Immunosuppressive effects of hydroxychloroquine and artemisinin combination therapy via the nuclear factor‑κB signaling pathway in lupus nephritis mice

Liang,Ning; Zhong,Yanchun; Zhou,Jie; Liu,Bihao; Lu,Ruirui; Guan,Yezhi; Wang,Qi; Liang,Chunlin; He,Yu; Zhou,Yuan; Song,Jianping; Zhou,Jiuyao

doi:10.3892/etm.2018.5708

Immunosuppressive effects of hydroxychloroquine and artemisinin combination therapy via the nuclear factor‑κB signaling pathway in lupus nephritis mice

Authors:
- Ning Liang
- Yanchun Zhong
- Jie Zhou
- Bihao Liu
- Ruirui Lu
- Yezhi Guan
- Qi Wang
- Chunlin Liang
- Yu He
- Yuan Zhou
- Jianping Song
- Jiuyao Zhou
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Affiliations: Department of Pharmacology, College of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China, Science and Technology Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510445, P.R. China, Artepharm Co., Ltd., Guangzhou, Guangdong 510032, P.R. China
Published online on: January 5, 2018 https://doi.org/10.3892/etm.2018.5708
Pages: 2436-2442
Copyright: © Liang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lupus nephritis (LN) is one of the most common and severe manifestations of systemic lupus erythematosus, leading to permanent renal damage and chronic kidney disease. Hydroxychloroquine (HCQ) serves a protective role against lupus-associated clinical manifestations and medical complications; however, it results in numerous adverse reactions, limiting its long‑term use. The aim of the present study was to investigate the combined effect of HCQ and artemisinin (ART) on LN, and to elucidate the underlying mechanisms. An in vivo LN mouse model was prepared, and the animals were administered prednisone (PDS; serving as a positive control), high‑dose HCQ (H‑HCQ) or low‑dose HCQ combined with ART (L‑HCQ + ART) once daily for 8 weeks. The body weight, serum biochemical parameters, immune and inflammatory indicators, renal and spleen histological alterations, and mRNA expression levels of Kruppel‑like factor 15 (KLF15) and nuclear factor‑κB (NF‑κB) were analyzed. It was observed that L‑HCQ + ART and H‑HCQ ameliorated the LN‑induced body weight decrease, and significantly decreased the levels of anti‑double stranded DNA, antinuclear antibodies, immunoglobulin G, interferon γ, tumor necrosis factor‑α and transforming growth factor‑β1, as well as improved the kidney and spleen pathology, when compared with the model group. In addition, L‑HCQ + ART and H‑HCQ treatments induced KLF15 upregulation and NF‑κB downregulation. These results indicated that treatment with L‑HCQ + ART exerted renoprotective effects by regulating the expression levels of cytokines, KLF15 and NF‑κB. This combination treatment may have a similar immunosuppressive effect as PDS and H‑HCQ, and may be a promising alternative for LN treatment.

