The Expression And Significance Of Interleukin 37 In Patients With Ankylosing Spondylitis

Background:Ankylosing spondylitis(AS)is a chronic inflammatory disease that mainly affects the axial,tendon and ligaments,and is characterized by sacroiliitis.Some patients may have eyes,lungs,kidneys,and heart.Vascular and other extra-articular symptoms.In China,AS often occurs in young men,and the age of onset is about 18-30 years old.Patients with advanced disease may have joint fusion malformation and ankylosis,which brings a heavy social and economic burden to the patient's family.The etiology and pathogenesis of AS are not very clear and are currently considered to be closely related to many factors such as genetic environment,immune mechanism,infection factors,and inflammatory response.Human leukocyte antigen(HLA-B27)is thought to be closely related to the pathogenesis of AS.The study confirmed that the single nucleotide polymorphism(SNP)(rs3811047)of the IL-1F7(also known as IL-37)gene in the Han population was associated with susceptibility to AS.Studies have shown that interleukin-1 ?(IL-1 ?),interleukin-6(IL-6),interleukin-18(IL-18),tumor necrosis factor-?(TNF)-?)as common pro-inflammatory factors are thought to participate in the pathogenesis of AS.Recently,studies have found that interleukin-37(IL-37)is a natural inhibitor of immune responses and inflammatory responses and can be used as an anti-inflammatory factor involved in immune responses and inflammatory reactions.IL-37 is a bi-functional cytokine with an intracellular and extracellular mechanism of action.Its main inhibitors of inflammatory response and regulation of immunity include:IL-37 precursor is cleaved by caspase-1(Caspase-1).IL-37b,which is an active mature body,has increased IL-18BP's ability to inhibit IL-18 by binding to IL-18 binding protein(IL-18BP),thereby inhibiting the production of interferon-Y(IFN-?);Transfer of IL-37b into the cell can bind to smad3 to form IL-37b-Smad3 complex,thereby reducing the expression of some inflammatory signaling pathway-related kinases such as FAK,MAPK p38 and c-Jun.The IL-37b-Smad3 complex also inhibits phosphorylation of STAT1-4 and inactivates GSK-3 ?/?expression;in addition,IL-37b can be directly released into immune neurons by autocrine or paracrine methods.Inhibits dendritic cell activation and delays antigen presentation.The study found that IL-37 can reduce the clinical symptoms of ischemic stroke,myocardial ischemia/reperfusion injury,psoriasis and asthma,and the expression of IL-37 is also associated with the disease activity of diffuse toxic goiter(GD).In the field of autoimmune diseases and rheumatic diseases,IL-37 is thought to play a role by down-regulating the expression and activation of pro-inflammatory cytokines.It has been reported that IL-37 is involved in systemic lupus erythematosus(SLE)and rheumatoid The pathogenesis of arthritis(RA),adult Still's disease,and ankylosing spondylitis(AS).TNF-a antagonists are important means for the treatment of AS and can significantly reduce clinical symptoms and reduce disease activity.In vitro studies,we found that blocking the expression of TNF-a,can reduce the expression of inflammatory cytokines IL-1?,IL-6,IL-18,and IL-1?,IL-18,TNF-a can promote IL-37 Expression.IL-37 can inhibit the expression of IL-1?,IL-6,TNF-a and other inflammatory cytokines.Objective:The purpose of this study was to investigate the expression and clinical significance of interleukin-37 inflammatory small body in ankylospondylitis.Methods:In this study,35 patients with ankylosing spondylitis admitted to the Shandong Provincial Hospital from January 2017 to January 2018 were selected as the AS group;tumor necrosis factor(TNF-a)antagonists were selected for injection.Twenty patients treated with recombinant human type II tumor necrosis factor receptor antibody fusion protein were treated as post-AS group.