Research Of Expression Of ABC Transporter BCRP And The Correlation With Inflammatory Cytokines In Peripheral Blood Lymphocytes Of Patients With Rheumatoid Arthritis

Backgroud:Rheumatoid arthritis(RA)is a systemic inflammatory disease,usually in a state of chronic disease,it could cause loss of function and increased mortality.The prevalence rate of RA is 0.34 to 0.36%.The incidence of rheumatoid arthritis in females is higher than that in males,about 2-3:1,and it can occur in any age.The majority patients are20-50 years old,and the duration of illness is 5-10 years.The rate of disability is as high as 60%.Once diagnosed,rheumatoid arthritis patients should begin to be treated as disease-modifying anti-rheumatic drugs(DMARDs)in the first six months,and combined with low-dose glucocorticoid treatment.Methotrexate(MTX)is anchor drug in the treatment of Rheumatoid arthritis,sulfasalazine(SSZ),hydroxychloroquine(HCQ),etc.are also DMARDs,they have been included in the guideline for the diagnosis and treatment of rheumatoid arthritis.Our previous series of studies focused on the resistant protein P-gp,we explored relationship between P-gp and resistance to MTX/CTX in patients with RA.We got following results: 1.It has been demonstrated that P-gp expression and disease activity in peripheral blood lymphocytes of patients with RA are parallel,and the efficacy and expression of DMARDs decrease and their expression increases;2.P-gp expression in peripheral blood lymphocytes and synovial fibroblasts in RA patients may be elevated in high IL-6 environment;3.IL-6 can regulate RA peripheral blood through ERKl/2 and JAK2-STAT3 signaling pathways.Expression and function of P-gp on lymphocyte surface;4.The expression level of P-gp in RA patients has a certain concentration andtime dependence with IL-17;5.MTX combined with CTX could alleviate the activation of JAK2-STAT3 signaling pathway by MTX alone,reduce the expression level of P-gp,MTX cycle combined with CTX may reverse drug resistance to some extent.But what is the current expression of ABC transporter BCRP/ABCG2 in peripheral blood lymphocytes in RA patients? Its multidrug resistance is also related to the regulation of which cytokines? This is a scientific issue of this study.BCRP is a semi-transporter.Therefore,at least two nucleotide binding domains are required to act as a drug efflux pump.In the functional state,BCRP/ABCG2 exists in the form of a homodimers or homomultimers.In studies of the mechanisms of drug resistance in leukemia and tumors,it has been found that high expression of BCRP is associated with clinical incompatibility and poor prognosis.This topic explores whether BCRP is highly expressed in RA patients and whether it is related to cytokines,which mediates multidrug resistance in RA.Objective:1.By measuring the level of BCRP expression of peripheral blood lymphocytes in RA patients with different disease activity,confirm whether it is related to disease activity;2.To investigate whether the expression of BCRP on peripheral blood lymphocytes in patients with RA is related to cytokines(TNF-α,IL-1β,IL-6,IL-17,IL-10,etc.)And to study the multidrugs mediated by BCRP.Is resistance associated with inflammatory cytokines?Methods:Thirty-five patients with rheumatoid arthritis were included.According to the disease activity,they were divided into remission,low,middle and high disease activity groups,and 7 healthy controls.RT-PCR was used to detect the expression level of BCRPmRNA in lymphocytes.CBA technology Serum TNF-α,IL-1β,IL-6,IL-17,IL-10 and IL-2 levels were measured.Results:1.RT-PCR detection of BCRP m RNA levels in each group: Compared with the healthy control group,RA group BCRP expression levels were significantly higher(P<0.05);mRNA levels between the groups were statistically significant differences(P<0.05),but compared in pairs found that there was a statistically significant difference between the healthy control group and the high-disease activity group(P=0.025),and there was no significant difference between the other two groups.2.Correlation between peripheral blood lymphocyte BCRP mRNA level and disease activity: There was no statistically significant correlation between peripheral blood lymphocyte BCRP mRNA level and disease activity,and it could not be considered that there was a correlation between them,but there was a positive correlation trend.3.Cytokine levels in serum of peripheral blood of each group were detected by CBA technology: Compared with healthy control group,IL-1 β,IL-17 and TNF-αlevels in RA group were significantly increased(P<0.05);IL-2,IL-6,IL-10 difference between the two groups was not statistically significant;4.Correlativity between cytokines and BCRP mRNA expression levels: IL-6,TNF-α and BCRP mRNA levels were correlated and positively correlated;IL-2,IL-1 β,IL-17,IL-10 were verified Obvious correlation.Conclusion:1.The expression of BCRP on peripheral blood lymphocytes in RA patients was significantly higher than that in normal people,but there was no direct relationship with the disease activity.2.High level of IL-6 and TNF-α mediates high expression of BCRP on peripheral blood lymphocytes of RA patients and mediates multidrug resistance.