Tetra-arsenic tetra-sulfide ameliorates lupus syndromes by inhibiting IL-17 producing double negative T cells
Yan Zhao
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorZhanglei Mu
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorLin Cai
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorXiaojing Liu
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorJun Jia
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorCorresponding Author
Jianzhong Zhang
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Correspondence
Jianzhong Zhang, Department of Dermatology, People's Hospital of Peking University, No. 11 South Avenue, Xi Zhi Men, Xicheng District, Beijing 100044, China.
Email: [email protected]
Search for more papers by this authorYan Zhao
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorZhanglei Mu
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorLin Cai
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorXiaojing Liu
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorJun Jia
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Search for more papers by this authorCorresponding Author
Jianzhong Zhang
Department of Dermatology, People's Hospital of Peking University, Beijing, China
Correspondence
Jianzhong Zhang, Department of Dermatology, People's Hospital of Peking University, No. 11 South Avenue, Xi Zhi Men, Xicheng District, Beijing 100044, China.
Email: [email protected]
Search for more papers by this authorFunding information National Natural Science Foundation of China , Grant/Award Number: No.81271756
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease of uncertain etiology that affects multiple tissues and organs. Tetra-arsenic tetra-sulfide (As4S4), a traditional Chinese medicine, is effective on acute promyelocytic leukemia with mild side effects. In our previous study, BXSB lupus-prone mice treated with As4S4 has showed improved monocytosis, decreased serum interleukin (IL)-6 and suppressed skin, liver and renal lesions with well-tolerance. In this study, we explored the effect and mechanism of As4S4 on the MRL/lpr mice. MRL/lpr and wild MRL/MpJ mice were divided into control and As4S4 treatment groups and dosed with As4S4 or placebo for 8 weeks. We found that As4S4 prevented the skin, renal and lung lesions of MRL/lpr mice. As4S4 significantly decreased the double negative T (DN T) cells and reduced the serum levels of IL-17, IL-10, and antinuclear antibodies titer. Further results revealed that the FasL was decreased, and activated caspases elevated in DN T cells in As4S4 treated MRL/lpr mice. Taken together, As4S4 could selectively suppresses DN T cells by inducing apoptosis. It also reduced inflammatory cytokines IL-17, which may be produced by DN T cells. As4S4 may represent a new therapy for SLE.
CONFLICTS OF INTEREST
None declared.
REFERENCES
- Anand, A., Dean, G. S., Quereshi, K., Isenberg, D. A., & Lydyard, P. M. (2002). Characterization of CD3+ CD4‑ CD8‑ (double negative) T cells in patients with systemic lupus erythematosus: Activation markers. Lupus, 11, 493–500.
- Andrews, B. S., Eisenberg, R. A., Theofilopoulos, A. N., Wilson, C. B., McConahey, P. J., Murphy, E. D., … Dixon, F. J. (1978). Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. The Journal of Experimental Medicine, 148, 1198–1215.
- Bobé, P., Bonardelle, D., Benihoud, K., Opolon, P., & Chelbi-Alix, M. K. (2006). Arsenic trioxide: A promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice. Blood, 108, 3967–3975.
- Brandt, D., & Hedrich, C. M. (2018). TCRαβ+CD3+CD4−CD8− (double negative) T cells in autoimmunity. Autoimmunity Reviews, 17, 422–430.
- Chen, G. Q., Shi, X. G., Tang, W., Xiong, S. M., Zhu, J., Cai, X., … Chen, Z. (1997). Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood, 89, 3345–3353.
- Chen, Z., Chen, G. Q., Shen, Z. X., Chen, S. J., & Wang, Z. Y. (2001). Treatment of acute promyelocytic leukemia with arsenic compounds: in vitro and in vivo studies. Seminars in Hematology, 38, 26–36.
- Chu, J. L., Drappa, J., Parnassa, A., & Elkon, K. B. (1993). The defect in Fas mRNA expression in MRL/lpr mice is associated with insertion of the retrotransposon, ETn. The Journal of Experimental Medicine, 178, 723–730.
