The Activity of JAK/STAT and NF-κB in Patients with Rheumatoid Arthritis

Świerkot, Jerzy; Nowak, Beata; Czarny, Anna; Zaczyńska, Ewa; Sokolik, Renata; Madej, Marta; Korman, Lucyna; Sebastian, Agata; Wojtala, Patryk; Lubiński, Łukasz; Wiland, Piotr

doi:10.17219/acem/61034

Cited by 34 publications

(13 citation statements)

References 22 publications

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“…Several works have established that nuclear factor NF-κB coordinates expression of inflammatory mediators and enzymes involved in the inflammatory response, including COX-2 41,42 . Furthermore, activation of this nuclear factor in the synovial membrane cells of patients with rheumatoid arthritis 43,44 and expression of NF-κB www.nature.com/scientificreports www.nature.com/scientificreports/ p50 and p65 subunits in FLSs under inflammatory stimulus have been reported 45,46 . Our findings that TPCK and SN50, the inhibitors of IK-B phosphorylation and NF-κB translocation and activation, respectively, prevented BaP1-induced expression of COX-2 indicate that activation of NF-κB is a key mechanism by which this metalloprotease triggers COX-2 gene and protein expression and PGE 2 synthesis in FLSs.…”

Section: Discussionmentioning

confidence: 99%

A representative metalloprotease induces PGE2 synthesis in fibroblast-like synoviocytes via the NF-κB/COX-2 pathway with amplification by IL-1β and the EP4 receptor

Viana

Leiguez

Gutiérrez

et al. 2020

Sci Rep

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Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints. This study showed that the snake venom metalloprotease (SVMP) BaP1 activates FLSs to produce PGE 2 by a mechanism dependent on COX-2, mPGES-1 and iPLA 2 s. BaP1 also induces IL-1β release, which up-regulates the production of PGE 2 at a late stage of the stimulation. Expression of COX-2 and mPGES-1 are induced by BaP1 via activation of NF-κB pathway. While NF-κB p50 and p65 subunits are involved in up-regulation of COX-2 expression, only p65 is involved in BaP1induced mPGES-1 expression. In addition, BaP1 up-regulates EP4 receptor expression. Engagement of this receptor by PGE 2 triggers a positive feedback loop for its production by up-regulating expression of key components of the PGE 2 biosynthetic cascade (COX-2, mPGES-1 and the EP4 receptor), thus contributing to amplification of BaP1-induced effects in FLSs. These data highlight the importance of FLS as a target for metalloproteases in joint inflammation and provide new insights into the roles of MMPs in inflammatory joint diseases. Moreover, our results may give insights into the importance of the catalytic domain, of MMPs for the inflammatory activity of these enzymes.

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Section: Discussionmentioning

confidence: 99%

A representative metalloprotease induces PGE2 synthesis in fibroblast-like synoviocytes via the NF-κB/COX-2 pathway with amplification by IL-1β and the EP4 receptor

Viana

Leiguez

Gutiérrez

et al. 2020

Sci Rep

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“…The pathophysiology of rheumatoid arthritis (RA) characteristically involves several deregulated cellular events that are responsible for the altered innate and adaptive immune responses which significantly impact the structural alterations observed in articular cartilage and subchondral bone in this disease [49,50]. Swierkot et al [51] indicated that the receptor activator of nuclear factor-κB ligand (RANKL) expression, which in RA contributes to the elevated level of osteoclast differentiation, is regulated by the IL-6/soluble IL-6 receptor, the JAK2/STAT3/SOCS-3 pathway. They also showed that the calcineurin inhibitor tacrolimus inhibited RANKL expression in RA-fibroblast-like synoviocytes by suppressing STAT3.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis

