RESUMEN

OBJECTIVE: To explore the association of disease activity, as evaluated by both the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K), with depression and anxiety in patients with systemic lupus erythematosus (SLE). METHODS: A cross-sectional study was conducted among 85 Chinese patients with SLE. Disease activity was measured using SLEDAI-2K and SLE-DAS scoring systems. Depression and anxiety were assessed using Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7), respectively. Multivariate logistic regression analysis was performed to evaluate the association of disease activity scores, as well as specific clinical and laboratory items, with depression and anxiety. RESULTS: There was a robust correlation between SLEDAI-2K and SLE-DAS scores in overall patients (Spearman's r = 0.764, 95% confidence interval (CI) 0.655-0.842; p< 0.001) and those with moderate-to-high disease activity (Spearman's r = 0.792, 95%CI 0.616-0.892; p< 0.0001). However, the correlation weakened for patients with mild disease activity or remission (Spearman's r = 0.450, 95%CI 0.188-0.652; p= 0.001). Multivariate logistic regression analysis did not show a significant correlation between SLEDAI-2K and SLE-DAS scores and depression/anxiety. The presence of mucosal ulcer/serositis significantly increased the risk of depression (OR = 4.472, 95%CI 1.035-19.328, p= 0.045) and anxiety (OR = 3.978, 95%CI 1.051-15.049, p= 0.042). CONCLUSION: The SLE-DAS scoring system demonstrated a comparable ability to assess disease activity in SLE compared with SLEDAI-2K. Though neither scoring system showed significant associations with depression and anxiety, the presence of mucosal ulcer/serositis markedly heightened the risk of both among SLE patients.

RESUMEN

OBJECTIVES: To explore the risk factors of anxiety and depression, especially their association with serum autoantibodies, in patients with connective tissue diseases (CTDs). METHODS: Three hundred and fifty-two inpatients with CTDs were recruited and their demographic, serological and imaging data were collected through the medical record system. Depression and anxiety were assessed by the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 Scale (GAD-7) respectively. Analysis of variance (ANOVA), rank sum test, chi-square test and logistic regression were performed to investigate risk factors for depression and anxiety. RESULTS: The prevalence of depression (PHQ-9 ≥ 5) and anxiety (GAD-7 ≥5) in CTD patients was significantly higher than that in the Chinese general population (depression: 44.3% vs. 32.2%, anxiety: 39.5% vs. 22.2%). Sleep time was a protective factor for both depression and anxiety (OR=0.734, 95% CI: 0.616~0.874, p<0.001 and OR=0.684, 95% CI: 0.559~0.835, P<0.001, respectively) while anti-Ro52 antibody was a risk factor for them (OR=5.466, 95% CI: 2.978~10.032, p<0.001 and OR=4.075, 95% CI: 2.073~8.010, p<0.001, respectively). Further analysis showed that anti-Ro52 antibody was a risk factor for depression and anxiety in all four subgroups, namely SLE, SS, RA, and other CTDs. CONCLUSIONS: Anti-Ro52 antibody is probably a risk factor for depression and anxiety in patients with connective tissue diseases. CTD patients with the presence of anti-Ro52 antibody are more prone to depression and anxiety than those without it.

Asunto(s)

Ansiedad , Enfermedades del Tejido Conjuntivo , Depresión , Ribonucleoproteínas , Humanos , Femenino , Masculino , Persona de Mediana Edad , Enfermedades del Tejido Conjuntivo/inmunología , Enfermedades del Tejido Conjuntivo/psicología , Enfermedades del Tejido Conjuntivo/sangre , Enfermedades del Tejido Conjuntivo/epidemiología , Enfermedades del Tejido Conjuntivo/diagnóstico , Estudios Transversales , Ansiedad/epidemiología , Ansiedad/inmunología , Ansiedad/psicología , Adulto , Factores de Riesgo , Depresión/epidemiología , Depresión/inmunología , Depresión/psicología , Ribonucleoproteínas/inmunología , Prevalencia , China/epidemiología , Anciano , Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Biomarcadores/sangre , Modelos Logísticos

