Effect of Guluronic Acid (G2013), As a New Anti-inflammatory Drug on Gene Expression of Pro-inflammatory and Anti-inflammatory Cytokines and Their Transcription Factors in Rheumatoid Arthritis Patients

  • Tahereh Bakhtiari Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  • ShahinKhadem Azarian Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  • Afshin Ghaderi Department of Internal Medicine, Hematology and Medical Oncology Ward, Cancer Research Centre, Cancer Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
  • Arman Ahmadzadeh Department of Rheumatology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Abbas Mirshafiey Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran AND Research Center for Immunodeficiencies, Children's Medical Centre, Tehran University of Medical Sciences, Tehran, Iran
Keywords: Guluronic acid (G2013), Non-steroidal anti-inflammatory drug (NSAID), Rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) as a long-term autoimmune disease is characterized by pain, swelling and joints destruction. The therapeutic efficacy of Guluronic acid (G2013) (patented, DEU: 102016113017.6) was reported in phase I/II clinical trial in RA patients. In this study, we aimed to evaluate the effect of G2013 as a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property on genes expression of anti-inflammatory and pro-inflammatory cytokines and their transcription factors in the blood sample of RA patients. This study was performed on 12 patients with RA who had an inadequate response to conventional treatments which were disease-modifying anti-rheumatic drugs (DMARDs), NSAID, and biologics. G2013 was administered orally at a dose of 500 mg twice daily for 12 weeks. Before and after the treatment of patients with drug G2013, the peripheral blood mononuclear cells (PBMCs) were isolated for evaluating the gene expression level of interleukin 10 (IL10), interleukin 22 (IL22), interferon γ (IFNγ), and transcription factors specific to the T helper cell lineages, forkhead box P3 (Fox-P3), Aryl hydrocarbon receptor (AHR) and T-box–containing protein expressed in T cells (T-bet) using the real-time PCR method. Since these cytokines have a key role in the progression of RA and disease condition expected induction of IFNγ, AHR, IL22, T-bet, and reduction of IL10, Fox-P3. Results indicated a significant reduction in the level of IFNγ, AHR and a significant induction in IL10, Fox-P3 gene expression in comparison with the control group. In conclusion; the results of this investigation showed a part of the immunological mechanism of G2013 as a novel anti-inflammatory that could reduce pro-inflammatory cytokine and their transcription factors. Furthermore, it increased the anti-inflammatory cytokine and its transcription factor (clinical trial identifier: IRCT2016092813739N5).

References

1. Cooper GS and BC Stroehla.The epidemiology of autoimmune diseases. Autoimmun Rev 2003; 2(3):119-25.
2. Marrelli A, Cipriani P, Liakouli V, Carubbi F, Perricone C, Perricone R, et al. Angiogenesis in rheumatoid arthritis: a disease-specific process or a common response to chronic inflammation? Autoimmun Rev 2011; 10(10):595-8.
3. Bazzichi, LA., Maser J, Piccinni A, Rucci P, Del Debbio A, Vivarelli L, et al. Quality of life in rheumatoid arthritis: impact of disability and lifetime depressive spectrum symptomatology. Clin Exp Rheumatol 2005; 23(6):783-8.
4. Roy N, Tanner KM, Merrill RM, Wright C, Pierce JL, Miller KL. Epidemiology of Swallowing Disorders in Rheumatoid Arthritis: Prevalence, Risk Factors, and Quality of Life Burden. Ann Otol Rhinol Laryngol 2018; 127(9):577-87.
5. Angelotti F, Parma A, Cafaro G, Capecchi R, Alunno A, Puxeddu I. One year in review 2017: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 2017; 35(3):368-78.
6. AlamanosY, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 2005; 4(3):130-6.
7. van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, van Zeben D, Kerstens PJ, Gerards AH, et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent-onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum Dis 2007; 66(10):1356-62.
8. Albrecht K, Müller-Ladner U.Side effects and management of side effects of methotrexate in rheumatoid arthritis.Clin Exp Rheumato 2010; 28(5):S95-101.
9. Weisman MH, Furst DE, Park GS, Kremer JM, Smith KM, Wallace DJ, et al. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum 2006; 54(2):607-12.
10. StallmachA,HagelS, BrunsT. Adverse effects of biologics used for treating IBD. Best Pract Res Clin Gastroenterol 2010; 24(2):167-82.
