Skip to main content

Advertisement

SpringerLink
Log in

DPP-4 (CD26) inhibitor sitagliptin exerts anti-inflammatory effects on rat insulinoma (RINm) cells via suppressing NF-κB activation

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Dipeptidyl peptidase-4 (CD26), a cell surface glycoprotein, is expressed by a variety of cells. It has been shown that dipeptidyl peptidase-4 (CD26) is involved in T cell activation. Nonetheless, its role in inflammatory effects in islet β cells has not been well investigated. In this study, we used sitagliptin, a classic inhibitor of dipeptidyl peptidase-4 (CD26), to research the effect of dipeptidyl peptidase-4 (CD26) on the activation of NF-κB, the expression of inflammatory cytokines, and cell apoptosis in rat insulinoma cells. Results showed that dipeptidyl peptidase-4 (CD26) was expressed on the surface of rat insulinoma cells. Lipopolysaccharide-induced NF-κB activation and expression of inflammatory cytokines were suppressed by sitagliptin treatment in rat insulinoma cells. Furthermore, sitagliptin treatment reduced cell apoptosis stimulated by lipopolysaccharide. Taken together, this study showed for the first time that sitagliptin suppressed NF-κB activation and inflammatory cytokines expression in rat insulinoma cells, suggesting that the dipeptidyl peptidase-4 inhibitor may exert direct anti-inflammatory effects in islet β cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. R.P. Robertson, Beta-cell deterioration during diabetes: what’s in the gun? Trends Endocrinol Metab 20(8), 388–393 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. K.J. Chang-Chen, R. Mullur, E. Bernal-Mizrachi, Beta-cell failure as a complication of diabetes. Rev. Endocr. Metab. Disord. 9(4), 329–343 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. K. Ohnuma, N. Takahashi, T. Yamochi, O. Hosono, N.H. Dang, C. Morimoto, Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front. Biosci. 13, 2299–2310 (2008)

    Article  CAS  PubMed  Google Scholar 

  4. D. Reinhold, S. Wrenger, U. Bank, F. Buhling, T. Hoffmann, K. Neubert, M. Kraft, R. Frank, S. Ansorge, CD26 mediates the action of HIV-1 Tat protein on DNA synthesis and cytokine production in U937 cells. Immunobiology 195(1), 119–128 (1996)

    Article  CAS  PubMed  Google Scholar 

  5. D. Reinhold, R.W. Vetter, K. Mnich, F. Buhling, U. Lendeckel, I. Born, J. Faust, K. Neubert, H. Gollnick, S. Ansorge, Dipeptidyl peptidase IV (DP IV, CD26) is involved in regulation of DNA synthesis in human keratinocytes. FEBS Lett 428(1-2), 100–104 (1998)

    Article  CAS  PubMed  Google Scholar 

  6. N.N. Ta, Y. Li, C.A. Schuyler, M.F. Lopes-Virella, Y. Huang, DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis 213(2), 429–435 (2010)

    Article  CAS  PubMed  Google Scholar 

  7. M.A. Nauck, T. Vilsboll, B. Gallwitz, A. Garber, S. Madsbad, Incretin-based therapies: viewpoints on the way to consensus. Diabetes Care 32(Suppl 2), S223–S231 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. J. Zhong, X. Rao, S. Rajagopalan, An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis 226(2), 305–314 (2013)

    Article  CAS  PubMed  Google Scholar 

  9. N. Busso, N. Wagtmann, C. Herling, V. Chobaz-Peclat, A. Bischof-Delaloye, A. So, E. Grouzmann, Circulating CD26 is negatively associated with inflammation in human and experimental arthritis. Am. J. Pathol. 166(2), 433–442 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. T. Tasic, W. Baumer, A. Schmiedl, F. Schwichtenhovel, R. Pabst, U. Raap, S. von Horsten, M. Stephan, Dipeptidyl peptidase IV (DPP4) deficiency increases Th1-driven allergic contact dermatitis. Clin. Exp. Allergy. 41(8), 1098–1107 (2011)

    Article  CAS  PubMed  Google Scholar 

  11. E. Leinonen, E. Hurt-Camejo, O. Wiklund, L.M. Hulten, A. Hiukka, M.R. Taskinen, Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis 166(2), 387–394 (2003)

    Article  CAS  PubMed  Google Scholar 

  12. C. de Luca, J.M. Olefsky, Inflammation and insulin resistance. FEBS Lett 582(1), 97–105 (2008)

    Article  PubMed  Google Scholar 

  13. H.P. Kopp, C.W. Kopp, A. Festa, K. Krzyzanowska, S. Kriwanek, E. Minar, R. Roka, G. Schernthaner, Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Arterioscler. Thromb. Vasc. Biol. 23(6), 1042–1047 (2003)

