The Impact Of Unfolded Protein Response In Patients With Spondyloarthritis

Objective（1）To investigate whether unfolded protein response (UPR) plays a role in thepathogenesis of spondyloarthritis (SpA) by assessing the UPR-related gene expressionof SpA and other kinds of arthritis patients.（2）To determin whether UPR contributesto the up-regulation of proinflammatory cytokines by developing a regression model forthe IL-23or IL-17expressions.Methods（1） Eighteen spondyloarthritis patients,12rheumatoid arthritis (RA) and6osteoarthritis (OA) patients were included. All the patients presented with the effusionof knee joints. Synovial fluid samples were collected by the operation ofarthrocentensis. Macrophages were isolated from synovial fluid samples by magneticseparation. UPR-regulated genes were assessed by measuring the expression ofmessenger RNA (mRNA) for binding immunoglobulin protein (BiP), glucose-regulatedprotein94(GRP94), C/EBP homologous protein (CHOP), growth arrested and DNAdamage-inducible34(GADD34), X-box binding protein1(XBP-1) and endoplasmicreticulum DnaJ homolog4(ERdj4).（2）The mRNA of IL-23p19and IL-12/23p40wasmessured by real-time PCR and the IL-17level of synovial fluid was analysed byELISA.Results（1）Compared with macrophages of OA, samples from SpAand RApatients expressedhigher level of BiP and GRP94[6.06±2.08and5.41±1.97vs1.11±0.72for BiP,11.8(7.3~38.4) and9.01(4.15~24.4) vs1.27(1.02~4.18) for GRP94, all of P values<0.01]. XBP1was also up-regulated [12.7±5.2and11.0±4.2vs4.14±2.56, P<0.01].However, none of the UPR-regulated genes showed differences between SpA group and RA group except GADD34[7.30(5.56~15.4) vs21.3(12.2~27.6), P=0.009].Furthermore, it revealed no discrepancies of UPR-regulated genes expression betweenSpA patients with positive or negetive HLA-B27profiles.（2）Compared withmacrophages of OA, samples from SpA patients expressed higher level of IL-23p19[(7.06±3.58)×10-5vs.(2.93±1.65)×10-5，P=0.013], but samples from RA patientsshowed no statistical significances. It revealed that IL-23p19was related to BiP, GRP94,XBP1, ERdj4, IL-12/23p40and patients’ age. However, in regression model, theup-regulation IL-23p19could only be predicted by elevated XBP-1(β=0.006, P<0.001)and IL-12/23p40(β=1.417, P<0.001), and decreased GRP94(β=-0.001, P=0.016). Incontrast to the synovial fluid supernatant of OA, that of SpA and RA patients expressedhigher level of IL-17[14.86（5.83~43.14）pg/mL and36.85（19.07~51.46）pg/mL vs.14.86（5.83~43.14）pg/mL，all the P values <0.01]. IL-17was relevant to GRP94,XBP1, CRP and patients’ age. However, it was indicated that only elevated CRP levelwas predictive of increased IL-17(β=0.635, P=0.005).ConclusionsOur data concluded that UPR participates in the pathogenesis of SpA and contributes tothe up-regulation of IL-23, although the relationship between HLA-B27and UPR stillrequires further investigations. IL-17is predicted by CRP levels.