Signaling Pathway In Rheumatoid Arthritis Research Articles

MiR-143-3p regulates cell proliferation and apoptosis by targeting IGF1R and IGFBP5 and regulating the Ras/p38 MAPK signaling pathway in rheumatoid arthritis.

It has been demonstrated that the deregulation of microRNAs (miRNAs) affects the development of rheumatoid arthritis (RA). The primary objective of the current study was to determine the role of miR-143-3p in the progression of RA. The expression of miR-143-3p in synovium taken from patients with RA was assessed by reverse transcription-quantitative polymerase chain reaction. The expression of miR-143-3p was higher in synovium tissues of RA than that of osteoarthritis (OA). The decreased expression of miR-143-3p suppressed cell proliferation and promoted apoptosis in vitro. In addition, inhibition of miR-143-3p decreased levels of inflammatory cytokines, as determined by an enzyme-linked immunosorbent assay. IGF1R and IGFBP5 were found to be the target genes of miR-143-3p, and it was demonstrated that miR-143-3p regulated the proliferation and apoptosis of MH7A cells by targeting IGF1R and IGFBP5. Furthermore, TNF-α treatment stimulated the Ras/p38 mitogen activated protein kinase (MAPK) signaling pathway, whereas miR-143-3p inhibition suppressed it. The results of the current study indicate that miR-143-3p may regulate cell proliferation and apoptosis by targeting IGF1R and IGFBP5 expression and regulating the Ras/p38 MAPK signaling pathways. Therefore, miR-143-3p may be a novel therapeutic target in RA.

Sinomenine inhibits the inflammatory responses of human fibroblast-like synoviocytes via the TLR4/MyD88/NF-κB signaling pathway in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder mainly characterized by inflammation of the synovial tissue that can lead to destruction of bone and cartilage. Sinomenine is an alkaloid extracted from the stem of the Chinese medicinal plant Sinomenium acutum. It has been reported that sinomenine has immunosuppressive and anti-inflammatory properties. However, the molecular mechanism underlying the effect of sinominine on IL-1β-induced human RA fibroblast-like synoviocytes (RAFLS) is poorly understood. Therefore, in this study, we investigated the effect of sinomenine on the expression of inflammatory cytokines in IL-1β-treated human RAFLS in vitro and the underlying mechanism. RAFLS viability was evaluated using the MTS assay after sinomenine treatment. The levels of inflammatory cytokines were measured with ELISA, RT-PCR and western blot, respectively. The levels of TLR4 and its downstream signaling targets were determined by western blot analysis. We found that sinomenine suppressed not only NO and PGE2 production but also iNOS and COX-2 expression in IL-1β-induced RAFLS. It also inhibited the expression of TNF-α and IL-6 in IL-1β-stimulated RAFLS. Furthermore, sinomenine prevented IL-1β-induced TLR4, MyD88 and p-NF-κB p65 expression. Taken together, these results demonstrated that sinomenine prevented IL-1β-induced inflammation in human RAFLS at least in part by inhibiting the TLR4/MyD88/NF-κB signaling pathway, suggesting that sinomenine could be a potential agent in the treatment of RA.

CD4 T-cell transcriptome analysis reveals aberrant regulation of STAT3 and Wnt signaling pathways in rheumatoid arthritis: evidence from a case-control study.

