Systemic lupus erythematosus (SLE) is an autoimmune disease of uncertain etiology that affects multiple tissues and organs. Arsenic trioxide (ATO) has been used in lupus-prone mice with a regulatory effect on immune abnormality. Tetra-arsenic tetra-sulfide (As4S4), a traditional Chinese medicine, is effective on acute promyelocytic leukemia with mild side effects than ATO. In this study, a pilot study was performed to investigate the effects and the mechanism of As4S4 on the lupus-prone BXSB mice. Improvement of monocytosis (p < 0.05) in spleen and decreased serum interleukin-6 (IL-6) (p = 0.0277) were observed with As4S4 treatment. As4S4-treated mice exhibited amelioration of skin, liver and renal disease with mild side effects. Histological analysis revealed that As4S4 suppressed immune complex deposition, mesangial proliferation and inflammatory cell infiltration in kidney and liver. Our study support that As4S4 selectively suppresses cutaneous lupus and nephritis in BXSB mice and might be a potential treatment for SLE.
AndrewsBSEisenbergRATheofilopoulosAN. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med1978; 148: 1198–1215.
4.
KarimMYPisoniCNKhamashtaMA. Update on immunotherapy for systemic lupus erythematosus–what's hot and what's not!. Rheumatology (Oxford)2009; 48: 332–341.
5.
LuDPQiuJYJiangB. Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: A pilot report. Blood2002; 99: 3136–3143.
6.
QiJHePChenW. Comparative proteome study of apoptosis induced by As4S4 in retinoid acid resistant human acute promyelocytic leukemia NB4-R1 cells. Leuk Res2010; 34: 1506–1516.
7.
TheofilopoulosANDixonFJ. Etiopathogenesis of murine SLE. Immunol Rev1981; 55: 179–216.
8.
LiuJLuYWuQ. Mineral arsenicals in traditional medicines: Orpiment, realgar, and arsenolite. J Pharmacol Exp Ther2008; 326: 363–368.
9.
BobePBonardelleDBenihoudK. Arsenic trioxide: A promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice. Blood2006; 108: 3967–3975.
10.
XiaXRLinSXZhouY. Effects of arsenic trioxide on the autoimmunity and survival time in BXSB lupus mice. Zhongguo Zhong Xi Yi Jie He Za Zhi2007; 27: 138–141.
11.
LindgrenAVahterMDenckerL. Autoradiographic studies on the distribution of arsenic in mice and hamsters administered 74As-arsenite or -arsenate. Acta Pharmacol Toxicol (Copenh)1982; 51: 253–265.
12.
WofsyDKergerCESeamanWE. Monocytosis in the BXSB model for systemic lupus erythematosus. J Exp Med1984; 159: 629–634.
13.
RogersNJGabrielLNunesCT. Monocytosis in BXSB mice is due to epistasis between Yaa and the telomeric region of chromosome 1 but does not drive the disease process. Genes Immun2007; 8: 619–627.
14.
MerinoRFossatiLLacourM. H-2-linked control of the Yaa gene-induced acceleration of lupus-like autoimmune disease in BXSB mice. Eur J Immunol1992; 22: 295–299.
15.
KikuchiSSantiago-RaberMLAmanoH. Contribution of NZB autoimmunity 2 to Y-linked autoimmune acceleration-induced monocytosis in association with murine systemic lupus. J Immunol2006; 176: 3240–3247.
16.
GranholmNACavalloT. Bacterial lipopolysaccharide enhances deposition of immune complexes and exacerbates nephritis in BXSB lupus-prone mice. Clin Exp Immunol1991; 85: 270–277.
17.
LemarieAMorzadecCBourdonnayEFardelOVernhetL. Human macrophages constitute targets for immunotoxic inorganic arsenic. J Immunol2006; 177: 3019–3027.
18.
GoussetisDJAltmanJKGlaserH. Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide. J Biol Chem2010; 285: 29989–29997.
19.
OndrouskováESoucekKHorváthV. Alternative pathways of programmed cell death are activated in cells with defective caspase-dependent apoptosis. Leuk Res2008; 32: 599–609.
20.
JacobCOZangSLiL. Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice. J Immunol2003; 171: 1564–1571.
21.
ChowdharyVRCrowsonCSPoteruchaJJ. Liver involvement in systemic lupus erythematosus: Case review of 40 patients. J Rheumatol2008; 35: 2159–2164.
22.
PistinerMWallaceDJNessimS. Lupus erythematosus in the 1980s: A survey of 570 patients. Semin Arthritis Rheum1991; 21: 55–64.
23.
TzangBSChiangSYLaiWX. Treatment with cystamine reduces apoptosis in liver from NZB/W F1 mice. Int Immunopharmacol2008; 8: 589–596.
24.
YapDYLaiKN. Cytokines and their roles in the pathogenesis of systemic lupus erythematosus: From basics to recent advances. J Biomed Biotechnol2010; 2010: 1–10.
25.
HiranoT. Interleukin 6 and its receptor: Ten years later. Int Rev Immunol1998; 16: 249–284.
26.
TakemuraTYoshiokaKMurakamiK. Cellular localization of inflammatory cytokines in human glomerulonephritis. Virchows Arch1994; 424: 459–464.
27.
CashHRelleMMenkeJ. Interleukin 6 (IL-6) deficiency delays lupus nephritis in MRL-Faslpr mice: The IL-6 pathway as a new therapeutic target in treatment of autoimmune kidney disease in systemic lupus erythematosus. J Rheumatol2010; 37: 60–70.
28.
SmithHRChusedTMSmathersPA. Evidence for thymic regulation of autoimmunity in BXSB mice: acceleration of disease by neonatal thymectomy. J Immunol1983; 130: 1200–1204.
29.
KulkarniOPRyuMKantnerC. Recombinant chaperonin 10 suppresses cutaneous lupus and lupus nephritis in MRL-(Fas)lpr mice. Nephrol Dial Transplant2012; 27: 1358–1367.
30.
KimNUssinLChengX. TNFalpha inhibition in MRL/lpr mice ameliorates pulmonary but not renal disease. J Autoimmun2002; 19: 215–222.