RESUMEN

OBJECTIVES: To investigate the association of serum interleukin-11 (IL-11) with disease activity and occurrence of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). METHODS: One hundred and six RA patients were included, including 31 with ILD. All patients were divided into two groups according to the 28-joint Disease Activity Score (DAS28), active-disease group (DAS28>3.2) and target-achieved group (DAS28≤3.2). Serum IL-11 was detected by ELISA. Serum autoantibodies [anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF)], inflammatory markers [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)], and complete blood count were measured with routine methods. RESULTS: Serum IL-11 was upregulated in RA patients compared with healthy controls (HC), and increased more significantly in patients with ILD (RA-ILD) than patients without ILD (RA-nonILD). In both RA-ILD and RA-nonILD patients, serum level of IL-11 was higher in the active-disease group than that in the target-achieved group. Pearson correlation analysis confirmed that IL-11 was positively correlated with DAS28. No significant correlation was found between serum level of IL-11 and ACPA or RF. IL-11 was positively correlated with ESR and CRP levels and PLT count in RA patients. CONCLUSIONS: IL-11 was found to be involved in the development of arthritis and ILD in RA patients, and might constitute a potential target for the treatment of RA-ILD.

Asunto(s)

Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Sedimentación Sanguínea , Humanos , Interleucina-11 , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Factor Reumatoide

RESUMEN

OBJECTIVE: This case-control study aimed to analyze the clinical features and determine the expression of type I interferon-induced genes in systemic lupus erythematosus (SLE) patients harboring the CD11b rs1143679 single-nucleotide polymorphism (SNP) and elucidate whether it is involved in the relapses of SLE. METHODS: One hundred twenty-five relatively inactive SLE patients with SLEDAI scores < 6, including 102 CD11b rs1143679 G allele patients as controls and 23 rs1143679 A allele carriers as cases, were enrolled from the SLE patient specimen bank in the Department of Rheumatology and Immunology. The sample set was retrospectively analyzed for differences in clinical features, and quantitative PCR and Western blot analyses were performed to evaluate the relative expression of type I interferon (IFN)-inducible genes. RESULTS: The 24-h urinary protein levels in the case group were significantly elevated, and serum C3 levels were significantly reduced compared with those in the control group (P = 0.019 and P = 0.021, respectively). The relative mRNA levels of IFN-inducible genes IFIT1, IFIT4, and ISG15 in the case group were higher than that in the control group (P = 0.0257, 0.0344, and 0.0311, respectively) and matched with the Western blot results. CONCLUSIONS: The relative expression of type I IFN-inducible genes in inactive SLE patients harboring the CD11b rs1143679 polymorphism was higher than that in other lupus patients. These findings suggest that the rs1143679 SNP can precipitate relapses in inactive SLE patients. KEY POINTS: • The rs1143679 GA genotype was associated with SLE clinical features. • The rs1143679 GA genotype showed higher interferon-inducible gene expression relative to the GG genotype.

Asunto(s)

Interferón Tipo I , Lupus Eritematoso Sistémico , Estudios de Casos y Controles , China , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Interferón Tipo I/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos

RESUMEN

A number of circular RNAs (circRNAs) have been implicated in rheumatoid arthritis (RA) pathogenesis; however, little is known about their function and hidden molecular mechanism in immune and inflammation regulation. We investigated the role and the underlying mechanism of circRNA_09505 in RA in this study. Real-time PCR and fluorescence in situ hybridization (FISH) are adopted to estimate the quantitative expression and localization of circRNA_09505 in macrophages. The altering effect of circRNA_09505 on inflammation is investigated in vitro and in vivo by use of macrophage cell models and collagen-induced arthritis (CIA) mice. Luciferase reporter assay and RNA-binding protein immunoprecipitation (RIP) are used to confirm the circRNA_09505/miR-6089 ceRNA network predicted by bioinformatics analysis. Compared with controls, the expression of circRNA_09505 is upregulated in peripheral blood mononuclear cells (PBMCs) from patients with RA. The proliferation and cell cycle are significantly promoted when circRNA_09505 is upregulated in macrophages, whereas knockdown of circRNA_09505 inhibits macrophage proliferation and cell- cycle progression. Besides, circRNA_09505 can act as a miRNA sponge for miR-6089 in macrophages, and promote the production of TNF-α, IL-6, and IL-12 through ceRNA mechanism. Moreover, AKT1 is a direct target of miR-6089. CircRNA_09505 can promote AKT1 expression by acting as a miR-6089 sponge via IκBα/NF-κB signaling pathway in macrophages. Most interestingly, knockdown of circRNA_09505 significantly alleviates arthritis and inflammation in vivo in CIA mice. These data support the hypothesis that circRNA_09505 can function as a miR-6089 sponge and regulate inflammation via miR-6089/AKT1/NF-κB axis in CIA mice.

Asunto(s)

Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Inflamación/sangre , ARN Circular/sangre , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/patología , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/patología , Proliferación Celular/fisiología , Colágeno/farmacología , Leucocitos Mononucleares/metabolismo , Macrófagos/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

Accumulating data have implicated that long noncoding RNA (lncRNA) plays an important role in osteoarthritis (OA), which may function as a competitive endogenous RNA (ceRNA) of microRNAs (miRNAs). lncRNA IGHCγ1 has been demonstrated to regulate inflammation and autoimmunity. Nonetheless, the altering effect of IGHCγ1 in OA remains unclear. This study is aimed at investigating the mechanism and function of lncRNA IGHCγ1 in OA. CCK-8, EdU, and transwell assays were used to estimate macrophage proliferation and migration. Fluorescence in situ hybridization (FISH) was performed to estimate the local expression of lncRNA IGHCγ1 in macrophages. Luciferase reporter assay was adopted to validate the ceRNA role of IGHCγ1 as miRNA sponge. lncRNA IGHCγ1 was primarily localized in macrophage cytoplasm and upregulated in OA. miR-6891-3p inhibited macrophage proliferation, migration, and inflammatory response by targeting TLR4, while lncRNA IGHCγ1 promoted TLR4 expression by functioning as a ceRNA for miR-6891-3p through the NF-κB signal in macrophages. This study strongly supports that lncRNA IGHCγ1 regulates inflammatory response via regulating the miR-6891-3p/TLR4/NF-κB axis in macrophages.

Asunto(s)

Macrófagos/metabolismo , MicroARNs/metabolismo , Osteoartritis/metabolismo , ARN Largo no Codificante/metabolismo , Receptor Toll-Like 4/metabolismo , Adulto , Anciano , Apoptosis/efectos de los fármacos , Autoinmunidad , Estudios de Casos y Controles , Movimiento Celular , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Inflamación , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Transducción de Señal/genética

RESUMEN

BACKGROUND: Although the genome of Chinese white pear ('Dangshansuli') has been released, little is known about the functions, evolutionary history and expression patterns of NAC families in this species to date. RESULTS: In this study, we identified a total of 183 NAC transcription factors (TFs) in the pear genome, among which 146 pear NAC (PbNAC) members were mapped onto 16 chromosomes, and 37 PbNAC genes were located on scaffold contigs. No PbNAC genes were mapped to chromosome 2. Based on gene structure, protein motif analysis, and topology of the phylogenetic tree, the pear PbNAC family was classified into 33 groups. By comparing and analyzing the unique NAC subgroups in Rosaceae, we identified 19 NAC subgroups specific to pear. We also found that whole-genome duplication (WGD)/segmental duplication played critical roles in the expansion of the NAC family in pear, such as the 83 PbNAC duplicated gene pairs dated back to the two WGD events. Further, we found that purifying selection was the primary force driving the evolution of PbNAC family genes. Next, we used transcriptomic data to study responses to drought and cold stresses in pear, and we found that genes in groups C2f, C72b, and C100a were related to drought and cold stress response. CONCLUSIONS: Through the phylogenetic, evolutionary, and expression analyses of the NAC gene family in Chinese white pear, we indentified 11 PbNAC TFs associated with abiotic stress in pear.