IntroductionRheumatoid arthritis (RA) is a systemic autoimmune disease in which T cells play a pivotal role in the pathogenesis. Knowledge in terms of the CD4 T-cell transcriptome in RA is limited. The aim of this study was to examine the whole-genome transcription profile of CD4 T cells in RA by comparing patients with RA to healthy controls.MethodsPeripheral blood CD4 T cells were isolated from 53 RA patients with active disease and 45 healthy individuals; 13 cases and 10 controls were enrolled in microarray analysis. The remaining 40 cases and 35 controls were recruited as an independent cohort for the validation study. Bioinformatics was performed on Gene Ontology (GO), gene-gene interaction networks, and pathway analysis. The gene modules, by combining the results from GO, gene networks, and pathway analysis, were selected for further validation.ResultsThe CD4 T cells showed 1,496 differentially expressed (DE) genes in RA patients relative to healthy individuals. GO analysis revealed that the DE genes were enriched in immune response, T-cell response, apoptosis process, and Wnt receptor signaling. Pathway analysis also identified that ‘Wnt signaling pathway’ was differentially regulated between two groups (P = 2.78 × 10−10). By gene-gene network analysis, we found that the DE genes were enriched in T-cell receptor (TCR), JAK-STAT signaling, and Wnt signaling pathway. By gene module analysis, we found that a number of DE genes overlapped in the three different analyses. In total, 23 genes were selected for further validation, and nine genes were confirmed. Of these, four genes (SOCS3, CBL, IFNAR1, and PIK3CA) were involved in STAT3 (signal transducer and activator of transcription 3) signaling, and three genes (CBL, KLF9, and CSNK2A1) were involved in the Wnt signaling pathway. Additionally, several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) were confirmed.ConclusionsWe report here the first case–control study of the CD4 T-cell transcriptome profile in RA. Our data provide evidence that CD4 T cells from patients with RA have abnormal functional networks in STAT3 signaling and Wnt signaling. Our results also suggest that the aberrant expression of several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) may be potential pathogenic factors for RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0590-9) contains supplementary material, which is available to authorized users.

Role of NLRP3 and NLRP1 inflammasomes signaling pathways in pathogenesis of rheumatoid arthritis

ObjectivesTo investigate the role of NLRP3 and NLRP1 inflammasomes signaling pathways in rheumatoid arthritis (RA). MethodsA total of 36 patients with RA were selected, peripheral blood mononuclear cell (PBMC) and granulocyte were separated from venous blood. RT-qPCR method was used to detect the expression level and diversity of NLRP3 and NLRP1 in PBMC and granulocyte mRNA in patients with RA, and detect the mRNA expression of downstream factor IL-1α. The correlation between RA and the expression of NLRP3 and NLRP1 was analyzed. Normal 30 cases were set as control group. ResultsExpression levels of NLRP1, and caspase-1 mRNA in PBMC of RA group were significantly lower than those of control group (P<0.05), while there was no significant difference in expression levels of NLRP3, ASC, IL-1α mRNA between these two groups (P>0.05); NLRP3, caspase-1, and ASC mRNA expression in granulocyte of RA patients were significantly lower than those in control group (P<0.05). There was no correlation between rheumatoid factor and expression levels of NLRP3, ASC, caspase-1 mRNA in RA group (P>0.05); NLRP1, IL-1α mRNA expression level had a negative correlation with anti-rheumatoid factor antibody (P=0.033 2, 0.034 0). ConclusionsNLRP3 and NLRP1 inflammasomes signaling pathways are involved in RA inflammatory reaction process as protective factors, and play an important role in RA inflammatory mechanisms.

Anti-inflammatory activities of Chinese herbal medicine sinomenine and Liang Miao San on tumor necrosis factor-α-activated human fibroblast-like synoviocytes in rheumatoid arthritis