- Crispin, J. C., Oukka, M., Bayliss, G., Cohen, R. A., Van Beek, C. A., Stillman, I. E., … Tsokos, G. C. (2008). Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. Journal of Immunology, 181, 8761–8766.
- El-Sayed, Z. A., El-Owaidy, R. H., Mohamed, N. L., & Shehata, B. A. (2018). Alpha beta double negative T cells in children with systemic lupus erythematosus: The relation to disease activity and characteristics. Modern Rheumatology, 28, 654–660.
- Ishida, H., Muchamuel, T., Sakaguchi, S., Andrade, S., Menon, S., & Howard, M. (1994). Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. The Journal of Experimental Medicine, 179, 305–310.
- Kinjyo, I., Gordon, S. M., Intlekofer, A. M., Dowdell, K., Mooney, E. C., Caricchio, R., … Reiner, S. L. (2010). Cutting edge: Lymphoproliferation caused by Fas deficiency is dependent on the transcription factor eomesodermin. Journal of Immunology, 185, 7151–7155.
- Koh, D. R., Ho, A., Rahemtulla, A., Fung-Leung, W. P., Griesser, H., & Mak, T. W. (1995). Murine lupus in MRL/lpr mice lacking CD4 or CD8 T cells. European Journal of Immunology, 25, 2558–2562.
- Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., … Cua, D. J. (2005). IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. The Journal of Experimental Medicine, 201, 233–240.
- Lauwerys, B. R., Garot, N., Renauld, J. C., & Houssiau, F. A. (2000). Interleukin-10 blockade corrects impaired in vitro cellular immune responses of systemic lupus erythematosus patients. Arthritis and Rheumatism, 43, 1976–1981.
- Le Gall, S. M., Legrand, J., Benbijja, M., Safya, H., Benihoud, K., Kanellopoulos, J. M., & Bobé, P. (2012). Loss of P2X7 receptor plasma membrane expression and function in pathogenic B220+ double-negative T lymphocytes of autoimmune MRL/lpr mice. PLoS One, 7, e52161.
- Lisnevskaia, L., Murphy, G., & Isenberg, D. (2014). Systemic lupus erythematosus. Lancet, 384, 1878–1888.
- Liu, Y., He, P., Liu, F., Zhou, N., Cheng, X., Shi, L., … Zhang, M. (2014). Tetra-arsenic tetra-sulfide (As4S4) promotes apoptosis in retinoid acid-resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine, 35, 3421–3430.
- Llorente, L., Richaud-Patin, Y., Garcia-Padilla, C., Claret, E., Jakez-Ocampo, J., Cardiel, M. H., … Galanaud, P. (2000). Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis and Rheumatism, 43, 1790–1800.
- Lu, D. P., Qiu, J. Y., Jiang, B., Wang, Q., Liu, K. Y., Liu, Y. R., & Chen, S. S. (2001). Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: A pilot report. Blood, 99, 3136–3143.
- Ma, L., Chan, K. W., Trendell-Smith, N. J., Wu, A., Tian, L., Lam, A. C., … Huang, F. P. (2005). Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains. European Journal of Immunology, 35, 3364–3375.
- Martin, J. C., Baeten, D. L., & Josien, R. (2014). Emerging role of IL-17 and Th17 cells in systemic lupus erythematosus. Clinical Immunology, 154, 1–12.
- Martina, M. N., Noel, S., Saxena, A., Rabb, H., & Hamad, A. R. (2015). Double negative (DN) alphabeta T cells: Misperception and overdue recognition. Immunology and Cell Biology, 93, 305–310.
- Niu, M., Shen, Y., Qi, J., Liu, X., Le Sang, W., Wu, Q., … Xu, K. (2017). Effects of realgar (As4S4) on degradation of PML-RARA harboring acquired arsenic-resistance mutations. Annals of Hematology, 96, 1945–1948.
- Ohga, S., Nomura, A., Takahata, Y., Ihara, K., Takada, H., Wakiguchi, H., … Hara, T. (2002). Dominant expression of interleukin 10 but not interferon gamma in CD4(−)CD8(−)alphabeta T cells of autoimmune lymphoproliferative syndrome. British Journal of Haematology, 119, 535–538.
