Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation.
Previous studies have shown that acute injury to rodent small intestinal mucosa as a result of either chemotherapy or radiation is caused by a combination of high-frequency cell death caused by apoptosis, continued migration of epithelial cells from the intestinal crypts toward the villi, and absence of adequate compensatory mitotic activity in the crypt bases. Recently, we have shown that IL-11, a novel multifunctional bone marrow stromal-derived growth factor, could stimulate rapid repair of small intestinal villous structures in mice treated with combined radiation and chemotherapy by increasing the mitotic index of crypt cells. To further clarify the biological mechanism responsible for its protective action, we used a similar experimental model to evaluate whether IL-11 could reduce the high frequency of apoptosis observed after cytoablative treatment. In the present study, 78 C3H/HeJ mice received 5-fluorouracil at 150 mg/kg body weight intraperitoneal injection 3 days before 7.0-Gy total body irradiation. The animals received IL-11 250 microg/kg body weight/day divided into two equal doses or vehicle control by subcutaneous injections beginning on the same day of irradiation within 1 hour of the end of the dose. The mice killed on Days 1, 2, and 5 after cytoablative treatment were autopsied, the small intestine was processed for histologic examination, and the mitotic index and other parameters were measured, including the expression of the proliferating cell nuclear antigen and of the p53 protein. Apoptosis was detected by a nonisotopic in situ DNA end-labeling technique applied to the same histologic sections. The cytoablative treatment caused marked degenerative changes in the small intestinal mucosa, including shortening of the villi and damage to the crypt cells. The degenerative changes, which included nuclear fragmentation with formation of apoptotic bodies, increased expression of proliferating cell nuclear antigen, and strong expression of p53 was seen in mice killed on Days 1 and 2 after cytotoxic treatment. IL-11 administration resulted in a partial suppression of apoptosis, as shown by a reduced number of crypt cells stained with in situ DNA end-labeling for fragmented DNA. In addition, IL-11 treatment was associated with an increase in the frequency of mitosis and proliferating cell nuclear antigen expression in crypt cells as compared with the vehicle treated mice. Morphometric analysis of intestinal villi and crypt depth showed increased villus length and decreased crypt to villus ratio after IL-11 treatment. These results indicate that IL-11 can exert a potent effect on the recovery of the small intestinal mucosa of mice by its combined effects on proliferation and apoptosis of crypt cells. IL-11 may thus have potential clinical applications in limiting the intestinal toxicity that is associated with cytotoxic therapies.
Orazi
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Division of Hematopathology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Du
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Yang
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Kashai
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Williams
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D000818:Animals; D000964:Antimetabolites, Antineoplastic; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003593:Cytoplasm / Q000473:pathology; D005472:Fluorouracil; D017370:Interleukin-11 / Q000494:pharmacology* / Q000627:therapeutic use; D007410:Intestinal Diseases / Q000139:chemically induced / Q000188:drug therapy*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D011994:Recombinant Proteins
D000964:Antimetabolites, Antineoplastic; D017370:Interleukin-11; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D005472:Fluorouracil