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Clinical Rheumatology

Erschienen in:

22.11.2019 | Original Article

Iguratimod dose dependently inhibits the expression of citrullinated proteins and peptidylarginine deiminases 2 and 4 in neutrophils from rheumatoid arthritis patients

verfasst von: Bingtong Li, Ping Li, Liqi Bi

Erschienen in: Clinical Rheumatology | Ausgabe 3/2020

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Abstract

Introduction

Anti-citrullinated protein antibodies (ACPAs) play an important role in rheumatoid arthritis (RA). Citrullinated proteins (CPs), which are produced by post-translational modification via peptidylarginine deiminase (PAD), are the target antigen of ACPAs and promote the generation thereof. Herein, we investigated whether iguratimod (IGU) affects the generation of CPs via PAD.

Methods

Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from three patients diagnosed with RA and treated with various concentrations of IGU, methotrexate (MTX), or dexamethasone (DXM) or without any drugs as a control for 8 h. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in culture supernatants were tested by ELISA. CPs were measured by western blot, and the expression of PAD2 and PAD4 in cells was detected by qRT-PCR and western blot.

Results

PAD2 and PAD4 expressions in neutrophils but not in PBMCs were decreased by IGU at both the protein and mRNA levels (P < 0.05). CP expression in neutrophils but not in PBMCs was also inhibited by IGU. The inhibitory effect of IGU was dose-dependent. IGU, MTX, and DXM dose dependently decreased the secretion of TNF-α, IL-1β, IL-6, and IL-8 in neutrophils and PBMCs (P < 0.05); the inhibitory effect of IGU was not significantly different from that of MTX and DXM.

Conclusions

IGU inhibited the expression of CPs by downregulating PADs in neutrophils from RA patients, and the effect was comparable to that of MTX and DXM at appropriate concentrations. These findings may provide guidance for more appropriate treatment of RA.

Key Points

• Iguratimod inhibited citrullinated protein expression in neutrophils from rheumatoid arthritis patients similarly to methotrexate and dexamethasone at appropriate concentrations.

• The inhibitory effect was mediated by downregulation of peptidylarginine deiminases, providing insight into the mechanism of iguratimod as a treatment for rheumatoid arthritis.

• This study may guide rheumatoid arthritis treatment and facilitate identification of other therapeutic targets.

Nur mit Berechtigung zugänglich

Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. Lancet 388(10055):2023–2038. https://doi.org/10.1016/S0140-6736(16)30173-8 CrossRefPubMed

Richards JS, Dowell SM, Quinones ME, Kerr GS (2015) How to use biologic agents in patients with rheumatoid arthritis who have comorbid disease. BMJ 351:h3658. https://doi.org/10.1136/bmj.h3658 CrossRefPubMed

Waaler E (2007) On the occurrence of a factor in human serum activating the specific agglutintion of sheep blood corpuscles. 1939. APMIS 115(5):422–438; discussion 439. https://doi.org/10.1111/j.1600-0463.2007.apm_682a.x CrossRefPubMed

Sokolove J, Zhao X, Chandra PE, Robinson WH (2011) Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcgamma receptor. Arthritis Rheum 63(1):53–62. https://doi.org/10.1002/art.30081 CrossRefPubMedPubMedCentral

Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ (1998) Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 101(1):273–281. https://doi.org/10.1172/JCI1316 CrossRefPubMedPubMedCentral

Li S, Yu Y, Yue Y, Liao H, Xie W, Thai J, Mikuls TR, Thiele GM, Duryee MJ, Sayles H, Payne JB, Klassen LW, O’Dell JR, Zhang Z, Su K (2016) Autoantibodies from single circulating plasmablasts react with citrullinated antigens and porphyromonas gingivalis in rheumatoid arthritis. Arthritis Rheum 68(3):614–626. https://doi.org/10.1002/art.39455 CrossRef

