Histological Examination of Colonic Mucosal Damage in Rats Induced by Proinflammatory Cytokines. -In Relation to the Role of Proinflammatory Cytokines in the Pathogenesis of Ulcerative Colitis-

• Project/Area Number: 06670513
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hirosaki University
• Principal Investigator: MURATA Yuhji Hirosaki University, School of Medicine, Associate Professor, 医学部, 助教授 (70174307)
• Co-Investigator(Kenkyū-buntansha): HAGA Yohichi National Hirosaki Hospital, Doctor, 内科, 医師 (20261448) ; TANAKA Masanori Hirosaki University, School of Medicine, Assistant Professor, 医学部, 講師 (10241473) ; MUNAKATA Akihiro Hirosaki University, School of Medicine, Professor, 医学部, 教授 (50003661)
• Project Period (FY): 1994 – 1996
• Project Status: Completed (Fiscal Year 1996)
• Budget Amount: ¥2,200,000 (Direct Cost: ¥2,200,000); Fiscal Year 1996: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 1995: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
• Keywords: proinflammatory cytokine / colonic mucosal damage / rat / histological examination / MHC class II antigen / apoptosis / ulcerative colitis / pathogenesis / 実験的大腸炎 / DR抗原 / ラット大腸炎 / 病理組織像 / MHC-classII発現

Research Abstract

Al though the cause of ulcerative colitis (UC) remains unknown, the increased production of proinflammatory cytokines such as IL-1, IL-6, IL-8 and TNF-alpha is believed to be involved in the colonic mucosal damage of this disease. However, it has not yet been clarified which of these cytokines could be most implicated or what role of each cytokine might play in the colonic mucosal damage in UC.The aim of this study was to evaluate the effects of proinflammatory cytokines on the colonic mucosa of rats. Human rIL-1beta, IL-6, TNF-alpha, and rat rIL-8, each in a volume of 0.25ml was injected endoscopically into the colonic mucosa of rats. Histological examination was made 6h after injection of these cytokines to determine their direct effects.
The mucosal damage was characterized by epithelial exfoliation, crypt distortion, goblet cell depletion, and infiltration of neutrophils and eosinophils in all rats receiving IL-8, by same changes in mucosal layr and a slight infiltration of neutroph ils in half rats receiving IL-6. All rats receiving TNF-alpha showed epithelial exfoliation, goblet cell depletion and infiltration of polymorphonuclear leukocytes, and the mucosal destruction was severe. All rats receiving IL-1beta, however, showed only hemorrhage in submucosa. The mucosal damage in rats receiving IL-8 was most similar to that of active UC.The expression of MHC class II antigen on mucosal mononuclear cells, which was examined by immunohistochemical stainning, was increased in rats receiving IL-6 and IL-8, and was markedly increased in rats receiving TNF-alpha. In addition, epithelial cell apoptosis detected by TUNEL's method was increased in rats receiving TNF-alpha, but was scattered in rats receiving other proinflammatory cytokines compared with controls.
These findings suggest that IL-8 might play a most important role in the inflammatory response of active UC,and that TNF-alpha have activated mucosal immunocytes and might play a role in the mechanism of epithelial cell death by apoptosis.