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1	Bhatt D and Ghosh S: Regulation of the NF-κB-mediated transcription of inflammatory genes. Front Immuno. 5:712014. View Article : Google Scholar
2	Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sánchez-Guerrero J, Solomons N, et al: Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 20:1103–1112. 2009. View Article : Google Scholar : PubMed/NCBI
3	Ruiz-Irastorza G, Danza A, Perales I, Villar I, Garcia M, Delgado S and Khamashta M: Prednisone in lupus nephritis: How much is enough? Autoimmun Rev. 13:206–214. 2014. View Article : Google Scholar : PubMed/NCBI
4	Illei GG, Austin HA, Crane M, Collins L, Gourley MF, Yarboro CH, Vaughan EM, Kuroiwa T, Danning CL, et al: Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med. 135:248–257. 2001. View Article : Google Scholar : PubMed/NCBI
5	Kawasaki H, Onuki R, Suyama E and Taira K: Identification of genes that function in the TNF-alpha-mediated apoptotic pathway using randomized hybrid ribozyme libraries. Nat Biotechnol. 20:376–380. 2002. View Article : Google Scholar : PubMed/NCBI
6	Zheng ZH, Zhang LJ, Liu WX, Lei YS, Xing GL, Zhang JJ, Quan SX, Liu D, Hu DS, Li LL and Liu ZS: Predictors of survival in Chinese patients with lupus nephritis. Lupus. 21:1049–1056. 2012. View Article : Google Scholar : PubMed/NCBI
7	Pons-Estel GJ, Alarcón GS, McGwin G Jr, Danila MI, Zhang J, Bastian HM, Reveille JD and Vilá LM; Lumina Study Group, : Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 61:830–839. 2009. View Article : Google Scholar : PubMed/NCBI
8	Lee SJ, Silverman E and Bargman JM: The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat Rev Nephrol. 7:718–729. 2011. View Article : Google Scholar : PubMed/NCBI
9	Wallace DJ, Gudsoorkar VS, Weisman MH and Venuturupalli SR: New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev Rheumatol. 8:522–533. 2012. View Article : Google Scholar : PubMed/NCBI
10	Costedoat-Chalumeau N, Dunogué B, Leroux G, Morel N, Jallouli M, Le Guern V, Piette JC, Brézin AP, Melles RB and Marmor MF: A critical review of the effects of hydroxychloroquine and chloroquine on the eye. Clin Rev Allergy Immunol. 49:317–326. 2015. View Article : Google Scholar : PubMed/NCBI
11	Bhavsar KV, Mukkamala LK and Freund KB: Multimodal imaging in a severe case of hydroxychloroquine toxicity. Ophthalmic Surg Lasers Imaging Retina. 46:377–379. 2015. View Article : Google Scholar : PubMed/NCBI
12	Ding HJ, Denniston AK, Rao VK and Gordon C: Hydroxychloroquine-related retinal toxicity. Rheumatology (Oxford). 55:957–967. 2016. View Article : Google Scholar : PubMed/NCBI
13	Abdel Galil SM: Hydroxychloroquine-induced toxic hepatitis in a patient with systemic lupus erythematosus: A case report. Lupus. 24:638–640. 2015. View Article : Google Scholar : PubMed/NCBI
14	Wu Y, He S, Bai B, Zhang L, Xue L, Lin Z, Yang X, Zhu F, He P, Tang W and Zuo J: Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation. Cell Mol Immunol. 13:379–390. 2016. View Article : Google Scholar : PubMed/NCBI
15	Wu XL, Zhang WG, Shi XM, An P, Sun WS, Qiao CL and Wang Z: Effect of artemisinin combined with glucocorticoid on the expressions of glucocorticoid receptor α mRNA, glucocorticoid receptor β mRNA and P300/CBP protein in lupus nephritis mice. Chin J Integr Med. 17:277–282. 2011. View Article : Google Scholar : PubMed/NCBI
16	The People's Republic of China of Laboratory Animals-Guideline of welfare and ethics. Standardization Administration of China. 2016.
17	Wen ZK, Xu W, Xu L, Cao QH, Wang Y, Chu YW and Xiong SD: DNA hypomethylation is crucial for apoptotic DNA to induce systemic lupus erythematosus-like autoimmune disease in SLE-non-susceptible mice. Rheumatology (Oxford). 46:1796–1803. 2007. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Shaharir SS, Ghafor AA, Said MM and Kong NC: A descriptive study of the factors associated with damage in Malaysian patients with lupus nephritis. Lupus. 23:436–442. 2014. View Article : Google Scholar : PubMed/NCBI
20	Zhang ZM, Zhao L, Zhang XL and Wang XF: Correlation analysis between urinary T lymphocyte subsets and lupus nephritis disease activity. Int J Clin Exp Med. 10:6061–6070. 2017.
21	Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, Boletis J, Cervera R, Dörner T, Doria A, et al: Joint European league against rheumatism and European renal association-European dialysis and transplant association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis. 71:1771–1782. 2012. View Article : Google Scholar : PubMed/NCBI
22	Imran TF, Yick F, Verma S, Estiverne C, Ogbonnaya-Odor C, Thiruvarudsothy S, Reddi AS and Kothari N: Lupus nephritis: An update. Clin Exp Nephrol. 20:1–13. 2016. View Article : Google Scholar : PubMed/NCBI
23	Tucci M, Stucci S, Strippoli S and Silvestris F: Cytokine overproduction, T-cell activation and defective T-regulatory functions promote nephritis in systemic lupus erythematosus. Bio Med Res Int. 2010:4571462010.
24	Deshmukh US, Bagavant H and Fu SM: Role of anti-DNA antibodies in the pathogenesis of lupus nephritis. Autoimmun Rev. 5:414–418. 2006. View Article : Google Scholar : PubMed/NCBI
25	Mallipattu SK, Liu R, Zheng F, Narla G, Ma'ayan A, Dikman S, Jain MK, Saleem M, D'Agati V, Klotman P, et al: Kruppel-like factor 15 (KLF15) is a key regulator of podocyte differentiation. J Biol Chem. 287:19122–19135. 2012. View Article : Google Scholar : PubMed/NCBI
26	Hong Q, Li C, Xie Y, Lv Y, Liu X, Shi S, Ding R, Zhang X, Zhang L, Liu S and Chen X: Kruppel-like factor-15 inhibits the proliferation of mesangial cells. Cell Physiol Biochem. 29:893–904. 2012. View Article : Google Scholar : PubMed/NCBI
27	Lu Y, Zhang L, Liao X, Sangwung P, Prosdocimo DA, Zhou G, Votruba AR, Brian L, Han YJ, Gao H, et al: Kruppel-like factor 15 is critical for vascular inflammation. J Clini Invest. 123:4232–4241. 2013. View Article : Google Scholar
28	Jain MK, Sangwung P and Hamik A: Regulation of an inflammatory disease. Arterioscler Thromb Vasc Biol. 34:499–508. 2014. View Article : Google Scholar : PubMed/NCBI
29	Yazici MU, Orhan D, Kale G, Besbas N and Ozen S: Studying IFN-gamma, IL-17 and FOXP3 in pediatric lupus nephritis. Pediatr Nephrol. 29:853–862. 2014. View Article : Google Scholar : PubMed/NCBI
30	Davidson A: What is damaging the kidney in lupus nephritis? Nat Rev Rheumatol. 12:143–153. 2016. View Article : Google Scholar : PubMed/NCBI
31	Yang L, Sun X, Zhan Y, Liu H, Wen Y, Mao H, Dong XI and Li P: Yi Qi Qing Re Gao-containing serum inhibits lipopolysaccharide-induced rat mesangial cell proliferation by suppressing the Wnt pathway and TGF-β1 expression. Exp Ther Med. 11:1410–1416. 2016. View Article : Google Scholar : PubMed/NCBI