Asunto(s)

Regulación de la Expresión Génica de las Plantas , Genoma de Planta , Estudio de Asociación del Genoma Completo , Pyrus/genética , Estrés Fisiológico/genética , Factores de Transcripción/metabolismo , Frío , Sequías , Exones/genética , Duplicación de Gen , Genes de Plantas , Intrones/genética , Familia de Multigenes , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Dominios Proteicos , Sintenía/genética , Factores de Transcripción/química

RESUMEN

WRKY comprises a large family of transcription factors in plants, but most WRKY members are still poorly understood. In this study, we report the identification and functional characterization of PbrWRKY53 isolated from Pyrus betulaefolia. PbrWRKY53 was greatly up-regulated by drought and abscisic acid, but slightly induced by salt and cold. Subcellar localization analyses showed that PbrWRKY53 was located in the nucleus. Ectopic expression of PbrWRKY53 in tobacco and Pyrus ussuriensis conferred enhanced tolerance to drought stress. The transgenic plants exhibited better water status, less reactive oxygen species generation and higher levels of antioxidant enzyme activities and metabolites than the wild type. In addition, overexpression of PbrWRKY53 in transgenic tobacco resulted in enhanced expression level of PbrNCED1, and led to the increase in larger amount of vitamin C accumulation in comparison to WT. Knock-down of PbrWRKY53 in P. ussuriensis down-regulated PbrNCED1 abundance, accompanied by compromised drought tolerance. Yeast one-hybrid assay, EMSA and transient expression analysis demonstrated that PbrWRKY53 could bind to the W-box element in the promoter region of PbrNCED1. Taken together, these results demonstrated that PbrWRKY53 plays a positive role in drought tolerance, which might be, at least in part, promoting production of vitamin C via regulating PbrNCED1 expression.

Asunto(s)

Sequías , Proteínas de Plantas/fisiología , Pyrus/fisiología , Estrés Fisiológico , Factores de Transcripción/fisiología , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente , Pyrus/genética , Nicotiana , Factores de Transcripción/genética

RESUMEN

To retrospectively analyze the efficacy and safety of febuxostat on gout patients with low serum uric acid level. A study was conducted in Nanjing First Hospital from October 2015 to September 2016. Thirty nine acute gouty arthritis patients from the emergency and outpatient department were included. Patients met the 2015 Gout Classification Criteria revised by American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) and had urate deposition around the joints detected by dual-energy computerized tomography (DECT). Patients whose serum uric acid (SUA) were between 5.0 and 7.0 mg/dl (300-420 µmol/l) received febuxostat treatment to maintain the SUA level between 3.0 and 5.0 mg/dl for 1 year. Efficacy and safety of febuxostat were observed during the process. Three of 39 subjects were excluded because of adverse events (AEs) after receiving an initial febuxostat treatment for 2 months. Thirty six subjects were enrolled. The mean SUA level was reduced significantly from 6.51 ± 0.28 mg/dl at baseline to 4.24 ± 0.38 mg/dl and SUA of all subjects decreased by 34.8% compared with baseline. After 1-year treatment, the volume of tophus was reduced approximately 62.8%. Serum creatinine decreased stepwise in 8 gout patients with chronic kidney diseases from 162.5 ± 9.2 µmol/l to 131.4 ± 11.0 µmol/l. Two months after initiation of treatment, the number of gout flares began to markedly decrease and almost did not occur after 1 year. After the 1-year treatment of febuxostat, the average SUA level declined significantly, and the renal function improved gradually. There was nearly complete abolition of gout flares by the end of the study. Tophi resolved markedly compared with baseline as assessed by DECT. Furthermore, only a few people experienced adverse events. Febuxostat has a notable effect for gout patients in the lower SUA level range.