    Article  CAS  PubMed  Google Scholar 

  14. K. Maedler, P. Sergeev, F. Ris, J. Oberholzer, H.I. Joller-Jemelka, G.A. Spinas, N. Kaiser, P.A. Halban, M.Y. Donath, Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110(6), 851–860 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. J. Li, S. Chen, J. Qiang, X. Wang, L. Chen, D. Zou, Diet-induced obesity mediates a proinflammatory response in pancreatic beta cell via toll-like receptor 4. Cent. Eur. J. Immunol. 39(3), 306–315 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. N.N. Ta, C.A. Schuyler, Y. Li, M.F. Lopes-Virella, Y. Huang, DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice. J. Cardiovasc. Pharmacol. 58(2), 157–166 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. G. Liuzzo, M. Santamaria, L.M. Biasucci, M. Narducci, V. Colafrancesco, A. Porto, S. Brugaletta, M. Pinnelli, V. Rizzello, A. Maseri, F. Crea, Persistent activation of nuclear factor kappa-B signaling pathway in patients with unstable angina and elevated levels of C-reactive protein evidence for a direct proinflammatory effect of azide and lipopolysaccharide-free C-reactive protein on human monocytes via nuclear factor kappa-B activation. J. Am. Coll. Cardiol. 49(2), 185–194 (2007)

    Article  CAS  PubMed  Google Scholar 

  18. G. Pesarini, A. Amoruso, V. Ferrero, C. Bardelli, L.G. Fresu, L. Perobelli, P. Scappini, G. De Luca, S. Brunelleschi, C. Vassanelli, F. Ribichini, Cytokines release inhibition from activated monocytes, and reduction of in-stent neointimal growth in humans. Atherosclerosis 211(1), 242–248 (2010)

    Article  CAS  PubMed  Google Scholar 

  19. Y.C. Lu, W.C. Yeh, P.S. Ohashi, LPS/TLR4 signal transduction pathway. Cytokine 42(2), 145–151 (2008)

    Article  CAS  PubMed  Google Scholar 

  20. T. Kawai, S. Akira, TLR signaling. Cell. Death. Differ. 13(5), 816–825 (2006)

    Article  CAS  PubMed  Google Scholar 

  21. K. Ohnuma, T. Yamochi, M. Uchiyama, K. Nishibashi, S. Iwata, O. Hosono, H. Kawasaki, H. Tanaka, N.H. Dang, C. Morimoto, CD26 mediates dissociation of Tollip and IRAK-1 from caveolin-1 and induces upregulation of CD86 on antigen-presenting cells. Mol. Cell. Biol. 25(17), 7743–7757 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. T. Shinjo, Y. Nakatsu, M. Iwashita, T. Sano, H. Sakoda, H. Ishihara, A. Kushiyama, M. Fujishiro, T. Fukushima, Y. Tsuchiya, H. Kamata, F. Nishimura, T. Asano, DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-kappaB activation. Am. J. Physiol. Endocrinol. Metab. 309(3), E214–E223 (2015)

    Article  CAS  PubMed  Google Scholar 

  23. R. Medzhitov, E.M. Shevach, G. Trinchieri, A.L. Mellor, D.H. Munn, S. Gordon, P. Libby, G.K. Hansson, K. Shortman, C. Dong, D. Gabrilovich, L. Gabrysova, A. Howes, A. O’Garra, Highlights of 10 years of immunology in Nature Reviews Immunology. Nat. Rev. Immunol. 11(10), 693–702 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. X.P. Huang, H. Ding, J.D. Lu, Y.H. Tang, B.X. Deng, C.Q. Deng, Effects of the Combination of the Main Active Components of Astragalus and Panax notoginseng on Inflammation and Apoptosis of Nerve Cell after Cerebral Ischemia-Reperfusion. Am. J. Chin. Med. 43(7), 1419–1438 (2015)

    Article  CAS  PubMed  Google Scholar 

  25. J.R. Weaver, J.L. Nadler, D.A. Taylor-Fishwick, Interleukin-12 (IL-12)/STAT4 Axis Is an Important Element for beta-Cell Dysfunction Induced by Inflammatory Cytokines. PLoS One 10(11), e0142735 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  26. K. Meyerovich, M. Fukaya, L.F. Terra, F., Ortis, Eizirik, D.L., Cardozo, A.K., The non-canonical NF-kappaB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro. Diabetologia (2015).

