Therapeutic Effects Of Tofacitinib On Pristane-induced Lupus Nephritis In Mice

Object:SLE(Systemic lupus erythematosus)is a kind of autoimmune disease with multiple organs damage,often accompanied by a variety of clinical symptoms with poor quality of life and high mortality.Lupus nephritis is one of the primary causes of death.There are still no drugs that can completely cure SLE,and drug treatment can only alleviate symptoms and the development of the disease.Tofacitinib is the first small molecule compound against JAK,which plays an important role in the treatment of rheumatoid arthritis by inhibiting JAK phosphorylation and regulating pro-inflammatory cytokine activity.Whether tofacitinib is effective for SLE treatment has not yet been clear.Therefore,this experiment aims to investigate the effect of tofacitinib in the treatment of systemic lupus erythematosus,and to study the improvement of symptoms such as systemic inflammation and lupus nephritis.Methods:Female BALB/c mice of 8-10 weeks old were divided into two groups,namely saline control group(SC)and pristane-induced group.The induction group was induced by intraperitoneal injection of 0.5 ml Pristane to induce lupus nephritis model.The induction components were pristane control group(PC)and treatment group,tofacitinib treatment group(T),methylprednisolone treatment group(MP),tofacitinib and methylprednisolone combination treatment group(T+MP).When constructing the model,the body weight,joint diameter and urine protein concentration were measured every 4 weeks,and the urine protein concentration was measured by the test paper method.At the 22 nd week,the treatment group began treatment.At the end of the 32 nd week,the spleen and kidney size and weight of the mice were measured.The serum levels of anti-ds-DNA,IL-6 and IFN-? were detected by ELISA,and the proportion of spleen Treg cells was detected by flow cytometry.RT-q PCR was used to detect the m RNA expression of Foxp3 and JAK/STAT downstream genes,and HE and PAS staining were used to detect renal injury.Results:Compared with the SC group,the urine protein concentration of the PC group was increased,the spleen was enlarged,the joints of the feet were red and swollen,the diameter of the joints was increased,the serum anti-ds-DNA,IL-6,IFN-? concentrations were increased,and the Treg ratio was also increased.HE staining showed diffuse hyperplasia of glomeruli,focal sclerosis.And the glomerular score was elevated.PAS staining showed a large amount of purple-red substance deposited in the glomerulus.After treatment,the spleen was shrank,the joint diameter was decreased,the serum anti-ds-DNA,IL-6,IFN-? concentration and Treg ratio were decreased in the T,MP,T+MP group.HE staining showed a decrease in glomerular score,and PAS staining showed a decrease in purple-red material.The spleen,joint diameter,serum anti-ds-DNA,IL-6,IFN-?,and glomerulonephritis scores in the T+MP group were decreased the most.The level of SOCS1 in the T group was decreased,while the IRF7 was increased.And the SOCS1 in the T+MP group was decreased significantly,while the IRF7 and SOCS3 levels increased significantly.Conclusions:1.Tofacitinib can reduce IL-6,IFN-? cytokine levels,improve systemic inflammation,and alleviate lupus nephritis in lupus mice;2.The therapeutic effect of tofacitinib combined with methylprednisolone is better than that of tofacitinib or methylprednisolone alone;3.The downstream molecule of JAK/STAT pathway,SOCS3,may be involved in the treatment of lupus nephritis with tofacitinib,and down-regulate the secretion of inflammatory cytokines.