Abstract
Dipeptidyl peptidase 4 (DPP4), a ubiquitously expressed protease that cleaves off the N-terminal dipeptide from proline and alanine on the penultimate position, has important roles in many physiological processes. In the present study, experimental colitis was induced in mice receiving 3% dextran sulfate sodium (DSS) in drinking water. We found that mice with DSS-induced colitis had significantly increased intestinal DPP activity and decreased serum DPP activity, suggesting a probable correlation of DPP4 with experimental colitis. Then, we investigated whether sitagliptin, a specific DPP4 inhibitor could protect against DSS-induced colitis. We showed that oral administration of single dose of sitagliptin (30 mg/kg) on D7 remarkably inhibited DPP enzyme activity in both serum and intestine of DSS-induced colitic mice. Repeated administration of sitagliptin (10, 30 mg/kg, bid, from D0 to D8) significantly ameliorated DSS-induced colitis, including reduction of disease activity index (DAI) and body weight loss, improvement of histological score and colon length. Sitagliptin administration dose-dependently increased plasma concentrations of active form of GLP-1 and colonic expression of GLP-2R. Co-administration of GLP-2R antagonist GLP-23-33 (500 μg/kg, bid, sc) abolished the protective effects of sitagliptin in DSS-induced colitic mice. Moreover, sitagliptin administration significantly decreased the ratio of apoptotic cells and increased the ratio of proliferative cells in colon epithelium of DSS-induced colitic mice, and this effect was also blocked by GLP-23-33. Taken together, our results demonstrate that sitagliptin could attenuate DSS-induced experimental colitis and the effects can be attributed to the enhancement of GLP-2 action and the subsequent protective effects on intestinal barrier by inhibiting epithelial cells apoptosis and promoting their proliferation. These findings suggest sitagliptin as a novel therapeutic approach for the treatment of ulcerative colitis.
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References
Loddo I, Romano C. Inflammatory bowel disease: genetics, epigenetics, and pathogenesis. Front Immunol. 2015;6:551.
Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390:2769–78.
Mak WY, Zhao M, Ng SC, Burisch J. The epidemiology of inflammatory bowel disease: east meets west. J Gastroenterol Hepatol. 2020;35:380–9.
Lucafò M, Franca R, Selvestrel D, Curci D, Pugnetti L, Decorti G, et al. Pharmacogenetics of treatments for inflammatory bowel disease. Expert Opin Drug Metab Toxicol. 2018;14:1209–23.
Matteucci E, Giampietro O. Dipeptidyl peptidase-4 (CD26): knowing the function before inhibiting the enzyme. Curr Med Chem. 2009;16:2943–51.
Klemann C, Wagner L, Stephan M, von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system. Clin Exp Immunol. 2016;185:1–21.
Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35:992–1019.
Birnbaum Y, Bajaj M, Qian J, Ye Y. Dipeptidyl peptidase-4 inhibition by Saxagliptin prevents inflammation and renal injury by targeting the Nlrp3/ASC inflammasome. BMJ Open Diabetes Res Care. 2016;4:e000227.
Benjamin MA, McKay DM, Yang PC, Cameron H, Perdue MH. Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse. Gut. 2000;47:112–9.
Bremholm L, Hornum M, Henriksen BM, Larsen S, Holst JJ. Glucagon-like peptide-2 increases mesenteric blood flow in humans. Scand J Gastroenterol. 2009;44:314–9.
Janssen P, Rotondo A, Mulé F, Tack J. Review article: a comparison of glucagon-like peptides 1 and 2. Aliment Pharmacol Ther. 2013;37:18–36.
Kato Y, Yu D, Schwartz MZ. Glucagonlike peptide-2 enhances small intestinal absorptive function and mucosal mass in vivo. J Pediatr Surg. 1999;34:18–20.
Boushey RP, Yusta B, Drucker DJ. Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. Am J Physiol. 1999;277:E937–47.
Boushey RP, Yusta B, Drucker DJ. Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res. 2001;61:687–93.
Nakame K, Kaji T, Mukai M, Shinyama S, Matsufuji H. The protective and anti-inflammatory effects of glucagon-like peptide-2 in an experimental rat model of necrotizing enterocolitis. Peptides. 2016;75:1–7.
Ban H, Bamba S, Imaeda H, Inatomi O, Kobori A, Sasaki M, et al. The DPP-IV inhibitor ER-319711 has a proliferative effect on the colonic epithelium and a minimal effect in the amelioration of colitis. Oncol Rep. 2011;25:1699–703.
Mimura S, Ando T, Ishiguro K, Maeda O, Watanabe O, Ujihara M, et al. Dipeptidyl peptidase-4 inhibitor anagliptin facilitates restoration of dextran sulfate sodium-induced colitis. Scand J Gastroenterol. 2013;48:1152–9.
