Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients

Juliana Cruz da Silva, Henrique Ataide Mariz, Laurindo Ferreira da Rocha Jr, Priscilla Stela Santana de Oliveira, Andrea Tavares Dantas, Angela Luzia Branco Pinto Duarte, Ivan da Rocha Pitta, Suely Lins Galdino, Maira Galdino da Rocha Pitta, Juliana Cruz da Silva, Henrique Ataide Mariz, Laurindo Ferreira da Rocha Jr, Priscilla Stela Santana de Oliveira, Andrea Tavares Dantas, Angela Luzia Branco Pinto Duarte, Ivan da Rocha Pitta, Suely Lins Galdino, Maira Galdino da Rocha Pitta

Abstract

Objectives: Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients.

Methods: Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients.

Results: We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine. CONCLUSIONS Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication.

Conflict of interest statement

No potential conflict of interest was reported.

Figures

Figure 1
Figure 1
Inhibition of IL-17A (A), IL-22 (B) and IL-6 (C) supernatants levels in PBMCs from five healthy individuals using HCQ at 25 μM, 50 μM and 100 μM doses.
Figure 2
Figure 2
Inhibition of IL-6 (A), IL-17 (B) and IL-22 (C) production using HCQ at a dose of 100 μM in PBMCs from SLE patients.
Figure 3
Figure 3
Inhibition of IL-6 (A), IL-17 (B) and IL-22 production (C) using HCQ at a dose of 100 μM in PBMCs from RA patients.

References

    1. Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. 2012;42(2):145–53.
    1. Katz SJ, Russell AS. Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action. Curr Opin Rheumatol. 2011;23(3):278–81.
    1. Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev Rheumatol. 2012;8(9):522–33.
    1. Kyburz D, Brentano F, Gay S. Mode of action of hydroxychloroquine in RA-evidence of an inhibitory effect on toll-like receptor signaling. Nat Clin Pract Rheumatol. 2006;2(9):458–9.
    1. Ziegler HK, Unanue ER. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. 1982;79(1):175–8.
    1. Ohkuma S, Poole B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci U S A. 1978;75(7):3327–31.
    1. Wozniacka A, Lesiak A, Boncela J, Smolarczyk K, McCauliffe DP, Sysa-Jedrzejowska A. The influence of antimalarial treatment on IL-1beta, IL-6 and TNF-alpha mRNA expression on UVB-irradiated skin in systemic lupus erythematosus. Br J Dermatol. 2008;159(5):1124–30.
    1. Maddur MS, Miossec P, Kaveri SV, Bayry J. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol. 2012;181(1):8–18.
    1. Nalbandian A, Crispin JC, Tsokos GC. Interleukin-17 and systemic lupus erythematosus: current concepts. Clin Exp Immunol. 2009;157(2):209–15.
    1. Wong CK, Ho CY, Li EK, Lam CW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus. 2000;9(8):589–93.
    1. Yang J, Chu Y, Yang X, Gao D, Zhu L, Wan L, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009;60(5):1472–83.
    1. Kwan BC, Tam LS, Lai KB, Lai FM, Li EK, Wang G, et al. The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus. Rheumatology (Oxford) 2009;48(12):1491–7.
    1. Dong G, Ye R, Shi W, Liu S, Wang T, Yang X, et al. IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chin Med J (Engl) 2003;116(4):543–8.
    1. Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, et al. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999;42(5):963–70.
    1. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204(12):2803–12.
    1. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):1271–7.
    1. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.
    1. Shah K, Lee WW, Lee SH, Kim SH, Kang SW, Craft J, et al. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther. 2010;12(2):R53.
    1. Crispin JC, Tsokos GC. Interleukin-17-producing T cells in lupus. Curr Opin Rheumatol. 2010;22(5):499–503.
    1. Koenders MI, Lubberts E, Oppers-Walgreen B, van den Bersselaar L, Helsen MM, Di Padova FE, et al. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol. 2005;167(1):141–9.
    1. da Rocha LF, Jr, Duarte AL, Dantas AT, Mariz HA, Pitta Ida R, Galdino SL, et al. Increased serum interleukin 22 in patients with rheumatoid arthritis and correlation with disease activity. J Rheumatol. 2012;39(7):1320–5.
    1. Meinao IM, Sato EI, Andrade LE, Ferraz MB, Atra E. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus. 5(3):8803897. 237-41. PubMed PMID.
    1. Williams HJ, Egger MJ, Singer JZ, Willkens RF, Kalunian KC, Clegg DO, et al. Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus. J Rheumatol. 1994;21(8):1457–62.
    1. Molad Y, Gorshtein A, Wysenbeek AJ, Guedj D, Majadla R, Weinberger A, et al. Protective effect of hydroxychloroquine in systemic lupus erythematosus. Prospective long-term study of an Israeli cohort. Lupus. 2002;11(6):356–61.
    1. The Canadian Hydroxychloroquine Study Group. N Engl J Med. 1991;324(3):150–4. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. 17.
    1. Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus. 1996;(Suppl 1):S16–22.
    1. Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano L, Simantov R, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003;349(25):2399–406.
    1. Alarcon GS, McGwin G, Bertoli AM, Fessler BJ, Calvo-Alen J, Bastian HM, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L) Ann Rheum Dis. 2007;66(9):1168–72.
    1. Ruiz-Irastorza G, Egurbide MV, Pijoan JI, Garmendia M, Villar I, Martinez-Berriotxoa A, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus. 2006;15(9):577–83.
    1. Clark P, Casas E, Tugwell P, Medina C, Gheno C, Tenorio G, et al. Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial. Ann Intern Med. 1993;119(11):1067–71.
    1. Wasko MC, Hubert HB, Lingala VB, Elliott JR, Luggen ME, Fries JF, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007;298(2):187–93.
    1. van den Borne BE, Dijkmans BA, de Rooij HH, le Cessie S, Verweij CL. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J Rheumatol. 1997;24(1):55–60.
    1. Jeong JY, Choi JW, Jeon KI, Jue DM. Chloroquine decreases cell-surface expression of tumour necrosis factor receptors in human histiocytic U-937 cells. Immunology. 2002;105(1):83–91.
    1. Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S, et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med. 2005;202(8):1131–9.
    1. Kyburz D, Brentano F, Gay S. Mode of action of hydroxychloroquine in RA-evidence of an inhibitory effect on toll-like receptor signaling. Nat Clin Pract Rheumatol. 2006;2(9):458–9.

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