Liraglutide Exerts Potential Anti-inflammatory Effect in Type 1 Diabetes by Inhibiting IFN-γ Production via Suppressing JAK-STAT Pathway

Author(s): Yunjuan Zhao , Yunliang Xie , Wangen Li* .

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets

Volume 19 , Issue 5 , 2019

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Abstract:

Background: Type 1 diabetes is a T cell-mediated autoimmune disease. Interferon γ plays a critical role in the pathogenesis of type 1 diabetes. Signal transducer and activator of transcription transduces type I interferon cytokines in T cells, leading to Th1 cell differentiation and production of interferon γ. Recent studies suggest that liraglutide reduces the plasma concentration of C-reative protein in patients with type 1 diabetes and protects β cell function in the non-obese diabetic mouse.

Objective: The study aimed to explore the effect of glucagon-like peptide-1 analogue on interferon γ production and the underlying signaling pathway in vitro.

Methods: Jurkat E6-1 cells were intervened with different concentrations of glucose and liraglutide during different time periods. Protein was extracted from Jurkat E6-1 cells. The target proteins (total and activated Janus kinase 2, signal transducers and activators of transcription 4 and interferon γ) were detected by Western blot.

Results: Glucose stimulates interferon γ expression and activates Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and timedependent manner. Under high glucose condition, liraglutide inhibits interferon γ expression and Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and time-dependent manner. The Janus kinase responsible for liraglutide-inhibited signal transducers and activators of transcription 4 phosphorylation is Janus kinase 2, which is also required for the interferon γ induction. Finally, we demonstrated that under high glucose condition, liraglutide inhibits interferon γ expression via Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells.

Conclusion: Liraglutide inhibits Jurkat E6-1 cells to produce interferon γ via the Janus kinase/signal transducers and activators of transcription signaling pathway under high glucose condition, which implies its potential in the immunoregulatory effect of type 1 diabetes.

Keywords: Liraglutide, IFN-γ, type 1 diabetes, T cell, JAK-STAT pathway, GLP-1.

[1]
Lundberg, M.; Krogvold, L.; Kuric, E.; Dahl-Jørgensen, K.; Skog, O. Expression of interferon-stimulated genes in insulitic pancreatic islets of patients recently diagnosed with type 1 diabetes. Diabetes, 2016, 65(10), 3104-3110.
[2]
Savinov, A.Y.; Wong, F.S.; Chervonsky, A.V. IFN-γ affects homing of diabetogenic T cells. J. Immunol., 2001, 167, 6637-6643.
[3]
Korman, B.D.; Kastner, D.L.; Gregersen, P.K.; Remmers, E.F. STAT4: Genetics, mechanisms, and implications for autoimmunity. Curr. Allergy. Asthmr., 2008, 8, 398-403.
[4]
Liang, Y.; Pan, H.F.; Ye, D.Q. Therapeutic potential of STAT4 in autoimmunity. Expert Opin. Ther. Tar, 2014, 18, 945-960.
[5]
Trivedi, P.M.; Graham, K.L.; Scott, N.A.; Jenkins, M.R.; Majaw, S.; Sutherland, R.M.; Fynch, S.; Lew, A.M.; Burns, J.C. Krishnamurthy. B.; Brodnicki, T.C. Repurposed JAK1/JAK2 inhibitor reverses established autoimmune insulitis in non-obese diabetic mice. Diabetes, 2017, 66, 1650-1660.
[6]
Kodera, R.; Shikata, K.; Kataoka, H.U.; Takatsuka, T.; Miyamoto, S.; Sasaki, M.; Kajitani, N.; Nishishita, S.; Sarai, K.; Hirota, D.; Sato, C.; Ogawa, D.; Makino, H. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia, 2011, 54, 965-978.
[7]
Li, L.R.; Lu, J.; Jia, X.L.; Hui, H.; Zhang, J.; Liu, Y.; Cui, W.J.; Xu, Q.Y.; Zhu, D.L. Liraglutide enhances the efficacy of human mesenchymal stem cells in preserving islet β-cell function in severe non-obese diabetic mice. Mol. Med., 2016, 22, 800.
[8]
Abraham, R.T.; Weiss, A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat. Rev. Immunol., 2004, 4, 301.
[9]
Darnell, Jr J.E., Studies of IFN-induced transcriptional activation uncover the jak-stat pathway. J. Interf Cytok Res., 1998, 18, 549-554.
[10]
Zhu, J.; Jankovic, D.; Oler, A.J.; Wei, G.; Sharma, S.; Hu, G.; Guo, L.Y.; Yagi, R.; Yamane, H.; Punkosdy, G.; Feigenbaum, L.; Zhao, K.; Paul, W.E. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity, 2012, 37, 660-673.
[11]
Dubé, M.C.; D’amours, M.; Weisnagel, S.J. Beyond glycaemic control: A cross‐over, double‐blinded, 24‐week intervention with liraglutide in type 1 diabetes. Diabetes Obes. Metab., 2018, 20, 178-184.
[12]
Panta, R.; Kunwar, S.; Batra, M.; Ghimire, D.; Mudgal, M.; Makdissi, A.; Chaudhuri, A.; Dandona, P. A systematic review and meta-analysis of randomized controlled trials in use of GLP1 receptor agonists in type 1 diabetes mellitus. Diabetes. USA. Amer. Diabetes Assoc., 2017, 66, A308-A308.
[13]
Garg, M.; Ghanim, H.; Kuhadiya, N.D.; Green, K.; Hejna, J.; Abuaysheh, S.; Torre, B.; Batra, M.; Makdissi, A.; Chaudhuri, A.; Dandona, P. Liraglutide acutely suppresses glucagon, lipolysis and ketogenesis in type 1 diabetes. Diabetes Obes. Metab., 2017, 19, 1306-1311.
[14]
Rydén, A.K.; Perdue, N.R.; Pagni, P.P.; Gibson, C.B.; Ratliff, S.S.; Kirk, R.K.; Friesen, T.J.; Haase, C.; Coppieters, K.; von Herrath, M.G.; Boursalian, T.E. Anti-IL-21 monoclonal antibody combined with liraglutide effectively reverses established hyperglycemia in mouse models of type 1 diabetes. J. Autoimmun., 2017, 84, 65-74.
[15]
Itoh, A.; Irie, J.; Tagawa, H.; Kusumoto, Y.; Kato, M.; Kobayashi, N.; Tanaka, K.; Kikuchi, R.; Fujita, M.; Nakajima, Y.; Wu Yamada, S.; Kawai, T.; Ridgway, W.M.; Itoh, H. GLP-1 receptor agonist, liraglutide, ameliorates hepatosteatosis induced by anti-CD3 antibody in female mice. J. Diabetes Complicat, 2017, 31, 1370-1375.


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Article Details

VOLUME: 19
ISSUE: 5
Year: 2019
Page: [656 - 664]
Pages: 9
DOI: 10.2174/1871530319666190301115654
Price: $58

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