Asunto(s)

Artritis Gotosa/tratamiento farmacológico , Febuxostat/uso terapéutico , Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Ácido Úrico/sangre , Anciano , Creatinina/sangre , Febuxostat/efectos adversos , Femenino , Gota/sangre , Supresores de la Gota/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento

RESUMEN

Systemic lupus erythematosus (SLE) is a typical autoimmune disease. Lymphotoxin ß receptor (LTßR) signaling plays an important role in autoimmune inflammations. LTßR-Ig fusion protein, LTßR blocking agent, has been used to treat SLE, while its mechanism remains to be fully elucidated. In this study, to investigate the expression of LTßR in the T cells of SLE patients and its roles in the pathogenesis of SLE, we isolated the peripheral blood T cells of SLE patients and normal controls to detect expression of LTßR by flow cytometry and RNA assay. T cells were also stimulated with LIGHT, a ligand of LTßR, and then detected for their LTßR expressions and apoptosis by flow cytometry. Also, their expressions of inflammatory factors and receptors were determined by RNA assay. The results showed that LTßR positive cells were 22.75%±6.98% in CD3+ cells of SLE patients, while there were almost no LTßR positive cells in CD3+ cells of normal persons. Moreover, LTßR expression was remarkably higher in CD3, CD4 and CD8 positive T cells of active SLE patients than non/low active patients (all P<0.05), and positively correlated with increased Ig level, decreased complement level and renal damage. Moreover, the stimulation of SLE T cells with LIGHT promoted higher expression of LTßR, IL-23R and IL-17A, and apoptosis of T cells. In conclusion, we demonstrated a high expression of LTßR in the T cells of SLE patients which may be associated with pathogenesis of SLE.

RESUMEN

Impaired apoptosis of fibroblast-like synoviocytes (FLSs) causes synovial hyperplasia, facilitating destruction of cartilage and bone in rheumatoid arthritis (RA). Tumor necrosis factor (TNF)-α, a dominant inflammatory mediator in RA pathogenesis, promotes progression of RA symptoms. Prevalence of 1, 25-dihydroxy-vitamin D3 (hereafter termed VD) deficiency is 30-63% in patients with RA. Whether VD leads to apoptosis or enhances TNF-α-mediated apoptosis in FLSs to ameliorate RA is unclear. To determine this, 10-week-old CYP27B1-deficient (CYP27B1-/-) mice with collagen-induced arthritis (CIA) were intraperitoneally treated with 1 µg/kg VD every other day for 9 weeks. RA phenotypes were compared between vehicle-treated CYP27B1-/- and wild-type CIA mice. Human rheumatoid FLS-MH7A cells were treated with Dulbecco's modified Eagle's medium (DMEM) without fetal bovine serum (FBS) for 24 h, then with different concentrations of VD and TNF-α, human vitamin D receptor (VDR) siRNA or the p53 pro-apoptotic inhibitor pifithrin-α. Apoptosis and p53 pro-apoptotic signaling were analyzed. The 19-week-old vehicle-treated CYP27B1-/- CIA mice had increased cumulative arthritis scores and levels of serous rheumatoid factors and C-reactive protein. They had exacerbated articular cartilage and bone destruction, joint space narrowing, joint stiffness, deformity and dysfunction, synovitis and TNF-α secretion, FLS hyperplasia with increased proliferation and decreased apoptosis compared to CIA mice. These RA phenotypes that were aggravated in CIA mice by CYP27B1 deficiency were largely rescued by VD treatment. In vitro, VD with TNF-α treatment upregulated p53 acetylation-mediated apoptosis in MH7A cells by promoting Sirt1 translocation from the nucleus to the cytoplasm. These findings indicated that VD with TNF-α protected against RA by promoting apoptosis of FLSs. The results indicated that clinical administration of VD could be a specific therapy to promote FLS apoptosis and prevent RA progression.