Sinomenine, an alkaloid isolated from the root of Sinomenium acutum, has been used to alleviate the symptoms of rheumatic diseases. Liang Miao San (LMS), composed of the herbs Rhizoma Atractylodis (Cangzhu) and Cotex Phellodendri (Huangbai), is another traditional Chinese medicine formula for rheumatoid arthritis (RA) treatment. Although numerous studies have demonstrated the potential anti-inflammatory activities of sinomenine and LMS, the underlying intracellular mechanisms regulating the anti-inflammatory activities of sinomenine and LMS on human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects have not been elucidated. We investigated the in vitro anti-inflammatory activity of sinomenine and LMS on inflammatory cytokine tumor necrosis factor (TNF)-α-mediated activation of human normal and RA-FLS. The underlying intracellular signaling molecules were analyzed quantitatively using flow cytometry. Sinomenine was found to significantly inhibit TNF-α induced cell surface expression of vascular cell adhesion molecule (VCAM)-1 and release of inflammatory cytokine and chemokine IL-6, CCL2 and CXCL8 from both normal and RA-FLS (all p<0.05). Moreover, the suppression of sinomenine on TNF-α induced VCAM-1 expression and IL-6 release of RA-FLS was significantly higher than that of normal FLS (p<0.05). LMS significantly inhibited TNF-α-induced inflammatory chemokines CXCL10 and CCL5 release from both normal and RA-FLS, with significantly higher suppression on CXCL10 secretion in RA-FLS than that of normal FLS (all p<0.05). Further investigations showed that sinomenine and LMS could significantly suppress TNF-α-induced phosphorylation of inhibitor κBα and extracellular signal-regulated protein kinase, the central signaling molecules mediating TNF-α-induced VCAM-1 expression and chemokine production. Our results therefore provide a new insight into the differential anti-inflammatory activities of sinomenine and LMS through the suppression of TNF-α-activated FLS by modulating distinct intracellular signaling pathways in RA.

Gene discovery in rheumatoid arthritis highlights the CD40/NF‐ĸB signaling pathway in disease pathogenesis

During the past several years, substantial progress has been made in the identification of genetic variants that predispose to rheumatoid arthritis (RA) and other autoimmune disorders. Progress in this area has been facilitated by the availability of new technology that allows for a much more comprehensive screen of the genome than was possible before, in conjunction with large samples of RA patients with well-characterized disease. Recent RA genetic studies have identified genes with important functions related to intracellular signaling mechanisms, transcription factors, cytokines, membrane receptors, costimulatory molecules, and enzymes. In particular, recent discoveries highlight the importance of the CD40/NF-kappaB signaling pathway in RA, based on genetic association with several genes relevant to this pathway, including CD40, TRAF1, TNFAIP3, and REL. Progress in the identification of genes that contribute to RA is proceeding at a very rapid pace. These genetic discoveries shed light on underlying disease mechanisms in RA and provide targets for the development of novel diagnostic and therapeutic tools for future use in this chronic inflammatory disorder.

The roles of the classical and alternative nuclear factor-kappaB pathways: potential implications for autoimmunity and rheumatoid arthritis

Nuclear factor-κB (NF-κB) is an inducible transcription factor controlled by two principal signaling cascades, each activated by a set of signal ligands: the classical/canonical NF-κB activation pathway and the alternative/noncanonical pathway. The former pathway proceeds via phosphorylation and degradation of inhibitor of NF-κB (IκB) and leads most commonly to activation of the heterodimer RelA/NF-κB1(p50). The latter pathway proceeds via phosphorylation and proteolytic processing of NF-κB2 (p100) and leads to activation, most commonly, of the heterodimer RelB/NF-κB2 (p52). Both pathways play critical roles at multiple levels of the immune system in both health and disease, including the autoimmune inflammatory response. These roles include cell cycle progression, cell survival, adhesion, and inhibition of apoptosis. NF-κB is constitutively activated in many autoimmune diseases, including diabetes type 1, systemic lupus erythematosus, and rheumatoid arthritis (RA). In this review we survey recent developments in the involvement of the classical and alternative pathways of NF-κB activation in autoimmunity, focusing particularly on RA. We discuss the involvement of NF-κB in self-reactive T and B lymphocyte development, survival and proliferation, and the maintenance of chronic inflammation due to cytokines such as tumor necrosis factor-α, IL-1, IL-6, and IL-8. We discuss the roles played by IL-17 and T-helper-17 cells in the inflammatory process; in the activation, maturation, and proliferation of RA fibroblast-like synovial cells; and differentiation and activation of osteoclast bone-resorbing activity. The prospects of therapeutic intervention to block activation of the NF-κB signaling pathways in RA are also discussed.