New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

Kato, Masaaki

doi:10.1080/25785826.2020.1751908

Cited by 63 publications

(39 citation statements)

References 63 publications

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“…While our results are open to interpretation, we hypothesize that testing a combinatorial use of IFNγ at a suboptimal dose with an engineered GBP-5 protein in preclinical models of RA may shed light on 2 synergistic approaches in controlling disease severity and progression. This is timely and clinically relevant given the fact that adverse events, such as opportunistic infections from JAK inhibitors, are partly due to their ability to inhibit IFNγ and its functions (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Synovial Inflammation and Tissue Destruction by Guanylate Binding Protein 5 in Synovial Fibroblasts From Patients With Rheumatoid Arthritis and Rats With Adjuvant‐Induced Arthritis

Haque

Singh

Ouseph

et al. 2021

Arthritis & Rheumatology

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Objective. Rheumatoid arthritis synovial fibroblasts (RASFs) are crucial mediators of synovial inflammation and joint destruction. However, their intrinsic immunoregulatory mechanisms under chronic inflammation remain unclear. Thus, the present study was undertaken to understand the role of a newly identified GTPase, guanylate binding protein 5 (GBP-5), in RA pathogenesis.Methods. The expression of GBP1-GBP7 transcripts was evaluated using quantitative reverse transcriptionpolymerase chain reaction in RA synovial tissue or synovial tissue unaffected by RA. Our investigation on transient small interfering RNA (siRNA) knockdown and lentiviral overexpression in human RASFs examined the regulatory role of GBP-5 on proinflammatory cytokine signaling pathways. Unbiased whole transcriptome RNA sequencing analysis was used to assess the impact of GBP-5 on RASF molecular functions. These findings were confirmed using a rat model of adjuvant-induced arthritis (AIA) in vivo.Results. Among different GBPs evaluated, GBP-5 was selectively up-regulated in RA synovial tissue (P < 0.05; n = 4) and in the joints of rats with AIA (P < 0.05; n = 6) and was significantly induced in human RASFs by interleukin-1β (IL-1β), tumor necrosis factor (TNF), and/or interferon-γ (IFNγ) (P < 0.05; n = 3). Bioinformatics analysis of RNA sequencing data identified cytokine-cytokine receptor signaling as a major function altered by GBP-5, with IL-6 signaling as a primary target. Knockdown of GBP-5 amplified IL-1β-induced IL-6, IL-8, and epithelial neutrophilactivating peptide 78/CXCL5 production by 44%, 54%, 45%, respectively, and matrix metalloproteinase 1 (MMP-1) production by several-fold-effects that reversed with exogenously delivered GBP-5. Lack of GBP-5 increased IFNγ-induced proliferation and migration of human RASFs. GBP-5 knockdown in vivo using intraarticular siRNA exacerbated disease onset, severity, synovitis, and bone destruction in rat AIA.Conclusion. Expressed by RASFs in response to cytokine stimulation, GBP-5 has potential to restore cellular homeostasis and blunt inflammation and tissue destruction in RA.

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Section: Discussionmentioning

confidence: 99%

Regulation of Synovial Inflammation and Tissue Destruction by Guanylate Binding Protein 5 in Synovial Fibroblasts From Patients With Rheumatoid Arthritis and Rats With Adjuvant‐Induced Arthritis

Haque

Singh

Ouseph

et al. 2021

Arthritis & Rheumatology

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“…The signaling of BTN2A has been proved to reduce the expression of various cytokines, including IL‐2 and IFN‐γ 39 . It was described that elevation of IL‐2 and IFN‐γ involved in pathogenesis of RA 40,41 . In this study, we found carriers of rs558555834 (−96A) or −1180A‐939C‐871 T‐336 T‐139 T‐96A and −1180 T‐939 T‐871C‐336 T‐139C‐96A haplotypes were significantly increased in RA patients, which might compromise CD209 signaling properties.…”

Section: Discussionmentioning

confidence: 99%

A novel CD209 polymorphism is associated with rheumatoid arthritis patients in Taiwan