Asunto(s)

Apoptosis/efectos de los fármacos , Artritis Reumatoide/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Sirtuina 1/metabolismo , Sinoviocitos/metabolismo , Factor de Necrosis Tumoral alfa/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Acetilación/efectos de los fármacos , Animales , Artritis Experimental/patología , Artritis Reumatoide/patología , Huesos/efectos de los fármacos , Huesos/patología , Cartílago/efectos de los fármacos , Cartílago/patología , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Inflamación/patología , Ratones Endogámicos BALB C , Sustancias Protectoras/farmacología , Transporte de Proteínas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Membrana Sinovial/patología , Sinoviocitos/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Vitamina D/sangre , Vitamina D/uso terapéutico

RESUMEN

AIM: γδ T cells exhibit important functions in the pathogenesis of rheumatoid arthritis (RA). In recent years, numerous studies harnessed the γδ T cell-activating capacity of aminobiphosphonates for the treatment of malignant tumors. As (99) Tc-methylene diphosphonate ((99) Tc-MDP) has long been widely used for the treatment of RA in China with good efficacy, we are interested in whether this drug exerts its therapeutic effect on RA by modulating peripheral γδ T cells of RA patients. OBJECTIVES: To investigate the effect of (99) Tc-MDP on the frequency of γδ T cells and CD4(+) CD25(+) Foxp3(+) Tregs in the peripheral blood of patients with active RA. METHODS: Nineteen patients with active RA were treated with (99) Tc-MDP intravenously at a dose of 20 µg/day consecutively for 10-14 days. Before and after treatment, the main clinical and laboratory parameters for each patient were evaluated. The frequency of CD3(+) γδ(+) T cells and CD4(+) CD25(+) Foxp3(+) Tregs was detected by flow cytometry. Serum levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-ß were measured with enzyme-linked immunosorbent assay. RESULTS: After intravenous (99) Tc-MDP therapy, the frequency of peripheral CD3(+) γδ(+) T cells and CD4(+) CD25(+) Foxp3(+) Tregs were significantly elevated, paralleled with decreased serum levels of TNF-α and IL-6 and increased level of serum TGF-ß. The elevation of peripheral CD3(+) γδ(+) T cells was positively correlated with increased serum TGF-ß and decreased disease activity. CONCLUSION: (99) Tc-MDP may improve the activity of RA through upregulating the frequency of peripheral γδ T cells and CD4(+) CD25(+) Foxp3(+) Tregs as well as affecting the serum cytokine environment by increasing TGF-ß and decreasing TNF-α and IL-6.

Asunto(s)

Artritis Reumatoide/radioterapia , Factores de Transcripción Forkhead/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Radiofármacos/uso terapéutico , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Linfocitos T Reguladores/efectos de la radiación , Medronato de Tecnecio Tc 99m/uso terapéutico , Administración Intravenosa , Anciano , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Citocinas/sangre , Citocinas/inmunología , Esquema de Medicación , Femenino , Factores de Transcripción Forkhead/sangre , Humanos , Subunidad alfa del Receptor de Interleucina-2/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Radiofármacos/administración & dosificación , Radiofármacos/efectos adversos , Receptores de Antígenos de Linfocitos T gamma-delta/sangre , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Medronato de Tecnecio Tc 99m/administración & dosificación , Medronato de Tecnecio Tc 99m/efectos adversos , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