11. Tanaka Y, Hirata S, Saleem B, Emery P. Discontinuation of biologics in patients with rheumatoid arthritis. Clin Exp Rheumatol 2013; 31(4 Suppl 78):S22-7.
12. Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Type 17 T helper cells—origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 2009; 5(6):325-31.
13. Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. J Clin Exp Immunol 2007; 148(1):32-46.
14. Hirahara K, Nakayama T. CD4+ T-cell subsets in inflammatory diseases: beyond the T h 1/T h 2 paradigm. IntImmunol 2016; 28(4):163-71.
15. Yoshimura A, Ito M, Chikuma S, Akanuma T, Nakatsukasa H. Negative regulation of cytokine signaling in immunity. Cold Spring Harb Perspect Biol 2018; 10(7):a028571.
16. van Hamburg JP, Tas SW. Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. J Autoimmun. 2018; 1(87):69-81.
17. Hertweck A, Evans CM, Eskandarpour M, Lau JC, Oleinika K, Jackson I, et al., T-bet activates Th1 genes through mediator and the super elongation complex. Cell Rep 2016; 15(12):2756-70.
18. Kondo Y, Yokosawa M, Kaneko S, Furuyama K, Segawa S, Tsuboi H, Matsumoto I, Sumida T. Transcriptional Regulation of CD 4+ T Cell Differentiation in Experimentally Induced Arthritis and Rheumatoid Arthritis. Arthritis Rheumatol 2018; 70(5):653-61.
19. Wang J, Fathman JW, Lugo-Villarino G, Scimone L, von Andrian U, Dorfman DM, et al. Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J Clin Invest 2006; 116(2):414-421.
20.Lee SH, ye Kwon J, Kim SY, Jung K, Cho ML. Interferon-gamma regulates inflammatory cell death by targeting necroptosis in experimental autoimmune arthritis. Sci Rep 2017; 7(1):10133.
21. Azizi G, Simhag A, El Rouby NM, Mirshafiey A. Th22 Cells Contribution in Immunopathogenesis of Rheumatic Diseases. Iran J Allergy Asthma Immunol 2015; 14(3):246-54
22. Azizi G, Yazdani R, Mirshafiey A. Th22 cells in autoimmunity: a review of current knowledge. Iran J Allergy Asthma Immunol 2015; 47(4):108-17.
23. Miyazaki Y, Nakayamada S, Kubo S, Nakano K, Iwata S, Miyagawa I, et al. Th22 cells promote osteoclast differentiation via production of IL-22 in rheumatoid arthritis. Front Immunol 2018; 9:2901.
24. Fu J, Nogueira SV, van Drongelen V, Coit P, Ling S, Rosloniec EF, et al. Shared epitope–aryl hydrocarbon receptor crosstalk underlies the mechanism of gene–environment interaction in autoimmune arthritis. Proc Natl Acad Sci U S A 2018; 115(18):4755-60.
25. Mielle J, Audo R, Hahne M, Macia L, Combe B, Morel J, et al. il-10 Producing B cells ability to induce regulatory T cells is Maintained in rheumatoid arthritis. Front Immunol 2018; 9:961.
26. Tao JH, Cheng M, Tang JP, Liu Q, Pan F, Li XP. Foxp3, regulatory T cell, and autoimmune diseases. Inflammation 2017; 40(1):328-39.
27. Liu B, Salgado OC, Singh S, Hippen KL, Maynard JC, Burlingame AL, et al. The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation. Nat Commun 2019; 10(1):354.
28. Mortazavi-Jahromi SS, Farazmand A, Motamed N, Navabi SS, Mirshafiey A. Effects of guluronic acid (G2013) on SHIP1, SOCS1 induction and related molecules in TLR4 signaling pathway. Int J Immunopharmacol 2018; 55:323-9.
29. Mortazavi-Jahromi SS, Nazeri S, Jafarnezhad-Ansariha F, Oraei M, Mirshafiey A. Assessment of immunological profile in ankylosing spondylitis patients following a clinical trial with guluronic acid (G2013), as a new NSAID with immunomodulatory properties. Immunol Res 2018; 67(1):108-15
30. Nazeri S, KhademAzarian S, Fattahi MJ, Sedaghat R, TofighiZavareh F, Aghazadeh Z, et al., Preclinical and pharmacotoxicology evaluation of α-l-guluronic acid (G2013) as a non-steroidal anti-inflammatory drug with immunomodulatory property. Immunopharmacol Immunotoxicol 2017; 39(2):59-65.
31. Afraei S, Azizi G, Zargar SJ, Sedaghat R, Mirshafiey A. New therapeutic approach by G2013 in experimental model of multiple sclerosis.Acta Neurol Belg 2015; 115(3):259-66.
32. KhademAzarian S, Akhlaghi M, Mahmoudi M, Mostafaei S, et al. A randomized clinical trial for the assessment of the efficacy and safety of guluronic acid (G2013) in patients with rheumatoid arthritis. Immunopharmaco lImmunotoxicol 2018; 41(1):95-101.
33. Fattahi MJ, Abdollahi M, Agha Mohammadi A, Rastkari N, Khorasani R, Ahmadi H, et al. Preclinical assessment of β-d-mannuronic acid (M2000) as a non-steroidal anti-inflammatory drug. Immunopharmacol Immunotoxicol 2015; 37(6):535-40.
34. Cochez PM, Michiels C, Hendrickx E, Van Belle AB, Lemaire MM, Dauguet N, et al. AhR modulates the IL‐22‐producing cell proliferation/recruitment in imiquimod-induced psoriasis mouse model. Eur J Immunol 2016; 46(6):1449-59.
35. Murai M, Turovskaya O, Kim G, Madan R, Karp CL, CheroutreH, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 2009; 10(11):1178-84.
36. Malmström V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat RevImmunol 2017; 17(1):60.
37. MalmströmV, CatrinaAI, Klareskog L. Theimmunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol 2017; 17(1):60-75.
38. Guidelines, A.C.o.R.S.o.R.A., Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheumatol 2002; 46(2):328-46.
39. Kay J, Winthrop KL. Pharmacotherapy: Biosimilar switching—“To set a form upon desired change”. Nat Rev Rheumatol 2017; 13(7):391.
40. Van Jaarsveld CH, Jahangier ZN, Jacobs JW, Blaauw AA, van Albada-Kuipers GA, Ter Borg EJ, et al. Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis. Rheumatology 2000; 39(12):1374-82.
41. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthrit Care Res 2012; 64(5):625-39.
42. Listing J, Strangfeld A, Kary S, Rau R, von Hinueber U, Stoyanova-Scholz M, et al., Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 2005; 52(11):3403-12.
43. McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis—shaping the immunological landscape. Nat Rev Rheumatol 2016; 12(1):63-8.
44. Opal SM, DePalo VA. Anti-inflammatory cytokines.Chest 2000; 117(4):1162-72.
45. Dinarello CA. Proinflammatory cytokines. Chest 2000; 118(2):503-8.
46. Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol 2019; 15(1):9-17.
47. Miossec P.Pro-and antiinflammatory cytokine balance in rheumatoid arthritis. Clin Exp Rheumatol 1995; (Suppl 12):S13-6.
48. Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura K, Ueki K, et al. Expression of interleukin 22 in rheumatoid arthritis: Potential role as a proinflammatory cytokine. Arthritis Rheum 2005; 52(4):1037-46.
49. Kobayashi S, Okamoto H, Iwamoto T, Toyama Y, Tomatsu T, Yamanaka H, et al. A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis. Rheumatology 2008; 47(9):1317-22.
50. Trifari S, Spits H. IL-22 producing CD4+ T cells: middlemen between the immune system and its environment. Eur J Immunol 2010; 40(9):2369-71.
51. Liang SC, Tan XY, Luxenberg DP, Karim R, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006; 203(10):2271-9.
52. Kreymborg K, Etzensperger R, Dumoutier L, Haak S, Rebollo A, Buch T, et al. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J Immunol 2007; 179(12):8098-104.
Published
2019-11-11
How to Cite
1.
Bakhtiari T, Azarian S, Ghaderi A, Ahmadzadeh A, Mirshafiey A. Effect of Guluronic Acid (G2013), As a New Anti-inflammatory Drug on Gene Expression of Pro-inflammatory and Anti-inflammatory Cytokines and Their Transcription Factors in Rheumatoid Arthritis Patients. Iran J Allergy Asthma Immunol. :639-648.
Section
Original Article(s)