  27. H.I. Marrif, S.I. Al-Sunousi, Pancreatic beta Cell Mass Death. Frontiers in pharmacology 7, 83 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  28. L. Wang, C.T. Luk, S.A. Schroer, A.M. Smith, X. Li, E.P. Cai, H. Gaisano, P.E. MacDonald, Z. Hao, T.W. Mak, M. Woo, Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions. Diabetologia 57(9), 1889–1898 (2014)

    Article  CAS  PubMed  Google Scholar 

  29. A. Kaminski, H.J. Welters, E.R. Kaminski, N.G. Morgan, Human and rodent pancreatic beta-cells express IL-4 receptors and IL-4 protects against beta-cell apoptosis by activation of the PI3K and JAK/STAT pathways. Bioscience reports 30(3), 169–175 (2010)

    Article  CAS  Google Scholar 

  30. R. Eldor, R. Abel, D. Sever, G. Sadoun, A. Peled, R. Sionov, D. Melloul, Inhibition of nuclear factor-kappaB activation in pancreatic beta-cells has a protective effect on allogeneic pancreatic islet graft survival. PLoS One 8(2), e56924 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. S.L. Conarello, Z. Li, J. Ronan, R.S. Roy, L. Zhu, G. Jiang, F. Liu, J. Woods, E. Zycband, D.E. Moller, N.A. Thornberry, B.B. Zhang, Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc. Natl. Acad. Sci. U. S. A. 100(11), 6825–6830 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. J.A. Pospisilik, J. Martin, T. Doty, J.A. Ehses, N. Pamir, F.C. Lynn, S. Piteau, H.U. Demuth, C.H. McIntosh, R.A. Pederson, Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 52(3), 741–750 (2003)

    Article  CAS  PubMed  Google Scholar 

  33. J. Mu, J. Woods, Y.P. Zhou, R.S. Roy, Z. Li, E. Zycband, Y. Feng, L. Zhu, C. Li, A.D. Howard, D.E. Moller, N.A. Thornberry, B.B. Zhang, Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 55(6), 1695–1704 (2006)

    Article  CAS  PubMed  Google Scholar 

  34. J. Mu, A. Petrov, G.J. Eiermann, J. Woods, Y.P. Zhou, Z. Li, E. Zycband, Y. Feng, L. Zhu, R.S. Roy, A.D. Howard, C. Li, N.A. Thornberry, B.B. Zhang, Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur. J. Pharmacol. 623(1-3), 148–154 (2009)

    Article  CAS  PubMed  Google Scholar 

  35. A. Duttaroy, F. Voelker, K. Merriam, X. Zhang, X. Ren, K. Subramanian, T.E. Hughes, B.F. Burkey, The DPP-4 inhibitor vildagliptin increases pancreatic beta cell mass in neonatal rats. Eur. J. Pharmacol. 650(2-3), 703–707 (2011)

    Article  CAS  PubMed  Google Scholar 

  36. D.A. Stoffers, The development of beta-cell mass: recent progress and potential role of GLP-1. Horm. Metab. Res. 36(11-12), 811–821 (2004)

    Article  CAS  PubMed  Google Scholar 

  37. A. Maida, T. Hansotia, C. Longuet, Y. Seino, D.J. Drucker, Differential importance of glucose-dependent insulinotropic polypeptide vs glucagon-like peptide 1 receptor signaling for beta cell survival in mice. Gastroenterology 137(6), 2146–2157 (2009)

    Article  CAS  PubMed  Google Scholar 

  38. B. Samikannu, C. Chen, N. Lingwal, M. Padmasekar, F.B. Engel, T. Linn, Dipeptidyl peptidase IV inhibition activates CREB and improves islet vascularization through VEGF-A/VEGFR-2 signaling pathway. PLoS One 8(12), e82639 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was funded by the National Natural Science Foundation of China (No. 81370847).

Author contributions

XY Hu drafted the article, acquired and analyzed the data, and wrote the article. SY Liu planned the experiments, performed the literature search, and revised the article. XD Liu, JL Zhang, and Y Liang collected data and revised the article. Y Li is the guarantor of this work and has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Xingyun Hu, Xiaodan Liu, Jinglu Zhang, Ying Liang & Yan Li

  2. Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Shanying Liu

Authors
  1. Xingyun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shanying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaodan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinglu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yan Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, X., Liu, S., Liu, X. et al. DPP-4 (CD26) inhibitor sitagliptin exerts anti-inflammatory effects on rat insulinoma (RINm) cells via suppressing NF-κB activation. Endocrine 55, 754–763 (2017). https://doi.org/10.1007/s12020-016-1073-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-016-1073-8

Keywords

Search

Navigation