Nozaki

Sakai

et al. 2019

Cells

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Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.Cells 2020, 9, 11 2 of 18 occurring IL-18 binding protein (IL-18BP) or a systemic neutralization by specific antibodies results in the amelioration of CIA, associated with reduced inflammation and cartilage erosion [6][7][8].The inhibition of cytokine signaling by the suppressors of cytokine signaling (SOCS) family constitutes a major negative feedback mechanism to prevent runaway inflammation. The transcription of SOCS proteins is rapidly upregulated in cells stimulated with cytokines. The SOCS then reduce the impact of cytokines by interacting with Janus kinases (JAKs) and by other mechanisms [9]. The roles of SOCS1 and −3 are underscored by the higher levels of the proinflammatory p38α and p38β mitogen-activated protein kinases (MAPKs) observed in IL-18Rα-deficient mouse embryonic fibroblasts (MEFs) compared to wild-type (WT) and IL-18-deficient MEFs. Since both SOCS1 [10][11][12] and SOCS3 [13,14] interfere with the IL-1/TLR-MAPK/nuclear factor-kappa (NF-κ)B pathway signaling, the increase in activity of these kinases in IL-18Rα-deficient cells may be due to a lesser degree of inhibition resulting from the reduced levels of both of these SOCS family members.In the present study, we confirmed that IL-18Rα was aberrantly expressed in the lymph nodes (LN) and splenocytes of mice with lipopolysaccharide (LPS)-induced arthritis. We hypothesized that if arthritis becomes hyper-responsive to LPS, which is a component of Gram-negative bacteria, this hyper-responsiveness may increase the levels of circulating inflammatory cytokines such as TNF, interferon-gamma (IFN-γ), and IL-6 and result in the blocking ...

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“…Currently, NF-κB has attracted more and more attention as a potential therapeutic target in the management of RA [78][79][80]. Modern pharmacological studies have proved that natural products can induce FLS apoptosis to prevent synovial hyperplasia via regulation of NF-κB pathway.…”

Section: Nf-κb Mediated Apoptotic Pathwaysmentioning

confidence: 99%

Apoptosis Induction of Fibroblast-Like Synoviocytes Is an Important Molecular-Mechanism for Herbal Medicine along with its Active Components in Treating Rheumatoid Arthritis

et al. 2019

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Rheumatoid arthritis (RA) is a known chronic autoimmune disease can cause joint deformity and even loss of joint function. Fibroblast-like synoviocytes (FLS), one of the main cell types in synovial tissues of RA patients, are key effector cells in the development of RA and are considered as promising therapeutic targets for treating RA. Herbal medicines are precious resources for finding novel agents for treating various diseases including RA. It is reported that induction of apoptosis in FLS is an important mechanism for the herbal medicines to treat RA. Consequently, this paper reviewed the current available references on pro-apoptotic effects of herbal medicines on FLS and summarized the related possible signal pathways. Taken together, the main related signal pathways are concluded as death receptors mediated apoptotic pathway, mitochondrial dependent apoptotic pathway, NF-κB mediated apoptotic pathways, mitogen-activated protein kinase (MAPK) mediated apoptotic pathway, endoplasmic reticulum stress (ERS) mediated apoptotic pathway, PI3K-Akt mediated apoptotic pathway, and other reported pathways such as janus kinase/signal transducers and activators of transcription (JAK-STAT) signal pathway. Understanding the apoptosis induction pathways in FLS of these herbal medicines will not only help clear molecular mechanisms of herbal medicines for treating RA but also be beneficial for finding novel candidate therapeutic drugs from natural herbal medicines. Thus, we expect the present review will highlight the importance of herbal medicines and its components for treating RA via induction of apoptosis in FLS, and provide some directions for the future development of these mentioned herbal medicines as anti-RA drugs in clinical.

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The Activity of JAK/STAT and NF-κB in Patients with Rheumatoid Arthritis

Cited by 34 publications

References 22 publications

A representative metalloprotease induces PGE2 synthesis in fibroblast-like synoviocytes via the NF-κB/COX-2 pathway with amplification by IL-1β and the EP4 receptor

A representative metalloprotease induces PGE2 synthesis in fibroblast-like synoviocytes via the NF-κB/COX-2 pathway with amplification by IL-1β and the EP4 receptor

Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis

Apoptosis Induction of Fibroblast-Like Synoviocytes Is an Important Molecular-Mechanism for Herbal Medicine along with its Active Components in Treating Rheumatoid Arthritis

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