Bicker KL, Thompson PR (2013) The protein arginine deiminases: structure, function, inhibition, and disease. Biopolymers 99(2):155–163. https://doi.org/10.1002/bip.22127 CrossRefPubMedPubMedCentral

Makrygiannakis D, Revu S, Engstrom M, af Klint E, Nicholas AP, Pruijn GJ, Catrina AI (2012) Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis. Arthritis Res Ther 14(1):R20. https://doi.org/10.1186/ar3702 CrossRefPubMedPubMedCentral

Fan L, Zong M, Gong R, He D, Li N, Sun LS, Ye Q, Yu S (2017) PADI4 epigenetically suppresses p21 transcription and inhibits cell apoptosis in fibroblast-like synoviocytes from rheumatoid arthritis patients. Int J Biol Sci 13(3):358–366. https://doi.org/10.7150/ijbs.16879 CrossRefPubMedPubMedCentral

10.

Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Mechin MC, Vincent C, Nachat R, Yamada M, Takahara H, Simon M, Guerrin M, Serre G (2007) Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum 56(11):3541–3553. https://doi.org/10.1002/art.22983 CrossRefPubMed

11.

Zhou Y, Chen B, Mittereder N, Chaerkady R, Strain M, An LL, Rahman S, Ma W, Low CP, Chan D, Neal F, Bingham CO 3rd, Sampson K, Darrah E, Siegel RM, Hasni S, Andrade F, Vousden KA, Mustelin T, Sims GP (2017) Spontaneous secretion of the citrullination enzyme PAD2 and cell surface exposure of PAD4 by neutrophils. Front Immunol 8:1200. https://doi.org/10.3389/fimmu.2017.01200 CrossRefPubMedPubMedCentral

12.

Vossenaar ER, Radstake TR, van der Heijden A, van Mansum MA, Dieteren C, de Rooij DJ, Barrera P, Zendman AJ, van Venrooij WJ (2004) Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis 63(4):373–381CrossRefPubMedPubMedCentral

13.

Mimori T, Harigai M, Atsumi T, Fujii T, Kuwana M, Matsuno H, Momohara S, Takei S, Tamura N, Takasaki Y, Yamamoto K, Ikeuchi S, Kushimoto S, Koike T (2018) Safety and effectiveness of iguratimod in patients with rheumatoid arthritis: final report of a 52-week, multicenter postmarketing surveillance study. Mod Rheumatol:1–10. https://doi.org/10.1080/14397595.2018.1460230

14.

Tanaka K, Shimotori T, Makino S, Eguchi M, Asaoka K, Kitamura R, Yoshida C (1992) Pharmacological studies on 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (T-614), a novel antiinflammatory agent. 3rd communication: the involvement of bradykinin in its analgesic actions. J Pharmacobiodyn 15(11):641–647CrossRefPubMed

15.

Kohno M, Aikawa Y, Tsubouchi Y, Hashiramoto A, Yamada R, Kawahito Y, Inoue K, Kusaka Y, Kondo M, Sano H (2001) Inhibitory effect of T-614 on tumor necrosis factor-alpha induced cytokine production and nuclear factor-kappaB activation in cultured human synovial cells. J Rheumatol 28(12):2591–2596PubMed

16.

Tanaka K, Yamamoto T, Aikawa Y, Kizawa K, Muramoto K, Matsuno H, Muraguchi A (2003) Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice. Rheumatology (Oxford) 42(11):1365–1371. https://doi.org/10.1093/rheumatology/keg381 CrossRef

17.

Zheng N, Guo C, Wu R (2018) Iguratimod is effective in refractory rheumatoid arthritis patients with inadequate response to methotrexate-cyclosporin A-hydroxychloroquine-prednisone. Scand J Rheumatol 47(5):422–424. https://doi.org/10.1080/03009742.2017.1376109 CrossRefPubMed

18.

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581. https://doi.org/10.1002/art.27584 CrossRefPubMed

19.

