Year 2023,
Volume: 13 Issue: 3, 163 - 169, 28.12.2023
Sina Nabiyi
,
Firozeh Sajedi
,
Alireza Zamani
,
Mahdi Behzad
Project Number
140205244164
References
- 1. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11(2): 98-107. google scholar
- 2. Liang Y, Pan HF, Ye DQ. Therapeutic potential of STAT4 in autoimmunity. Expert Opin Ther Targets 2014; 18(8): 945-60. google scholar
- 3. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 2005; 5(8): 593605. google scholar
- 4. O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 2011; 11(4): 239-50. google scholar
- 5. Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D. STAT4: an immunoregulator contributing to diverse human diseases. Int J Biol Sci 2020; 16(9): 1575-85. google scholar
- 6. Magalhaes J, Tresse E, Ejlerskov P, Hu E, Liu Y, Marin A, et al. PIAS2-mediated blockade of IFN-beta signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry 2021; 26(10): 608399. google scholar
- 7. Xiao J, Cai X, Zhou W, Wang R, Ye Z. Curcumin relieved the rheumatoid arthritis progression via modulating the linc00052/ miR-126-5p/PIAS2 axis. Bioengineered 2022; 13(4): 10973-83. google scholar
- 8. Ueno H. The IL-12-STAT4 axis in the pathogenesis of human systemic lupus erythematosus. Eur J Immunol 2020; 50(1): 10-6. google scholar
- 9. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357(10): 977-86. google scholar
- 10. Lee M, Rhee MK. Sitagliptin for Type 2 diabetes: a 2015 update. Expert Rev Cardiovasc Ther 2015; 13(6): 597-610. google scholar
- 11. Mahabadi-Ashtiyani E, Sheikh V, Borzouei S, Salehi I, Alahgholi-Hajibehzad M. The increased T helper cells proliferation and inflammatory responses in patients with type 2 diabetes mellitus is suppressed by sitagliptin and vitamin D3 in vitro. Inflamm Res 2019; 68(10): 857-66. google scholar
- 12. Al-Rasheed NM, Al-Rasheed NM, Hasan IH, Al-Amin MA, Al-Ajmi HN, Mahmoud AM. Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats. Drug Des Devel Ther 2016; 10: 2095-107. google scholar
- 13. Telikani Z, Sheikh V, Zamani A, Borzouei S, Salehi I, Amirzargar MA, et al. Effects of sitagliptin and vitamin D3 on T helper cell transcription factors and cytokine production in clinical subgroups of type 2 diabetes mellitus: highlights upregulation of FOXP3 and IL-37. Immunopharmacol Immunotoxicol 2019; 41(2): 299-311. google scholar
- 14. Alahgholi-Hajibehzad M, Durmus H, Aysal F, Gulsen-Parman Y, Oflazer P, Deymeer F, et al. The effect of interleukin (IL)-21 and CD4(+) CD25(++) T cells on cytokine production of CD4(+) responder T cells in patients with myasthenia gravis. Clin Exp Immunol 2017; 190(2): 201-7. google scholar
- 15. Borzouei S, Gholamian-Hamadan M, Behzad M. Impact of interleukin-32alpha on T helper cell-related cytokines, transcription factors, and proliferation in patients with type 2 diabetes mellitus. Immunopharmacol Immunotoxicol 2023; 45(3): 268-76. google scholar
- 16. Walker JG, Ahern MJ, Coleman M, Weedon H, Papangelis V, Beroukas D, et al. Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66(8): 992-9. google scholar
- 17. Lee PW, Smith AJ, Yang Y, Selhorst AJ, Liu Y, Racke MK, et al. IL-23R-activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity. JCI Insight 2017; 2(17): e91663. google scholar
- 18. Yang M, Tian M, Zhang X, Xu J, Yang B, Yu J, et al. Role of the JAK2/ STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications. Oncotarget 2017; 8(57): 96958-69. google scholar
- 19. Rezaeepoor M, Hoseini-Aghdam M, Sheikh V, Eftekharian MM, Behzad M. Evaluation of Interleukin-23 and JAKs/STATs/SOCSs/ ROR-gammat expression in type 2 diabetes mellitus patients treated with or without sitagliptin. J Interferon Cytokine Res 2020; 40(11): 515-23. google scholar
- 20. Feng X, Tang H, Leng J, Jiang Q. Suppressors of cytokine signaling (SOCS) and type 2 diabetes. Mol Biol Rep 2014; 41(4): 2265-74. google scholar
- 21. Chen H, Ren X, Liao N, Wen F. Th17 cell frequency and IL-17A concentrations in peripheral blood mononuclear cells and vitreous fluid from patients with diabetic retinopathy. J Int Med Res 2016; 44(6): 1403-13. google scholar
- 22. Zhang H, Nair V, Saha J, Atkins KB, Hodgin JB, Saunders TL, et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int 2017; 92(4): 909-21. google scholar
Alteration in Gene Expression of STAT4 and PIAS2 in Individuals with Type 2 Diabetes Mellitus Treated with the Dipeptidyl Peptidase 4 Inhibitor
Year 2023,
Volume: 13 Issue: 3, 163 - 169, 28.12.2023
Sina Nabiyi
,
Firozeh Sajedi
,
Alireza Zamani
,
Mahdi Behzad
Abstract
Objective: Impairment of immune cell signaling molecules is involved in diseases pathogenesis. The evaluation of signal transducer and activator of transcription (STAT) 4 and protein inhibitor of activated STAT (PIAS) 2 as well as immunoregulatory role of the dipeptidyl peptidase-4 inhibitor, sitagliptin were investigated in type 2 diabetes mellitus (T2DM).
