Enhanced intestinal expression of the proteasome subunit low molecular mass polypeptide 2 in patients with inflammatory bowel disease.
ABSTRACT Low molecular mass polypeptide 2 is an inducible immunoproteasome subunit. The expression of low molecular mass polypeptide 2 has not been examined in the intestine of patients with inflammatory bowel disease. This study was designed to determine whether the intestinal expression of low molecular mass polypeptide 2 was enhanced in a group of patients with inflammatory bowel disease compared with a group of control patients without inflammatory bowel disease. Moreover, we examined the association between low molecular mass polypeptide 2 expression and histologic pathology in these patients.
Twenty-one patients participated in the study. These included six control subjects without inflammatory bowel disease, eight patients with ulcerative colitis, and seven patients with Crohn's disease. Intestinal low molecular mass polypeptide 2 expression was evaluated by immunohistochemistry, as well as by Western blot. Histology scores (0-40 severity scale) were determined on the same sections of intestine as those used for low molecular mass polypeptide 2 histochemistry.
By immunohistochemistry, low molecular mass polypeptide 2 expression was significantly enhanced (P < 0.05 vs. control subjects) throughout visibly diseased areas of colon, rectum, and ileum from patients with inflammatory bowel disease. Low molecular mass polypeptide 2 expression also was increased in macroscopically normal intestine from patients with inflammatory bowel disease compared with normal tissue from control subjects. There was a significant correlation (P < 0.0001) between low molecular mass polypeptide 2 expression and histologic pathology in our patients. Western blot results confirmed that low molecular mass polypeptide 2 expression was enhanced in patients with ulcerative colitis (3.1-fold) and in patients with Crohn's disease (3.5-fold).
Intestinal low molecular mass polypeptide 2 expression is significantly increased in inflammatory bowel disease. The association between intestinal low molecular mass polypeptide 2 expression and histologic pathology suggests that this proteasome subunit plays a role in the pathogenesis of inflammatory bowel disease.
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ABSTRACT: The ubiquitin-proteasome system (UPS) plays a vital role in maintaining protein homeostasis and regulating numerous cellular processes. The proteasome, a multi-protease complex, is the key component of the UPS that has been validated as a therapeutic target by the FDA's approval of bortezomib and carfilzomib. These proteasome inhibitor drugs have substantially improved outcomes in patients with hematological malignancies and are currently being investigated for other types of cancer as well as several other diseases. These approved proteasome inhibitors target the catalytic activity of both the constitutive proteasome and immunoproteasome indiscriminately and their inhibitory effects on the constitutive proteasome in normal cells are believed to contribute to unwanted side effects. In addition, selective immunoproteasome inhibition has been proposed to have unique effects on other diseases, including those involving aberrant immune function. Initially recognized for its role in the adaptive immune response, the immunoproteasome is often upregulated in disease states such as inflammatory diseases and cancer, suggesting functions beyond antigen presentation. In an effort to explore the immunoproteasome as a potential therapeutic target in these diseases, the development of immunoproteasome-specific inhibitors has become the focus of recent studies. Owing to considerable efforts by both academic and industry groups, immunoproteasome-selective inhibitors have now been identified and tested against several disease models. These inhibitors also provide a valuable set of chemical tools for investigating the biological function of the immunoproteasome. In this review, we will focus on the recent efforts towards the development of immunoproteasome-selective inhibitors.Current pharmaceutical design 11/2012; · 4.41 Impact Factor
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