Salaga M, Binienda A, Draczkowski P, Kosson P, Kordek R, Jozwiak K, et al. Novel peptide inhibitor of dipeptidyl peptidase IV (Tyr-Pro-D-Ala-NH2) with anti-inflammatory activity in the mouse models of colitis. Peptides. 2018;108:34–45.
Salaga M, Mokrowiecka A, Zielinska M, Malecka-Panas E, Kordek R, Kamysz E, et al. New peptide inhibitor of dipeptidyl peptidase IV, EMDB-1 extends the half-life of GLP-2 and attenuates colitis in mice after topical administration. J Pharmacol Exp Ther. 2017;363:92–103.
Yazbeck R, Sulda ML, Howarth GS, Bleich A, Raber K, von Hörsten S, et al. Dipeptidyl peptidase expression during experimental colitis in mice. Inflamm Bowel Dis. 2010;16:1340–51.
Lee M, Rhee MK. Sitagliptin for Type 2 diabetes: a 2015 update. Expert Rev Cardiovasc Ther. 2015;13:597–610.
Ceriello A, Sportiello L, Rafaniello C, Rossi F. DPP-4 inhibitors: pharmacological differences and their clinical implications. Expert Opin Drug Saf. 2014; 13(Suppl 1):S57–68.
Zou Y, Lin J, Li W, Wu Z, He Z, Huang G, et al. Huangqin-tang ameliorates dextran sodium sulphate-induced colitis by regulating intestinal epithelial cell homeostasis, inflammation and immune response. Sci Rep. 2016;6:39299.
Matsunaga T, Hashimoto S, Yamamoto N, Kawasato R, Shirasawa T, Goto A, et al. Protective effect of daikenchuto on dextran sulfate sodium-induced colitis in mice. Gastroenterol Res Pract. 2017;2017:1298263.
Yazbeck R, Howarth GS, Butler RN, Geier MS, Abbott CA. Biochemical and histological changes in the small intestine of mice with dextran sulfate sodium colitis. J Cell Physiol. 2011;226:3219–24.
Durinx C, Lambeir AM, Bosmans E, Falmagne JB, Berghmans R, Haemers A, et al. Molecular characterization of dipeptidyl peptidase activity in serum: soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides. Eur J Biochem. 2000;267:5608–13.
Friedrich D, Hoffmann T, Bär J, Wermann M, Manhart S, Heiser U, et al. Does human attractin have DP4 activity? Biol Chem. 2007;388:155–62.
Zhang H, Chen Y, Keane FM, Gorrell MD. Advances in understanding the expression and function of dipeptidyl peptidase 8 and 9. Mol Cancer Res. 2013;11:1487–96.
Araki Y, Mukaisyo K, Sugihara H, Fujiyama Y, Hattori T. Increased apoptosis and decreased proliferation of colonic epithelium in dextran sulfate sodium-induced colitis in mice. Oncol Rep. 2010;24:869–74.
Korom S, De Meester I, Stadlbauer TH, Chandraker A, Schaub M, Sayegh MH, et al. Inhibition of CD26/dipeptidyl peptidase IV activity in vivo prolongs cardiac allograft survival in rat recipients. Transplantation. 1997;63:1495–500.
Hildebrandt M, Rose M, Ruter J, Salama A, Mönnikes H, Klapp BF. Dipeptidyl peptidase IV (DP IV, CD26) in patients with inflammatory bowel disease. Scand J Gastroenterol. 2001;36:1067–72.
Lee TM, Chen WT, Chang NC. Dipeptidyl peptidase-4 inhibition attenuates arrhythmias via a protein kinase A-dependent pathway in infarcted hearts. Circ J. 2015;79:2461–70.
Mulvihill EE, Varin EM, Gladanac B, Campbell JE, Ussher JR, Baggio LL, et al. Cellular sites and mechanisms linking reduction of dipeptidyl peptidase-4 activity to control of incretin hormone action and glucose homeostasis. Cell Metab. 2017;25:152–65.
Reichetzeder C, von Websky K, Tsuprykov O, Mohagheghi Samarin A, Falke LG, Dwi Putra SE, et al. Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury. Br J Pharmacol. 2017;174:2273–86.
Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913.
Acknowledgements
This study was financially supported by a grant from the National Natural Science Foundation of China (no. 81872922).
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MMN and YL designed the study. MMN, WJY, WBG, YPG, and YF conducted the experiments. MMN and WBG analyzed the data. MMN and YL wrote the manuscript.
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Ning, Mm., Yang, Wj., Guan, Wb. et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protected against dextran sulfate sodium-induced experimental colitis by potentiating the action of GLP-2. Acta Pharmacol Sin 41, 1446–1456 (2020). https://doi.org/10.1038/s41401-020-0413-7
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DOI: https://doi.org/10.1038/s41401-020-0413-7
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