the intrinsic, rather than the extrinsic, apoptotic pathway.
Key words: IL-1 radioprotection, gastrointestine, apoptosis, caspase
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