Targeting Interleukin-6 Signaling in Clinic

Kang, Sujin; Tanaka, Toshio; Narazaki, Masashi; Kishimoto, Tadamitsu

doi:10.1016/j.immuni.2019.03.026

Cited by 667 publications

(604 citation statements)

References 150 publications

(139 reference statements)

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“…IL-6 has prominent proinflammatory properties (see the figure). IL-6 can signal through two main pathways referred to as classic cis signaling or trans signaling (10). In cis signaling, IL-6 binds to membrane-bound IL-6 receptor (mIL-6R) in a complex with gp130; downstream signal transduction is mediated by JAKs (Janus kinases) and STAT3 (signal transducer and activator of transcription 3).…”

mentioning

confidence: 99%

Cytokine release syndrome in severe COVID-19

Moore

June

2020

Science

1,771

1,715

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mentioning

confidence: 99%

Cytokine release syndrome in severe COVID-19

Moore

June

2020

Science

1,771

1,715

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“…We hypothesize that JAK inhibitors could be superior agents in terms of attenuating the cytokine storm caused by COVID-19 relative to existing anti-IL6 agents, which consist of injectable monoclonal antibodies that inhibit the interaction between IL-6 and its receptor IL-6R (26). In contrast, JAK inhibitors are available as drugs administered orally, with very well characterized pharmacodynamics and pharmacokinetics, and may provide a more appropriate strategy to transiently tone down the cytokine storm to prevent ARDS and fulminant myocarditis.…”

Section: Incb54707mentioning

confidence: 99%

JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy

Tuttle

Minter

Waugh

et al. 2020

Preprint

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Cytokine storms are drivers of pathology and mortality in myriad viral infections affecting the human population. In SARS-CoV-2-infected patients, the strength of the cytokine storm has been associated with increased risk of acute respiratory distress syndrome, myocardial damage, and death. However, the therapeutic value of attenuating the cytokine storm in COVID-19 remains to be defined. Here, we report results obtained using a novel mouse model of lethal sterile anti-viral immune responses. Using a mouse model of Down syndrome (DS) with a segmental duplication of a genomic region encoding four of the six interferon receptor genes (Ifnrs), we demonstrate that these animals overexpress Ifnrs and are hypersensitive to IFN stimulation. When challenged with viral mimetics that activate Toll-like receptor signaling and IFN anti-viral responses, these animals overproduce key cytokines, show exacerbated liver pathology, rapidly lose weight, and die. Importantly, the lethal immune hypersensitivity, accompanying cytokine storm, and liver hyperinflammation are blocked by treatment with a JAK1-specific inhibitor. Therefore, these results point to JAK1 inhibition as a potential strategy for attenuating the cytokine storm and consequent organ failure during overdrive immune responses. Additionally, these results indicate that people with DS, who carry an extra copy of the IFNR gene cluster encoded on chromosome 21, should be considered at high risk during the COVID-19 pandemic.

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“…Next, we quantified mRNA expression by RNA sequencing and compared transcriptome signatures of SFs between the 10 conditions (i.e., non-stimulated, IFN-α, IFN-γ, TNF-α, IL-1β, IL-6/sIL-6R, 7 IL-17, TGF-β1, IL-18 or 8-mix) and the diseases (i.e., RA, OA). Principal component analysis (PCA) of gene expression levels showed that the 8-mix condition induced a distinct transcriptome signature compared with the other stimulatory conditions, corresponding to the first component (PC1 in Fig.…”

Section: Cytokine Mixture Induced a Distinctive Transcriptome Signatumentioning

confidence: 99%

“…2B). For instance, the markedly high expression of IL6, which codes a pivotal cytokine in RA pathogenesis with a diverse repertoire of functions (e.g., osteoclast differentiation) (7), was achieved by the 8-mix stimulation (Primary component loading on PC1 = -0.76, PC2 = 0.26.…”

Section: Cytokine Mixture Induced a Distinctive Transcriptome Signatumentioning

confidence: 99%

“…They are major local effectors in the initiation and perpetuation of destructive joint inflammation through their production of a variety of immunomodulators, adhesion molecules and matrix-degrading enzymes (3). For example, SFs are a leading source of IL-6, a central hub in the synovial cytokine network, and its receptor antagonist has shown efficacy for patients with RA (7).…”

Section: Introductionmentioning

confidence: 99%

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Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Tsuchiya

Sumitomo

et al. 2019

Preprint

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One Sentence Summary: SFs under synergistic inflammation is associated with RA heritability, and MTF1 and RUNX1 could be crucial for the pathogenic chromatin rearrangement. Abstract:In rheumatoid arthritis (RA), synovial fibroblasts (SFs) produce a variety of pathogenic molecules in the inflamed synovium. Despite their potential importance, comprehensive genetic network of SFs under inflammatory conditions remains elusive. Here, to elucidate the actions of SFs and their contributions to RA pathogenesis, SFs, stimulated with 8 proinflammatory cytokines, were analyzed using genomic, epigenomic and transcriptomic approaches. SFs exposed to synergistically acting cytokines produced markedly higher levels of pathogenic molecules, including CD40 whose expression was significantly affected by a RA risk SNP (rs6074022). Upon chromatin remodeling in 2 7

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Targeting Interleukin-6 Signaling in Clinic

Cited by 667 publications

References 150 publications

Cytokine release syndrome in severe COVID-19

Cytokine release syndrome in severe COVID-19

JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

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