Enhanced Intestinal Expression of the Proteasome Subunit Low Molecular Mass Polypeptide 2 in Patients with Inflammatory Bowel Disease

Abstract

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.

Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors

“…28 Diseases associated with an aberrant immune response, such as inflammatory bowel disease 29,30 and rheumatoid arthritis, 31 have also been identified as having increased 20S i expression. This may be due in part to the ability of inflammatory cytokines, such as tumor necrosis factor and interferon-␥, to induce expression and preferential incorporation of ␤1 i , ␤2 i , and ␤5 i into the proteasome.…”

Structural and Functional Characterization of the Immunoproteasome

“…Additionally, Alzheimer's [45] and Huntington's [46] disease as well as amyotrophic lateral sclerosis [47] and inflammatory bowel disease [48] are characterized by increased expression rates of iCPs or single i subunits. 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] .…”

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.…”

“…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. [5][6][7] Of note, two recent review papers (published in 2015) provide recent insights, which may further aid in the development of safe and effective drugs that inhibit immuno proteasome activity. Such drugs could be used not only for treating IBD, but also for the treatment of other autoimmune diseases (e.g., Rheumatoid Arthritis).…”