(Note:The 20 patients were treated only with non-steroidal anti-inflammatory drugs and recombinant human type ? tumor necrosis factor receptor antibody fusion protein for 6 weeks,once weekly,once subcutaneously 50 mg)and 30 healthy people attending the hospital's health examination center for the same period as the healthy control group.The serum levels of IL-37,IL-1?,IL-6,IL-18 and TNF-? in the three groups were measured by enzyme-linked immunosorbent assay(ELISA).Real-time polymerase chain reaction real-time PCR was used to detect IL-37,IL-1 1?,IL-6,IL-18,TNF-a mRNA expression;analysis of AS group and healthy control group and before and after treatment of the above cytokines expression changes and IL-37 and clinical laboratory indicators,disease activity correlation.Results:1.Changes of serum cytokines in patients with AS and changes in serum factors after treatment with TNF-a antagonist,"Recombinant human type ? tumor necrosis factor receptor antibody fusion protein for injection:The cytokines detected in patients with AS including IL-37,IL-1?,IL-6,IL-18,TNF-a were significantly higher than those in the normal control group.Serum levels of IL-37,IL-1??IL-6,IL-18,TNF-? were highly expressed in AS group(P<0.0001,P<0.000),P<0.0001,P<0.0001,P<0.0001).and after treatment the expression levels of serum IL-1?,IL-6,IL-18,IL-37 and TNF-a were significantly decreased(P<0.0001,P<0.0001,P<0.0001,P<0.0001,P<0.0001).2.Cytokine mRNA expression changes and post-treatment changes in PBMC of AS patients:Compared with the healthy control group,the five factors measured in AS patients were higher than those in the control group.The expression of IL-37 mRNA in PBMC of AS patients before treatment was 2.3 times(P<0.0001),and the expression of IL-1? mRNA was 3.5 times(P<0.0001)in healthy controls.The mRNA level of IL-6 mRNA was 2.6 times that of healthy control(P<0.0001),the mRNA expression of IL-18 was 3.6 times that of healthy control(P=0.0002),and the expression level of TNF-a mRNA was healthy.2.3 times of the control group(P<0.0001).After treatment with "injection of recombinant human type II tumor necrosis factor receptor antibody fusion protein",the serum levels of IL-37,IL-1 ?,IL-6,IL-18 and IL-37 in AS group were significantly decreased.IL-37 mRNA expression was 1.7 times that of the normal control group(P<0.0001),IL-1? mRNA expression was 2.7 times that of the normal control group(P<0.0001),and IL-6 mRNA was expressed 1.9 times that of the normal control group(P<0.0001),the expression level of IL-18 mRNA was 2.3 times that of the normal control group(P=0.0002),and the expression level of TNF-+ mRNA was 1.7 times that of the normal control group(P<0.0001).3.The correlation between IL-37 mRNA expression and other cytokine mRNA expression in PBMC of AS patients:The expression of IL-37 mRNA and IL-1 ?(R=0.826,p=0.0001)and IL-6(R=)in the PBMCs of patients with AS before the injection of�Recombinant human type II tumor necrosis factor receptor antibody fusion protein for injection" The mRNA expression levels of 0.576,p=0.001),IL-18(R=0.760,p=0.0001),and TNF-a(R=0.788,p=0.0001)were significantly correlated and were positively correlated.After 6 weeks of treatment,the mRNA expression of IL-37 in PBMC was still correlated with IL-1 ?(R=0.516,p=0.024),IL-6(R=0.741,p=0.0001),and IL-18(R=0.460).,p=0.041)and mRNA expression levels of TNF-?(R=0.577,p=0.008)were closely related and positively correlated.4.Correlation of IL-37 with clinical laboratory indicators and disease activity in AS patients:4.1 Serum levels of IL37 in patients with AS before treatment were positively correlated with CRP expression(R=0.828,P<0.0001),positively correlated with ESR expression(R=0.544,P=0.001),and positively correlated with BASDAI score(R=0.590,P=0.0001),no correlation with platelets(R=0.293,P=0.092).4.2 The expression of IL37 in AS patients was positively correlated with the expression of CRP after treatment(R=0.767,P=0.0001),positively correlated with the expression of ESR(R=0.644,P=0.004),and had no correlation with platelets(R=0.372,P=0.117).Conclusion:1.The expression of IL-37 is closely related to the immune-inflammatory reaction of AS,and the expression level of IL-37 is increased in AS,and it is positively correlated with the disease activity of AS.It may be one of the indicators reflecting the activity of AS disease.2.IL-1?,IL-6,IL-18,TNF-? and other inflammatory factors were elevated in AS,and there was a significant positive correlation with IL-3 expression.Inflammatory responses and inflammatory cytokines can increase the expression of IL-37,and the imbalance of IL-37 and pro-inflammatory cytokines may be involved in the pathogenesis of AS.3.TNF-? antagonists can reduce the expression of IL-1?,IL-6,IL-18 and IL-37in AS.