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Editorial Volume 4 Issue 1
Evidence that the ubiquitin proteasome system plays a prominent role in inflammatory bowel disease: possible pharmacological approaches
Leo R Fitzpatrick
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Department of Pharmaceutical & Biomedical Sciences, California North state University College of Pharmacy, USA
Correspondence: Leo R Fitzpatrick, Assistant Dean of Research Affairs, Associate Professor, Department of Pharmaceutical & Biomedical Sciences, California North state University, College of Pharmacy, 9700 West Taron Drive, Elk Grove, CA 95757, USA, Tel 9166868364
Received: January 21, 2016 | Published: February 2, 2016
Citation: Fitzpatrick LR. Evidence that the ubiquitin proteasome system plays a prominent role in inflammatory bowel disease: possible pharmacological approaches. Pharm Pharmacol Int J. 2016;4(1):308-309. DOI: 10.15406/ppij.2016.04.00062
Keywords
ubiquitin, proteasome, epithelial, colonic, endopeptidase, genetic, cylindromatosis, pharmacological
Abbreviations
IBD, inflammatory bowel disease; CD, crohn’s disease; UC, ulcerative colitis; CYLD, cylindromatosis
Editorial
Inflammatory Bowel Disease (IBD), which exists predominantly as Crohn’s Disease (CD) and Ulcerative Colitis (UC) involves genetic and microbial factors, which result in chronic inflammation of the GI Tract.1 A recent manuscript by Cleynen and colleagues showed that the ubiquitin proteasome system (UPS), which is present in mammalian cells (e.g., intestinal epithelial cells) relevant to Inflammatory Bowel Disease (IBD), is an important contributor to the pathogenesis of intestinal inflammation.1 Specifically, these authors proposed that Cylindromatosis (CYLD) protein, which is a de-ubiquitinase that acts as a negative regulator of NF-κB signaling, plays a prominent role in IBD.1 This manuscript also provided good evidence that genetic polymorphisms in CYLD are significantly associated with human CD.1 Moreover, the authors showed that pathogenic bacteria (E. Coli strain LF82) decrease the expression of CYLD, thereby resulting in enhanced NF-kB activation in intestinal epithelial cells.1 This transcription factor has frequently been cited as a central mediator of inflammation in IBD.2 Other manuscripts published over the last 10years have also implicated various components of the UPS as being important in the pathogenesis of IBD.
CYLD
In 2006, Zhang, et al.3 (working at the NIH) showed that CYLD deficient mice were more susceptible to colonic inflammation, as well as developing colitis associated cancer.3 Subsequent studies by Reilly and co-investigators (including myself) at the Penn State College of Medicine confirmed these murine colitis findings.4 Moreover, we showed that adoptive transfer of CYLD-/- T cells induced colonic inflammation and symptoms of colitis in recipient mice.4
Immuno proteasome subunits (LMP2, LMP7, LMP10)
It is now established that when cells are exposed to pro-inflammatory cytokines (IFN-γ, IL-1β, TNF-α), which are up-regulated during the course of IBD, there is a replacement of constitutive catalytic proteasome subunits with immuno proteasome subunits.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 complex-like-1 (b2i), and LMP7 (b5i)] are involved in the pathogenesis of experimental colitis and IBD.5‒7
Novel pharmacological treatments targeting the UPS
A review of the references cited in this editorial implies that modulation of the UPS, particularly by developing drugs that selectively target the immuno proteasome would be a worthwhile endeavor.1‒7 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.5‒7 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).8,9 Therefore, the transition of immuno proteasome-selective inhibitors into clinical trials for chronic inflammatory diseases seems to be highly warranted in 2016.9
Acknowledgements
None.
Conflict of interest
Author declares that there is no conflict of interest.
References
- Cleynen I, Vazielle E, Artieda M, et al. Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease. Gut. 2014;63(8):1265‒1274.
- Fitzpatrick LR. Novel Pharmacological Approaches for Inflammatory Bowel Disease: Targeting Key Intracellular Pathways and the IL-23/IL-17 Axis. Int J Inflam. 2012:389404.
- Zhang J, Stirling B, Temmerman ST, et al. Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. J Clin Invest. 2006;116(11):3042‒3049.
- Reiley WW, Wei J, Lee AJ, et al. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med. 2007;204(6):1475‒85.
- Fitzpatrick LR, Small JS, Poritz LS, et al. Enhanced intestinal expression of the proteasome subunit low molecular mass polypeptide 2 in patients with inflammatory bowel disease. Dis Colon Rectum. 2007;50(3):337‒348; discussion 348‒350.
- Visekruna A, Slavova N, Dullat S, et al. Expression of catalytic proteasome subunits in the gut of patients with Crohn's disease. Int J Colorectal Dis. 2009;24(10):1133‒1139.
- Basler M, Dajee M, Moll C, et al. Prevention of experimental colitis by a selective inhibitor of the immuno proteasome. J Immunol. 2010;185(1):634‒641.
- Kimura H, Caturegli P, Takahashi M, et al. New Insights into the Function of the Immuno proteasome in Immune and Non immune Cells. J Immunol Res. 2015;2015:541984.
- Basler M, Mundt S, Bitzer A, et al. The immuno proteasome: a novel drug target for autoimmune diseases. Clin Exp Rheumatol. 2015;33(4 Suppl 92):S74‒79.
©2016 Fitzpatrick. This is an open access article distributed under the terms of the, which permits unrestricted use, distribution, and build upon your work non-commercially.
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