Corkum CP, Ings DP, Burgess C, Karwowska S, Kroll W, Michalak TI (2015) Immune cell subsets and their gene expression profiles from human PBMC isolated by vacutainer cell preparation tube (CPT) and standard density gradient. BMC Immunol 16:48. https://doi.org/10.1186/s12865-015-0113-0 CrossRefPubMedPubMedCentral

20.

Kuhns DB, Long Priel DA, Chu J, Zarember KA (2015) Isolation and functional analysis of human neutrophils. Curr Protoc Immunol 111:7 23 21-16. https://doi.org/10.1002/0471142735.im0723s111 CrossRef

21.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262 CrossRefPubMed

22.

Kallberg H, Ding B, Padyukov L, Bengtsson C, Ronnelid J, Klareskog L, Alfredsson L, Group ES (2011) Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis 70(3):508–511. https://doi.org/10.1136/ard.2009.120899 CrossRefPubMed

23.

Webber MP, Moir W, Zeig-Owens R, Glaser MS, Jaber N, Hall C, Berman J, Qayyum B, Loupasakis K, Kelly K, Prezant DJ (2015) Nested case-control study of selected systemic autoimmune diseases in World Trade Center rescue/recovery workers. Arthritis Rheum 67(5):1369–1376. https://doi.org/10.1002/art.39059 CrossRef

24.

Dissick A, Redman RS, Jones M, Rangan BV, Reimold A, Griffiths GR, Mikuls TR, Amdur RL, Richards JS, Kerr GS (2010) Association of periodontitis with rheumatoid arthritis: a pilot study. J Periodontol 81(2):223–230. https://doi.org/10.1902/jop.2009.090309 CrossRefPubMed

25.

Nagai T, Matsueda Y, Tomita T, Yoshikawa H, Hirohata S (2018) The expression of mRNA for peptidylarginine deiminase type 2 and type 4 in bone marrow CD34+ cells in rheumatoid arthritis. Clin Exp Rheumatol 36(2):248–253PubMed

26.

Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34(4):395–402. https://doi.org/10.1038/ng1206 CrossRefPubMed

27.

Chang X, Xia Y, Pan J, Meng Q, Zhao Y, Yan X (2013) PADI2 is significantly associated with rheumatoid arthritis. PLoS One 8(12):e81259. https://doi.org/10.1371/journal.pone.0081259 CrossRefPubMedPubMedCentral

28.

Darrah E, Andrade F (2018) Rheumatoid arthritis and citrullination. Curr Opin Rheumatol 30(1):72–78. https://doi.org/10.1097/BOR.0000000000000452 CrossRefPubMedPubMedCentral

29.

Wang F, Chen FF, Gao WB, Wang HY, Zhao NW, Xu M, Gao DY, Yu W, Yan XL, Zhao JN, Li XJ (2016) Identification of citrullinated peptides in the synovial fluid of patients with rheumatoid arthritis using LC-MALDI-TOF/TOF. Clin Rheumatol 35(9):2185–2194. https://doi.org/10.1007/s10067-016-3247-4 CrossRefPubMedPubMedCentral

30.

Neeli I, Khan SN, Radic M (2008) Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol 180(3):1895–1902CrossRefPubMed

31.

Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Subramanian V, Thompson P, Chen P, Fox DA, Pennathur S, Kaplan MJ (2013) NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 5(178):178ra140. https://doi.org/10.1126/scitranslmed.3005580 CrossRef

32.

Dong X, Zheng Z, Zhai Y, Zheng Y, Ding J, Jiang J, Zhu P (2018) ACPA mediates the interplay between innate and adaptive immunity in rheumatoid arthritis. Autoimmun Rev 17(9):845–853. https://doi.org/10.1016/j.autrev.2018.02.014 CrossRefPubMed

33.

Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C (2016) Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis. BMJ 353:i1777. https://doi.org/10.1136/bmj.i1777 CrossRefPubMedPubMedCentral

34.

