| 抄録 |
Intestinal epithelial cells（IECs）are organized as a single cell layer which covers the small and large intestine. Their primary task is to absorb nutrients present in the intestinal lumen. However, IECs also play an important role in the immune defense of our body by building a barrier that separates the bowel wall from potentially hazardous gut contents such as bacteria. Cell death in the intestinal epithelium has to be tightly regulated and irregularities might cause pathologies. Accordingly, excessive cell death has been associated with chronic inflammation as seen in Crohn’s disease and ulcerative colitis patients. On the other hand, escape from cell death might be involved in the development of colorectal cancer. While until recently, apoptosis was discussed as being essential for epithelial turnover and tissue homeostasis in the intestinal epithelium, recent data using gene deficient mice have challenged this concept. Moreover, we have described an apoptosis-independent mode of programmed cell death, termed necroptosis, in the intestine. Intestinal epithelial caspase expression has been shown to regulate not only survival versus cell death, but also whether apoptotic or necroptotic cell death is executed. Caspases are cysteine proteases that regulate embryonic development, cell differentiation, tissue homoeostasis, and removal of damaged and harmful cells from the intestine and other parts of the body. Caspase activity is mainly regulated at the post-translational level, which allows their rapid activation and response to cellular stress and pathogenic stimuli. In most cell types, caspases are initially expressed as inactive proenzymes, which undergo proteolytic cleavage to become functional enzymes. Although the roles of caspases have been studied extensively in regulation of apoptosis, recent discoveries have highlighted cell-death independent functions of this protein family. In particular, caspase-1, caspase-4, caspase-5, and caspase-12 are activated during innate immune responses and participate in the formation of the inflammasome. Caspase-8 controls necroptosis of Paneth cells and potentially the death of intestinal epithelial cells in patients with Crohn’s disease, and appears to be involved in mucosal inflammation. Regulators of caspase-8 might therefore be used to prevent cell death in patients with IBD. Improving our understanding of the regulation and function of caspases in the intestine might lead to new therapeutics for chronic intestinal inflammation and inflammation-associated cancer. |
