OBJECTIVE: The cytokine interleukin-21 (IL-21) can have both proinflammatory and immunosuppressive effects. The purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis in relation to Th17 cells. METHODS: Antigen-induced arthritis (AIA) and chronic streptococcal cell wall (SCW) arthritis were induced in IL-21 receptor-deficient (IL-21R(-/-) ) and wild-type mice. Knee joints, synovial tissue, and serum were analyzed for arthritis pathology and inflammatory markers. RESULTS: During AIA and chronic SCW arthritis, IL-21R deficiency protected against severe inflammation and joint destruction. This was accompanied by suppressed serum IgG1 levels and antigen-specific T cell responses. Levels of IL-17 were reduced during AIA, and synovial lymphocytes isolated during SCW arthritis for flow cytometry demonstrated that mainly IL-17+ interferon-γ (IFNγ)-positive T cells were reduced in IL-21R(-/-) mice. However, during the acute phases of SCW arthritis, significantly higher joint swelling scores were observed, consistent with enhanced tumor necrosis factor and IL-6 expression. Interestingly, IL-21R(-/-) mice were significantly less capable of up-regulating suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 messenger RNA. IL-21 stimulation also affected the Toll-like receptor 2 (TLR-2)/caspase recruitment domain 15 response to SCW fragments in vitro, indicating that impaired SOCS regulation in the absence of IL-21 signaling might contribute to the increased local activation during SCW arthritis. CONCLUSION: In contrast to the proinflammatory role of IL-21 in adaptive immunity, which drives IL-17+IFN+ cells and joint pathology during chronic experimental arthritis, IL-21 also has an important immunosuppressive role, presumably by inhibiting TLR signaling via SOCS-1 and SOCS-3. If this dual role of IL-21 in various immune processes is present in human disease, it could make IL-21 a difficult therapeutic target in rheumatoid arthritis.
OBJECTIVE: The cytokine interleukin-21 (IL-21) can have both proinflammatory and immunosuppressive effects. The purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis in relation to Th17 cells. METHODS: Antigen-induced arthritis (AIA) and chronic streptococcal cell wall (SCW) arthritis were induced in IL-21 receptor-deficient (IL-21R(-/-) ) and wild-type mice. Knee joints, synovial tissue, and serum were analyzed for arthritis pathology and inflammatory markers. RESULTS: During AIA and chronic SCW arthritis, IL-21R deficiency protected against severe inflammation and joint destruction. This was accompanied by suppressed serum IgG1 levels and antigen-specific T cell responses. Levels of IL-17 were reduced during AIA, and synovial lymphocytes isolated during SCW arthritis for flow cytometry demonstrated that mainly IL-17+ interferon-γ (IFNγ)-positive T cells were reduced in IL-21R(-/-) mice. However, during the acute phases of SCW arthritis, significantly higher joint swelling scores were observed, consistent with enhanced tumor necrosis factor and IL-6 expression. Interestingly, IL-21R(-/-) mice were significantly less capable of up-regulating suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 messenger RNA. IL-21 stimulation also affected the Toll-like receptor 2 (TLR-2)/caspase recruitment domain 15 response to SCW fragments in vitro, indicating that impaired SOCS regulation in the absence of IL-21 signaling might contribute to the increased local activation during SCW arthritis. CONCLUSION: In contrast to the proinflammatory role of IL-21 in adaptive immunity, which drives IL-17+IFN+ cells and joint pathology during chronic experimental arthritis, IL-21 also has an important immunosuppressive role, presumably by inhibiting TLR signaling via SOCS-1 and SOCS-3. If this dual role of IL-21 in various immune processes is present in human disease, it could make IL-21 a difficult therapeutic target in rheumatoid arthritis.
Authors: Rafael Scaf de Molon; Chingyun Hsu; Olga Bezouglaia; Sarah M Dry; Flavia Q Pirih; Akrivoula Soundia; Fernando Queiroz Cunha; Joni Augusto Cirelli; Tara L Aghaloo; Sotirios Tetradis Journal: J Bone Miner Res Date: 2016-05-04 Impact factor: 6.741
Authors: Rui Xing; Yingjian Zhang; Changhong Li; Lin Sun; Lin Yang; Jinxia Zhao; Xiangyuan Liu Journal: Int J Mol Med Date: 2016-08-30 Impact factor: 4.101
Authors: Debbie M Roeleveld; Renoud J Marijnissen; Birgitte Walgreen; Monique M Helsen; Liduine van den Bersselaar; Fons A van de Loo; Peter L van Lent; Peter M van der Kraan; Wim B van den Berg; Marije I Koenders Journal: PLoS One Date: 2017-02-03 Impact factor: 3.240
Authors: Harry C Blair; Jonathan Soboloff; Lisa J Robinson; Irina L Tourkova; Quitterie C Larrouture; Michelle R Witt; Ida Holaskova; Rosana Schafer; Meenal Elliott; Raphael Hirsch; John B Barnett Journal: RMD Open Date: 2016-01-08
Authors: Mushtaq A Ansari; Ahmed Nadeem; Saleh A Bakheet; Sabry M Attia; Mudassar Shahid; Faris S Alyousef; Mohammed A Alswailem; Mohammed Alqinyah; Sheikh F Ahmad Journal: Molecules Date: 2021-03-25 Impact factor: 4.411
Authors: Jos W G van Rosmalen; Maarten van der Linden; Renato G S Chirivi; Maximilien Euler; Gonny Schmets; Galina Bogatkevich; Konstantinos Kambas; Jonas Hahn; Quinte Braster; Oliver Soehnlein; Markus H Hoffmann; Helmuth H G van Es; Jos M H Raats Journal: Cell Mol Immunol Date: 2020-03-20 Impact factor: 11.530