Liu D, Liu CF, Wang N, Min XY, Ma N, Lin Y, Chen QP, Li K (2014) The research of effects of iguratimod (T-614) on the apoptosis of peripheral blood mononuclear cell and TH1 in rheumatoid arthritis. Value Health 17(7):A772. https://doi.org/10.1016/j.jval.2014.08.321 CrossRefPubMed

35.

Shelef MA, Sokolove J, Lahey LJ, Wagner CA, Sackmann EK, Warner TF, Wang Y, Beebe DJ, Robinson WH, Huttenlocher A (2014) Peptidylarginine deiminase 4 contributes to tumor necrosis factor alpha-induced inflammatory arthritis. Arthritis Rheum 66(6):1482–1491. https://doi.org/10.1002/art.38393 CrossRef

36.

Laurent L, Anquetil F, Clavel C, Ndongo-Thiam N, Offer G, Miossec P, Pasquali JL, Sebbag M, Serre G (2015) IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies. Ann Rheum Dis 74(7):1425–1431. https://doi.org/10.1136/annrheumdis-2013-204543 CrossRefPubMed

37.

Mateen S, Zafar A, Moin S, Khan AQ, Zubair S (2016) Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta 455:161–171. https://doi.org/10.1016/j.cca.2016.02.010 CrossRefPubMed

38.

Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117(14):3720–3732. https://doi.org/10.1182/blood-2010-07-273417 CrossRefPubMedPubMedCentral

39.

Sun B, Dwivedi N, Bechtel TJ, Paulsen JL, Muth A, Bawadekar M, Li G, Thompson PR, Shelef MA, Schiffer CA, Weerapana E, Ho IC (2017) Citrullination of NF-kappaB p65 promotes its nuclear localization and TLR-induced expression of IL-1beta and TNFalpha. Sci Immunol 2(12). https://doi.org/10.1126/sciimmunol.aal3062

40.

Srirangan S, Choy EH (2010) The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis 2(5):247–256. https://doi.org/10.1177/1759720X10378372 CrossRefPubMedPubMedCentral

41.

Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16(5):448–457. https://doi.org/10.1038/ni.3153 CrossRefPubMed

42.

Krishnamurthy A, Joshua V, Haj Hensvold A, Jin T, Sun M, Vivar N, Ytterberg AJ, Engstrom M, Fernandes-Cerqueira C, Amara K, Magnusson M, Wigerblad G, Kato J, Jimenez-Andrade JM, Tyson K, Rapecki S, Lundberg K, Catrina SB, Jakobsson PJ, Svensson C, Malmstrom V, Klareskog L, Wahamaa H, Catrina AI (2016) Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis 75(4):721–729. https://doi.org/10.1136/annrheumdis-2015-208093 CrossRefPubMed

43.

Xu Y, Zhu Q, Song J, Liu H, Miao Y, Yang F, Wang F, Cheng W, Xi Y, Niu X, He D, Chen G (2015) Regulatory effect of iguratimod on the balance of Th subsets and inhibition of inflammatory cytokines in patients with rheumatoid arthritis. Mediat Inflamm 2015:356040. https://doi.org/10.1155/2015/356040 CrossRef

Titel: Iguratimod dose dependently inhibits the expression of citrullinated proteins and peptidylarginine deiminases 2 and 4 in neutrophils from rheumatoid arthritis patients
verfasst von: Bingtong Li
Ping Li
Liqi Bi
Publikationsdatum: 22.11.2019
Verlag: Springer London
Erschienen in: Clinical Rheumatology / Ausgabe 3/2020
Print ISSN: 0770-3198
Elektronische ISSN: 1434-9949
DOI: https://doi.org/10.1007/s10067-019-04835-4

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Iguratimod dose dependently inhibits the expression of citrullinated proteins and peptidylarginine deiminases 2 and 4 in neutrophils from rheumatoid arthritis patients

Abstract

Introduction

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Results

Conclusions

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Abstract

Introduction

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