Historical overview of the interleukin-6 family cytokine

Kang, Sujin; Narazaki, Masashi; Metwally, Hozaifa; Kishimoto, Tadamitsu

doi:10.1084/jem.20190347

Cited by 142 publications

(130 citation statements)

References 97 publications

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“…In addition to local effects, IL-6 provides a proximal stimulus to the acute phase response. 45 This programne of protein synthesis elicited in the hepatocyte by IL-6 boosts the synthesis of fibrinogen, the precursor of clots, of PAI-1, a major inhibitor of our endogenous fibrinolytic mediators, and of C-reactive protein, a biomarker of inflammation that rises consistently in COVID-19. 46 The havoc wreaked by the cytokine storm thus not only affects local endothelial function but can also provoke a prothrombotic and antifibrinolytic imbalance in blood that favours thrombus accumulation.…”

Section: Cytokine Storm: a Perfect Storm In Covid-19mentioning

confidence: 99%

COVID-19 is, in the end, an endothelial disease

Libby

Lüscher

2020

European Heart Journal

778

768

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The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.

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Section: Cytokine Storm: a Perfect Storm In Covid-19mentioning

confidence: 99%

COVID-19 is, in the end, an endothelial disease

Libby

Lüscher

2020

European Heart Journal

778

768

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“…To test the hypothesis that IL-6 inhibition may represent a preferential target for Pax5-dependent B-ALLs, and to expand our studies to more clinically relevant settings, we first tested whether IL-6 contributes to Pax5-dependent B-ALL maintenance, since IL-6 is a secreted protein, and as such it is amenable to targeting by neutralizing antibodies 26 and, moreover, such an antibody treatment has already been shown to be tolerated in humans 27 . In the past, the efficiency of experimental therapies against B-ALL has been routinely measured by transplanting leukemic B cells into recipient mice that had been preconditioned by irradiation 28,29 .…”

Section: Pax5 Mutant B-all Is Not Sensitive To Il-6 Inhibition In Tramentioning

confidence: 99%

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

Isidro-Hernández

Mayado²,

Casado-García

et al. 2020

Sci Rep

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PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers have been detected in neonatal blood spot samples of children who later developed B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 heterozygosis, in the presence of infections, results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. Furthermore, in vivo genetic downregulation of IL-6 in these Pax5 heterozygous mice retards B-cell leukemogenesis, and in vivo pharmacologic inhibition of IL-6 with a neutralizing antibody in Pax5 mutant mice with B-ALL clears leukemic cells. Additionally, this novel IL–6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.

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“…Interleukin (IL)-6 is a prototypical cytokine, featuring pleiotropic and redundant functional activity. IL-6 belongs to a family of cytokines, which includes IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1), and cardiotrophin-like cytokine factor 1 (CLCF1); all these cytokines use the common IL-6 signal transducer gp130 [ 1 ]. IL-6 production can be induced by both infection and other types of inflammation.…”

Section: Interleukin-6 In Health and Diseasementioning

confidence: 99%

Interleukin-6 in Rheumatoid Arthritis

Pandolfi

Franza

Carusi

et al. 2020

IJMS

110

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The role of interleukin (IL)-6 in health and disease has been under a lot of scrutiny in recent years, particularly during the recent COVID-19 pandemic. The inflammatory pathways in which IL-6 is involved are also partly responsible of the development and progression of rheumatoid arthritis (RA), opening interesting perspectives in terms of therapy. Anti-IL-6 drugs are being used with variable degrees of success in other diseases and are being tested in RA. Results have been encouraging, particularly when anti-IL-6 has been used with other drugs, such as metothrexate (MTX). In this review we discuss the main immunologic aspects that make anti-IL-6 a good candidate in RA, but despite the main therapeutic options available to target IL-6, no gold standard treatment has been established so far.

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Historical overview of the interleukin-6 family cytokine

Cited by 142 publications

References 97 publications

COVID-19 is, in the end, an endothelial disease

COVID-19 is, in the end, an endothelial disease

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

Interleukin-6 in Rheumatoid Arthritis

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