Materials and Methods: Peripheral blood mononuclear cells were purified from three study groups including healthy controls, T2DM patients with 6 months of sitagliptin treatment, and T2DM patients without sitagliptin. Expressions of STAT4 and PIAS2 were assessed with real-time polymerase chain reaction (qPCR).
Results: The expression of STAT4 in patients without sitagliptin was higher than the healthy controls (p=0.001). Its expression was down-regulated in the sitagliptin treated patient group compared to those without sitagliptin (p=0.005). PIAS2 expression in patients without sitagliptin was lower than the healthy controls (p=0.009). PIAS2 was elevated in the sitagliptin treated group versus patients without sitagliptin (p=0.003). A negative correlation between STAT4 and PIAS2 was found in individuals without sitagliptin (p=0.01). In patients without sitagliptin, fasting plasma glucose was positively and negatively correlated with STAT4 and PIAS2, respectively (p=0.004 and p=0.001).
Conclusion: Aberrant expression of STAT4 and reduced expression of PIAS2 were found in the T2DM patients. Sitagliptin may regulate the cell signaling pathways by elevating PIAS2 and reducing STAT4.
Project Number
140205244164
References
- 1. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11(2): 98-107. google scholar
- 2. Liang Y, Pan HF, Ye DQ. Therapeutic potential of STAT4 in autoimmunity. Expert Opin Ther Targets 2014; 18(8): 945-60. google scholar
- 3. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 2005; 5(8): 593605. google scholar
- 4. O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 2011; 11(4): 239-50. google scholar
- 5. Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D. STAT4: an immunoregulator contributing to diverse human diseases. Int J Biol Sci 2020; 16(9): 1575-85. google scholar
- 6. Magalhaes J, Tresse E, Ejlerskov P, Hu E, Liu Y, Marin A, et al. PIAS2-mediated blockade of IFN-beta signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry 2021; 26(10): 608399. google scholar
- 7. Xiao J, Cai X, Zhou W, Wang R, Ye Z. Curcumin relieved the rheumatoid arthritis progression via modulating the linc00052/ miR-126-5p/PIAS2 axis. Bioengineered 2022; 13(4): 10973-83. google scholar
- 8. Ueno H. The IL-12-STAT4 axis in the pathogenesis of human systemic lupus erythematosus. Eur J Immunol 2020; 50(1): 10-6. google scholar
- 9. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357(10): 977-86. google scholar
- 10. Lee M, Rhee MK. Sitagliptin for Type 2 diabetes: a 2015 update. Expert Rev Cardiovasc Ther 2015; 13(6): 597-610. google scholar
- 11. Mahabadi-Ashtiyani E, Sheikh V, Borzouei S, Salehi I, Alahgholi-Hajibehzad M. The increased T helper cells proliferation and inflammatory responses in patients with type 2 diabetes mellitus is suppressed by sitagliptin and vitamin D3 in vitro. Inflamm Res 2019; 68(10): 857-66. google scholar
- 12. Al-Rasheed NM, Al-Rasheed NM, Hasan IH, Al-Amin MA, Al-Ajmi HN, Mahmoud AM. Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats. Drug Des Devel Ther 2016; 10: 2095-107. google scholar
- 13. Telikani Z, Sheikh V, Zamani A, Borzouei S, Salehi I, Amirzargar MA, et al. Effects of sitagliptin and vitamin D3 on T helper cell transcription factors and cytokine production in clinical subgroups of type 2 diabetes mellitus: highlights upregulation of FOXP3 and IL-37. Immunopharmacol Immunotoxicol 2019; 41(2): 299-311. google scholar
- 14. Alahgholi-Hajibehzad M, Durmus H, Aysal F, Gulsen-Parman Y, Oflazer P, Deymeer F, et al. The effect of interleukin (IL)-21 and CD4(+) CD25(++) T cells on cytokine production of CD4(+) responder T cells in patients with myasthenia gravis. Clin Exp Immunol 2017; 190(2): 201-7. google scholar
- 15. Borzouei S, Gholamian-Hamadan M, Behzad M. Impact of interleukin-32alpha on T helper cell-related cytokines, transcription factors, and proliferation in patients with type 2 diabetes mellitus. Immunopharmacol Immunotoxicol 2023; 45(3): 268-76. google scholar
- 16. Walker JG, Ahern MJ, Coleman M, Weedon H, Papangelis V, Beroukas D, et al. Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66(8): 992-9. google scholar
- 17. Lee PW, Smith AJ, Yang Y, Selhorst AJ, Liu Y, Racke MK, et al. IL-23R-activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity. JCI Insight 2017; 2(17): e91663. google scholar
- 18. Yang M, Tian M, Zhang X, Xu J, Yang B, Yu J, et al. Role of the JAK2/ STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications. Oncotarget 2017; 8(57): 96958-69. google scholar
- 19. Rezaeepoor M, Hoseini-Aghdam M, Sheikh V, Eftekharian MM, Behzad M. Evaluation of Interleukin-23 and JAKs/STATs/SOCSs/ ROR-gammat expression in type 2 diabetes mellitus patients treated with or without sitagliptin. J Interferon Cytokine Res 2020; 40(11): 515-23. google scholar
- 20. Feng X, Tang H, Leng J, Jiang Q. Suppressors of cytokine signaling (SOCS) and type 2 diabetes. Mol Biol Rep 2014; 41(4): 2265-74. google scholar
- 21. Chen H, Ren X, Liao N, Wen F. Th17 cell frequency and IL-17A concentrations in peripheral blood mononuclear cells and vitreous fluid from patients with diabetic retinopathy. J Int Med Res 2016; 44(6): 1403-13. google scholar
- 22. Zhang H, Nair V, Saha J, Atkins KB, Hodgin JB, Saunders TL, et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int 2017; 92(4): 909-21. google scholar