Chan

Wang

Lin

et al. 2021

Clinical Laboratory Analysis

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Single nucleotide polymorphisms (SNPs) in the promoter region of CD209 (cluster of differentiation 209) may influence expression levels, and higher expression of CD209 on immune cells correlate with severity of cartilage destruction in patients with rheumatoid arthritis (RA). Due to the lack of a comprehensive study, this study aimed to investigate the CD209 promoter variants and haplotypes in a Taiwanese population and the association with RA development. Deoxyribonucleic acid (DNA) of peripheral blood mononuclear cells from 126 RA patients and 124 healthy controls was purified, and the CD209 gene promoter was amplified by polymerase chain reaction and analyzed by Sanger sequencing. Results showed that a novel variant −96C>A polymorphism in CD209 promoter was identified in the Taiwanese population, and the frequency was significantly higher in RA patients than in controls (11.51% vs. 2.42%, P < .0001). The odds ratio (OR) for the development of RA was 5.88 (95% CI 2.35–14.74, P < .0001). Other known variants were also evaluated; for instance, −1180 T/T (rs7359874) was increased in RA patients, and the OR for the development of RA was 3.26, 95% CI 0.85–12.52, P = .07). Besides, the haplotype frequencies were calculated; −1180A‐939C‐871 T‐336 T‐139 T‐96A and −1180 T‐939 T‐871C‐336 T‐139C‐96A were increased in RA patients (P = .004 and 0.05, respectively). In summary, CD209‐96A variant could be an important factor for the development of RA in the Taiwanese population.

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“…Rheumatoid arthritis (RA), an autoimmune disorder, was always accompanied by the activation of monocytes/ macrophage. Since synovial inflammation is a hallmark of RA, the understanding of synovial biology and pathophysiology may be the best way to approach the pathogenesis of RA which has not yet been fully elucidated [21]. Studies have found that excessive proliferation and inflammatory response and inactive apoptosis can aggravate RA injury, and the main injury mechanism is related to proliferation and apoptosis of synoviocytes, inflammatory reaction, etc.…”

Section: Discussionmentioning

confidence: 99%

Galuteolin suppresses proliferation and inflammation in TNF-α-induced RA-FLS cells by activating HMOX1 to regulate IKKβ/NF-κB pathway

et al. 2020

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Objective Galuteolin (Galu) is a substance extracted and purified from honeysuckle. The purpose of this study was to explore the effects of Galu on the TNF-α-induced RA-FLS cells (synoviocytes) and reveal its potential molecular mechanism from the perspectives of anti-apoptosis and anti-inflammation. Methods After TNF-α stimulation, cell proliferation of RA-FLS was assessed by CCK-8 assay. TUNEL staining was used to detect the apoptosis. Western blot was used to detect the expressions of Iκκβ, p-p65, p65, p-IκB, IκB, Cleaved-caspase3, Caspase-3, Bcl-2, and Bax. HO-1 were determined by RT-PCR. The contents of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MMP-1 were determined by ELISA. Results Galu significantly suppressed cell proliferation in a dose-dependent manner. Additionally, Galu obviously promotes cell apoptosis rate of RA-FLS cells and elevated the expression levels of HO-1, caspase-3, and Bax, while reducing the expression level of Bcl-2. Furthermore, Galu apparently inhibited the levels of Iκκβ, p-p65, and p-IκB. Moreover, Galu also significantly reduced the levels of pro-inflammatory factors IL-1β, IL-6, IL-8, and MMP-1 in RA-FLS cells. Conclusion Galuteolin exerts protective effects against TNF-α-induced RA-FLS cells by inhibiting apoptosis and inflammation, which can guide the clinical use of rheumatoid arthritis.

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New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

Cited by 63 publications

References 63 publications

Regulation of Synovial Inflammation and Tissue Destruction by Guanylate Binding Protein 5 in Synovial Fibroblasts From Patients With Rheumatoid Arthritis and Rats With Adjuvant‐Induced Arthritis

Regulation of Synovial Inflammation and Tissue Destruction by Guanylate Binding Protein 5 in Synovial Fibroblasts From Patients With Rheumatoid Arthritis and Rats With Adjuvant‐Induced Arthritis

A novel CD209 polymorphism is associated with rheumatoid arthritis patients in Taiwan

Galuteolin suppresses proliferation and inflammation in TNF-α-induced RA-FLS cells by activating HMOX1 to regulate IKKβ/NF-κB pathway

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