BACKGROUND/AIMS: Interleukin-29 (IL-29), a critical member of type III interferons (IFNs) family, has been implicated in protecting against viral infection and modulating autoimmune inflammation. Toll-like receptor 4 (TLR4) plays a crucial role in synovial inflammation and may contribute to the pathogenesis of rheumatology arthritis (RA). However, little is known about the modifying effect of IL-29 on TLR4-mediated inflammation in RA. We aim to investigate the potential association between IL-29 and TLR4 in RA. METHODS: Peripheral blood mononuclear cells (PBMCs) and serum from 77 patients with RA and 70 controls were collected to determine levels of IL-29 and TLR4 mRNA by real-time polymerase chain reaction (PCR). Levels of IL-29 and TLR4 in synovial tissues and fluid from 25 RA patients and 24 controls were detected by enzyme-linked immunosorbent assay (ELISA) or western blot assay, respectively. RAW264.7 cells were stimulated by lipopolysaccharide (LPS) and/or IL-29. The production of inflammatory cytokines including IL-6, IL-8 as well as TNF-α and the activation of nuclear factor-κB (NF-κB) signaling were determined. RESULTS: In comparison with controls, increased IL-29 was observed in PBMCs, synovial tissue, serum and synovial fluid of patients with RA. Besides, TLR4 was significantly elevated in PBMCs and synovium of RA patients. Moreover, IL-29 was positively associated with TLR4 in RA, suggested by Pearson's correlation analysis. When RAW264.7 cells were stimulated by LPS with or without IL-29 in vitro, IL-29 could enhance LPS-mediated TLR4 expression and the production of IL-6, IL-8 and TNF-α in RAW264.7 cells via the activation of NF-κB signaling. CONCLUSION: The present study suggests, for the first time, that IL-29 can aggravate LPS/TLR4-mediated inflammation in RA depending on NF-κB signaling activation.

Asunto(s)

Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Interleucinas/metabolismo , Lipopolisacáridos/farmacología , Receptor Toll-Like 4/metabolismo , Animales , Línea Celular , Femenino , Humanos , Interferones , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Persona de Mediana Edad , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Líquido Sinovial/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis (EAE) in rats. In this study, we further investigated the mechanisms of sinomenine treatment in EAE rats. In EAE rats, treatment with sinomenine exerted an anti-inducible NO synthase (anti-iNOS) effect, which is related to the reductions of Th1 cytokine interferon-γ (IFN-γ) and its transcription factor, T-bet, in spinal cords. Moreover, sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat interleukin 12 reduced the expression of T-bet and IFN-γ in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, sinomenine had no direct inhibitory effect on iNOS produced by astrocytes cultured with IFN-γ and tumor necrosis factor α in vitro. In conclusion, the anti-iNOS effect of sinomenine on EAE is mediated via the suppression of T-bet /IFN-γ pathway.

RESUMEN

The therapeutic value of an antirheumatic alkaloid, sinomenine (SIN), was investigated in the acute experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). SIN is a bioactive alkaloid derived from the Chinese medicinal plant, Sinomenium acutum REHDER & E. H. WILSON (Family Menispermaceae). Chinese doctors have utilized this plant to treat rheumatic and arthritic diseases for over one thousand years. Experiments in which EAE-induced Lewis rats exhibit an acute monophasic episode of disease demonstrated that SIN is effective in preventing clinical signs of disease. The therapeutic effect on disease activity was observed at preonset administration times and at various doses tested. Consistent with disease activity in vivo, SIN-treated animals have reduced cellular infiltration within the spinal cord along with decreased TNF-alpha and IFN-gamma expression levels. SIN can significantly inhibit proliferation response of splenocytes induced by MBP(68-82). TNF-alpha and IFN-gamma, secreted by splenocytes induced by MBP(68-82) are inhibited by SIN by dose-dependence manner. The mRNA levels of CC chemokines, RANTES, MIP-1alpha and MCP-1, are inhibited in SIN-treated EAE rats. The data in this proof of concept study support the premise that SIN may be a promising new therapeutic intervention in MS.

Asunto(s)

Antiinflamatorios no Esteroideos/farmacología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Morfinanos/farmacología , Enfermedad Aguda , Animales , Acuaporinas/biosíntesis , Proliferación Celular/efectos de los fármacos , Quimiocina CCL5/metabolismo , Quimiocinas/biosíntesis , Citocinas/biosíntesis , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/patología , Proteínas del Ojo/biosíntesis , Femenino , Interferón gamma/biosíntesis , Interferón gamma/genética , Glicoproteínas de Membrana/biosíntesis , Ratas , Ratas Endogámicas Lew , Receptores CCR2 , Receptores de Quimiocina/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética