Expression of catalytic proteasome subunits in the gut of patients with Crohn’s disease

Abstract

Background and purposeActivation of the transcription factor NF-κB by proteasomes and subsequent nuclear translocation of cytoplasmatic complexes play a crucial role in the intestinal inflammation. Proteasomes have a pivotal function in NF-κB activation by mediating degradation of inhibitory IκB proteins and processing of NF-κB precursor proteins. This study aims to analyze the expression of the human proteasome subunits in colonic tissue of patients with Crohn’s disease.Materials and methodsThirteen patients with Crohn’s disease and 12 control patients were studied. The expression of immunoproteasomes and constitutive proteasomes was examined by Western blot analysis, immunoflourescence and quantitative real-time PCR. For real-time PCR, AK2C was used as housekeeping gene.ResultsThe results indicate the influence of the intestinal inflammation on the expression of the proteasomes in Crohn’s disease. Proteasomes from inflamed intestine of patients with Crohn’s disease showed significantly increased expression of immunosubunits on both protein and mRNA levels. Especially, the replacement of the constitutive proteasome subunit β1 by inducible immunosubunit β1i was observed in patients with active Crohn’s disease. In contrast, relatively low abundance of immunoproteasomes was found in control tissue.ConclusionsOur data demonstrate that in contrast to normal colonic tissue, the expression of immunoproteasomes was evidently increased in the inflamed colonic mucosa of patients with Crohn’s disease. Thus, the chronic intestinal inflammation process in Crohn’s disease leads to significant alterations of proteasome subsets.

Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

“…Comparable results were obtained from CD patients, who showed high LMP2 and MECL-1 expression in inflamed mucosa (27). Because LMP7 is already expressed in high amounts in healthy control patients, no upregulation of this subunit was observed in CD patients in two additional studies (39,40). Induction of colitis by oral administration of DSS in the drinking water of LMP2-, LMP7-, and MECL-1-deficient mice revealed a nearly complete protection of these mice compared with WT mice (Figs.…”

“…Administration of a b5-selective inhibitor had no effect on colitis severity. Taken together, these data suggest that, despite the high basal expression of LMP7 in normal colon tissue (39,40), LMP7 represents a targeted approach to the treatment of CD because of the unique role of the immunoproteasome in regulatory inflammatory responses. Our results indicated that LMP7 is directly involved in disease development, presumably as the result of regulation of cytokine production in inflammatory cells.…”

Structural and Functional Characterization of the Immunoproteasome

“…Moreover, abnormal levels of i subunits were observed in Sjogren's syndrome [49] , inclusion body myositis, myofibrillar myopathy [50] , Crohn's disease [51] and dextran sulfate sodium-induced colitis [52] . These findings suggest a therapeutic benefit from blocking solely the iCP, at least for the above mentioned diseases.…”

Evidence that the Ubiquitin Proteasome System Plays a Prominent Role in Inflammatory Bowel Disease: Possible Pharmacological Approaches

“…5,6 Results from my laboratory, as well as other investigators, suggest that these immuno proteasome subunits [low molecular mass polypeptide (LMP) 2 (b1i), multi-catalytic endopeptidase complexlike-1 (b2i), and LMP7 (b5i)] are involved in the pathogenesis of experimental colitis and IBD.…”

“…[1][2][3][4][5][6][7] In this regard, targeting the LMP7 subunit with a selective small molecule inhibitor (PR-957, ONX-0914) was shown to be effective in a mouse model of UC. 7 To date, the relevant literature seems to suggest that targeting the LMP7 or LMP2 immuno proteasome subunits may be most beneficial for the treatment of IBD.…”