Recent advances in neutralizing the IL-6 pathway in arthritis

Malemud, Charles

doi:10.2147/oarrr.s6266

Cited by 23 publications

(2 citation statements)

References 145 publications

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“…This "epigenomic signature" of IFN-γ-primed macrophages is linked to the onset of inflammatory diseases (22,23). Activation of the JAK-STAT signaling pathway in IFN-γ-primed macrophages leads to the phosphorylation of both STAT1 and STAT3 (24)(25)(26)(27). The competition between STAT1 and STAT3 for binding to specific cis-regulatory elements can influence gene expression and the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Selective epigenetic regulation of IFN-γ signature genes by JAK inhibitor in inflammatory diseases

Kwon,

Park,

Kang

et al. 2024

Preprint

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This study addresses the molecular mechanisms behind JAK inhibitors (JAKi)' epigenetic regulation of IFN-γ-induced genes in macrophages, key players in controlling inflammation in chronic diseases such as rheumatoid arthritis (RA) and COVID-19. Utilizing transcriptomic and epigenomic approaches, we reveal that JAKi selectively regulate gene programs in IFN-γ-activated human macrophages. Our single-cell analysis identified high expression of IFN-γ signature genes in macrophages from RA and severe COVID-19 patients. JAKi suppressed some inflammatory genes, while a subset remained unresponsive to JAK-STAT inhibition. We discovered that JAKi selectively target IRF-STAT-dependent open chromatin regions, leaving AP-1-C/EBP-regulated genes with open chromatin unaffected. Some JAKi-insensitive genes could be inhibited by JNK inhibitors in IFN-γ-primed macrophages. Our analysis also identified JAKi-sensitive and -insensitive IFN-γ signature genes in RA patients resistant to MTX treatments and COVID-19 vaccinated donors, highlighting JAKi's therapeutic potential and risks. These findings uncover new JAKi responsiveness mechanisms through epigenomic changes in IFN-γ-primed macrophages, advancing our understanding of inflammation regulation in chronic diseases.

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Section: Introductionmentioning

confidence: 99%

Selective epigenetic regulation of IFN-γ signature genes by JAK inhibitor in inflammatory diseases

Kwon,

Park,

Kang

et al. 2024

Preprint

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“…In particular, IL6 neutralization is a recently developed therapeutic strategy for controlling RA. Neutralization of IL6 plays a critical role in both the initiation and perpetuation of immunologic dysfunction and inflammatory responses in RA via modulation of the IL6/IL6 receptor/gp130 pathway [20]. A novel role of IL6/IL6R/gp130 signaling in autoimmune arthritis has been reported.…”

Section: Introductionmentioning

confidence: 99%

A Synthetic Cell-Penetrating Heparin-Binding Peptide Derived from BMP4 with Anti-Inflammatory and Chondrogenic Functions for the Treatment of Arthritis

Choi

Lee

et al. 2020

IJMS

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We report dual therapeutic effects of a synthetic heparin-binding peptide (HBP) corresponding to residues 15–24 of the heparin binding site in BMP4 in a collagen-induced rheumatic arthritis model (CIA) for the first time. The cell penetrating capacity of HBP led to improved cartilage recovery and anti-inflammatory effects via down-regulation of the iNOS-IFNγ-IL6 signaling pathway in inflamed RAW264.7 cells. Both arthritis and paw swelling scores were significantly improved following HBP injection into CIA model mice. Anti-rheumatic effects were accelerated upon combined treatment with Enbrel® and HBP. Serum IFNγ and IL6 concentrations were markedly reduced following intraperitoneal HBP injection in CIA mice. The anti-rheumatic effects of HBP in mice were similar to those of Enbrel®. Furthermore, the combination of Enbrel® and HBP induced similar anti-rheumatic and anti-inflammatory effects as Enbrel®. We further investigated the effect of HBP on damaged chondrocytes in CIA mice. Regenerative capacity of HBP was confirmed based on increased expression of chondrocyte biomarker genes, including aggrecan, collagen type II and TNFα, in adult human knee chondrocytes. These findings collectively support the utility of our cell-permeable bifunctional HBP with anti-inflammatory and chondrogenic properties as a potential source of therapeutic agents for degenerative inflammatory diseases.

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Emerging therapies in the treatment of rheumatoid arthritis

Liu

Mehmet

2011

Drug Development Research

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Rheumatoid arthritis (RA) is an autoimmune disease with a significant morbidity defined by marked destruction and deformity of joints. It is characterized by autoantibody production, synovial inflammation, and erosion of the cartilage and bone. The current first‐line treatment for RA is methotrexate (MTX), an orally active disease‐modifying anti‐rheumatic drug (DMARD). Biologic DMARDs that target tumor necrosis factor (TNF) or other molecules have emerged as potent alternative therapies for patients with inadequate response to MTX therapy. Despite the huge success of MTX and/or biologics, there is still a significant unmet medical need in RA. Approximately one‐third of RA patients are nonresponsive to currently available therapies. With their critical roles in mediating multiple inflammatory pathways, small‐molecule tyrosine kinase (TK) inhibitors are gaining attention as candidates for oral RA drugs with positive outcomes for a number of late‐stage clinical trials of small‐molecule Jak (Tasocitinib) or Syk (fostamatinib) inhibitors. With the potential for attenuating multiple inflammatory pathways activated in RA, tasocitinib and fostamatinib may represent new and welcome additions to the RA therapeutic landscape. Drug Dev Res 72:805–816, 2011. © 2011 Wiley Periodicals, Inc.

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Recent advances in neutralizing the IL-6 pathway in arthritis

Cited by 23 publications

References 145 publications

Selective epigenetic regulation of IFN-γ signature genes by JAK inhibitor in inflammatory diseases

Selective epigenetic regulation of IFN-γ signature genes by JAK inhibitor in inflammatory diseases

A Synthetic Cell-Penetrating Heparin-Binding Peptide Derived from BMP4 with Anti-Inflammatory and Chondrogenic Functions for the Treatment of Arthritis

Emerging therapies in the treatment of rheumatoid arthritis

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