IL-18 binding protein suppresses IL-17-induced osteoclastogenesis and rectifies type 17 helper T cell / regulatory T cell imbalance in rheumatoid arthritis
Tóm tắt
Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro.
Serum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed.
IL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients’ PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of
We showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment.
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Tài liệu tham khảo
Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320:1360–72.
Kondo Y, Yokosawa M, Kaneko S, Furuyama K, Segawa S, Tsuboi H, Matsumoto I, Sumida T. Review: transcriptional regulation of CD4+ T cell differentiation in experimentally induced arthritis and rheumatoid arthritis. Arthritis Rheumatol. 2018;70:653–61.
Pène J, Chevalier S, Preisser L, Vénéreau E, Guilleux MH, Ghannam S, Molès JP, Danger Y, Ravon E, Lesaux S, et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol. 2008;180:7423–30.
Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, Skapenko A. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 2010;62:2876–85.
Kanjana K, Chevaisrakul P, Matangkasombut P, Paisooksantivatana K, Lumjiaktase P. Inhibitory activity of FOXP3+ regulatory T cells reveals high specificity for displaying immune tolerance in remission state rheumatoid arthritis. Sci Rep. 2020;10:19789.
Jung YK, Kang YM, Han S. Osteoclasts in the inflammatory arthritis: implications for pathologic osteolysis. Immune Netw. 2019;19:e2.
Amarasekara DS, Yun H, Kim S, Lee N, Kim H, Rho J. Regulation of osteoclast differentiation by cytokine networks. Immune Netw. 2018;18:e8.
Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, Kennedy K, Carter R, Wei XQ, Xu D, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest. 1999;104:1393–401.
Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 binding protein. Front Immunol. 2013;4:289.
Rex DAB, Agarwal N, Prasad TSK, Kandasamy RK, Subbannayya Y, Pinto SM. A comprehensive pathway map of IL-18-mediated signalling. J Cell Commun Signal. 2020;14:257–66.
Kim KW, Kim HR, Kim BM, Cho ML, Lee SH. Th17 cytokines regulate osteoclastogenesis in rheumatoid arthritis. Am J Pathol. 2015;185:3011–24.
Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity. 1999;10:127–36.
Banda NK, Vondracek A, Kraus D, Dinarello CA, Kim SH, Bendele A, Senaldi G, Arend WP. Mechanisms of inhibition of collagen-induced arthritis by murine IL-18 binding protein. J Immunol. 2003;170:2100–5.
Smeets RL, van de Loo FA, Arntz OJ, Bennink MB, Joosten LA, van den Berg WB. Adenoviral delivery of IL-18 binding protein C ameliorates collagen-induced arthritis in mice. Gene Ther. 2003;10:1004–11.
Shao XT, Feng L, Gu LJ, Wu LJ, Feng TT, Yang YM, Wu NP, Yao HP. Expression of interleukin-18, IL-18BP, and IL-18R in serum, synovial fluid, and synovial tissue in patients with rheumatoid arthritis. Clin Exp Med. 2009;9:215–21.
Volin MV, Koch AE. Interleukin-18: a mediator of inflammation and angiogenesis in rheumatoid arthritis. J Interferon Cytokine Res. 2011;31:745–51.
Bresnihan B, Roux-Lombard P, Murphy E, Kane D, FitzGerald O, Dayer JM. Serum interleukin 18 and interleukin 18 binding protein in rheumatoid arthritis. Ann Rheum Dis. 2002;61:726–9.
Mansoori MN, Shukla P, Kakaji M, Tyagi AM, Srivastava K, Shukla M, Dixit M, Kureel J, Gupta S, Singh D. IL-18BP is decreased in osteoporotic women: Prevents Inflammasome mediated IL-18 activation and reduces Th17 differentiation. Sci Rep. 2016;6:33680.
Keerthivasan S, Suleiman R, Lawlor R, Roderick J, Bates T, Minter L, Anguita J, Juncadella I, Nickoloff BJ, Le Poole IC, et al. Notch signaling regulates mouse and human Th17 differentiation. J Immunol. 2011;187:692–701.
Min HK, Won JY, Kim BM, Lee KA, Lee SJ, Lee SH, Kim HR, Kim KW. Interleukin (IL)-25 suppresses IL-22-induced osteoclastogenesis in rheumatoid arthritis via STAT3 and p38 MAPK/IκBα pathway. Arthritis Res Ther. 2020;22:222.
Abdallah D, Jourdain ML, Braux J, Guillaume C, Gangloff SC, Jacquot J, Velard F. An Optimized Method to Generate Human Active Osteoclasts From Peripheral Blood Monocytes. Front Immunol. 2018;9:632.
Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic potential of targeting the Th17/Treg axis in autoimmune disorders. Molecules. 2017;22:154.
Bystrom J, Clanchy FI, Taher TE, Mangat P, Jawad AS, Williams RO, Mageed RA. TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases. Cytokine. 2018;101:4–13.
Kim DS, Min HK, Kim EK, Yang SC, Na HS, Lee SY, Choi JW, Jung KA, Kwok SK, Park SH, Cho ML. Suberoylanilide Hydroxamic Acid Attenuates Autoimmune Arthritis by Suppressing Th17 Cells through NR1D1 Inhibition. Mediators Inflamm. 2019;2019:5648987.
Kim EK, Min HK, Lee SY, Kim DS, Ryu JG, Na HS, Jung KA, Choi JW, Park SH, Cho ML. Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome. Arthritis Res Ther. 2020;22:77.
Bhaumik S, Basu R. Cellular and molecular dynamics of Th17 differentiation and its developmental plasticity in the intestinal immune response. Front Immunol. 2017;8:254.
Gabay C, Fautrel B, Rech J, Spertini F, Feist E, Kötter I, Hachulla E, Morel J, Schaeverbeke T, Hamidou MA, et al. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease. Ann Rheum Dis. 2018;77:840–7.