- Qi, J., He, P., Chen, W., Wang, H., Wang, X., & Zhang, M. (2010). Comparative proteome study of apoptosis induced by As4S4 in retinoid acid resistant human acute promyelocytic leukemia NB4-R1 cells. Leukemia Research, 34, 1506–1516.
- Reap, E. A., Leslie, D., Abrahams, M., Eisenberg, R. A., & Cohen, P. L. (1995). Apoptosis abnormalities of splenic lymphocytes in autoimmune lpr and gld mice. Journal of Immunology, 154, 936–943.
- Rousset, F., Garcia, E., Defrance, T., Peronne, C., Vezzio, N., Hsu, D. H., … Banchereau, J. (1992). Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proceedings of the National Academy of Sciences of the United States of America, 89, 1890–1893.
- Saxena, A., Khosraviani, S., Noel, S., Mohan, D., Donner, T., & Hamad, A. R. (2015). Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy. Cytokine, 74, 27–34.
- Schneider, P., Holler, N., Bodmer, J. L., Hahne, M., Frei, K., Fontana, A., & Tschopp, J. (1998). Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. The Journal of Experimental Medicine, 187, 1205–1213.
- Shivakumar, S., Tsokos, G. C., & Datta, S. K. (1989). T cell receptor alpha/beta expressing double-negative (CD4−/CD8−) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. Journal of Immunology, 143, 103–112.
- Teng, Z. P., Zhang, P., Zhu, H. H., Hao, H. Y., Qin, X. Y., Hao, L., … Lu, D. P. (2006). Mechanism of tetra-arsenic tetra-sulfide in inducing apoptosis of acute promyelocytic leukemia cells. Beijing da Xue Xue Bao. Yi Xue Ban = Journal of Peking University. Health Sciences, 38, 236–238.
- Teramoto, K., Negoro, N., Kitamoto, K., Iwai, T., Iwao, H., Okamura, M., & Miura, K. (2008). Microarray analysis of glomerular gene expression in murine lupus nephritis. Journal of Pharmacological Sciences, 106, 56–67.
- Theofilopoulos, A. N., & Dixon, F. J. (1985). Murine models of systemic lupus erythematosus. Advances in Immunology, 37, 269–390.
- Wang, S., Zhou, M., Ouyang, J., Geng, Z., & Wang, Z. (2015). Tetraarsenictetrasulfide and arsenic trioxide exert synergistic effects on induction of apoptosis and differentiation in acute Promyelocytic leukemia cells. PLoS One, 10, e0130343.
- Wang, Y., He, P. C., Qi, J., Liu, Y. F., & Zhang, M. (2015). Tetra-arsenic tetra-sulfide induces cell cycle arrest and apoptosis in retinoic acid-resistant acute promyelocytic leukemia cells. Biomedical Reports, 3, 583–587.
- Wang, Y., Zhang, M., He, P. C., Liu, Y. F., Qi, J., Cheng, X. Y., & Zhu, H. C. (2015). Apoptosis of retinoic acid-resistant APL NB4-R1 cells induced by As4S4 and its molecular mechanism. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 23, 83–87.
- Watanabe-Fukunaga, R., Brannan, C. I., Copeland, N. G., Jenkins, N. A., & Nagata, S. (1992). Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature, 356, 314–317.
- Yin, Z., Bahtiyar, G., Zhang, N., Liu, L., Zhu, P., Robert, M. E., … Craft, J. (2002). IL-10 regulates murine lupus. Journal of Immunology, 169, 2148–2155.
- Zhang, Z., Kyttaris, V. C., & Tsokos, G. C. (2009). The role of IL-23/IL-17 axis in lupus nephritis. Journal of Immunology, 183, 3160–3169.
- Zhao, Y., Wen, G., Qiao, Z., Xu, H., Sun, Q., Huang, H., … Zhang, J. (2013). Effects of tetra-arsenic tetra-sulfide on BXSB lupus-prone mice: A pilot study. Lupus, 22, 469–476.