Interleukin (IL)-6 Inhibits IL-27- and IL-30-Mediated Inflammatory Responses in Human Monocytes

Petes, Carlene; Mariani, Mélissa K.; Yang, Yan; Grandvaux, Nathalie; Gee, Katrina

doi:10.3389/fimmu.2018.00256

Cited by 33 publications

(42 citation statements)

References 44 publications

(75 reference statements)

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“…We also demonstrated that all egc operon nonclassical SAgs have specific interaction with gp130, showing a similar kinetic behavior (Figure 10). The physiological role of these interactions could be explained considering that SAgs block gp130, preventing IL-6 stimuli and the activation of STAT-3 pathway, which is needed for the expression of IL-30 in monocytes (73). Since it has been suggested that IL-30 could be involved in the sepsis-control-modulating cytokines secreted by NKT cells (83), inhibition of the synthesis of IL-30 would suit the spread of bacteria.…”

Section: Discussionmentioning

confidence: 99%

egc Superantigens Impair Monocytes/Macrophages Inducing Cell Death and Inefficient Activation

et al. 2020

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Bacterial superantigens (SAgs) are enterotoxins that bind to MHC-II and TCR molecules, activating as much as 20% of the T cell population and promoting a cytokine storm which enhances susceptibility to endotoxic shock, causing immunosuppression, and hindering the immune response against bacterial infection. Since monocytes/macrophages are one of the first cells SAgs find in infected host and considering the effect these cells have on directing the immune response, here, we investigated the effect of four non-classical SAgs of the staphylococcal egc operon, namely, SEG, SEI, SEO, and SEM on monocytic-macrophagic cells, in the absence of T cells. We also analyzed the molecular targets on APCs which could mediate SAg effects. We found that egc SAgs depleted the pool of innate immune effector cells and induced an inefficient activation of monocytic-macrophagic cells, driving the immune response to an impaired proinflammatory profile, which could be mediated directly or indirectly by interactions with MHC class II. In addition, performing surface plasmon resonance assays, we demonstrated that non-classical SAgs bind the gp130 molecule, which is also present in the monocytic cell surface, among other cells.

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Section: Discussionmentioning

confidence: 99%

egc Superantigens Impair Monocytes/Macrophages Inducing Cell Death and Inefficient Activation

et al. 2020

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“…This pathway does not use IL-6R: the IL-6 inhibitor, but the not IL-6R inhibitor, may interfere with EBI3-dependent signaling. In addition, IL-30, the p28 subunit of the heterodimeric cytokine IL-27, binds IL-6R and modulates inflammatory responses [130,131]. The IL-6R inhibitor, but not the IL-6 inhibitor, may interfere with IL-30 signaling.…”

Section: Recent Advancements In Il-6 Inhibitorsmentioning

confidence: 99%

IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review

Ogata

Kato

Higa

et al. 2019

Modern Rheumatology

160

124

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Tocilizumab (TCZ) is an interleukin-6 (IL-6) inhibitor used for the treatment of rheumatoid arthritis (RA). It was developed in 2008, and its effectiveness is supported by evidence from all over the world based on its first decade of use. Although the overall efficacy and safety profiles of TCZ are similar to those of tumor necrosis factor (TNF) inhibitors, TCZ displays certain differences. The most notable advantage of TCZ is its usefulness as a monotherapy. Additionally, TCZ is favorable in the improvement of systemic inflammatory symptoms such as anemia and fatigue. The low immunogenicity of TCZ contributes favorably to long-term drug retention. Due to frequent relapse after TCZ cessation, TCZ use should be tapered beyond remission. During TCZ therapy, C-reactive protein (CRP) is unable to recognize disease activity and the severity of infection. The most common adverse events (AEs) are infection and abnormalities in laboratory findings including dyslipidemia, neutropenia, thrombocytopenia, and abnormality of liver enzymes. TCZ obscures the symptoms of infection. Therefore, stealth infections without obvious CRP elevation can sometimes cause severe damage to patients. Lower intestinal perforation is an uncommon but serious AE in TCZ therapy. Further clinical investigations will continue to refine the IL-6 inhibitory strategy.

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“…In both mice and humans, IL-30/IL-6R activates signal transduction, solely via the β-receptor chain gp130, with subsequent STAT1 and STAT3 phosphorylation, without the need of WSX-1. In addition, IL-30 can also form a biologically active complex with sIL-6R, both in mice and in humans [69,77], which implies that IL-30 trans-signaling is possible on cells lacking membrane-bound IL-6R [69], a mechanism that enlarges the spectrum of IL-30 responsive cells to virtually all cells of the body, in analogy to IL-6. Such as for the best known and longer studied homologue cytokine IL-6 [78,79], a prominent role is emerging for IL-30 in tumorigenesis, given its ability in shaping the TME and cancer stem cell niche, in which myeloid cells are critically involved.…”

Section: Il-30 Immunobiology In Man and Mousementioning

confidence: 99%

Decoding the Role of Interleukin-30 in the Crosstalk between Cancer and Myeloid Cells

Carlo

2020

Cells

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In the last few years, a new actor hit the scene of the tumor microenvironment, the p28 subunit of interleukin (IL)-27, known as IL-30. Its molecular structure allows it to function as an autonomous cytokine and, alternatively, to pair with other subunits to form heterodimeric complexes and enables it to play different, and not fully elucidated, roles in immunity. However, data from the experimental models and clinical samples, suggest IL-30 s engagement in the relationship between cancer and myeloid cells, which fosters the tumor microenvironment and the cancer stem cell niche, boosting the disease progression. Activated myeloid cells are the primary cellular source and one of the targets of IL-30, which can also be produced by cancer cells, especially, in aggressive tumors, as observed in the breast and prostate. This review briefly reports on the immunobiology of IL-30 and related cytokines, by comparing mouse and human counterparts, and then focuses on the mechanisms whereby IL-30 amplifies intratumoral myeloid cell infiltrate and triggers a vicious cycle that worsens immunosuppression in the tumor microenvironment (TME) and constitutes a real threat for a successful immunotherapeutic strategy.Cells 2020, 9, 615 2 of 14 of reactive oxygen species (ROS), nitric oxide (NO), and ectoenzymes, which regulate the adenosine metabolism; expression of immune checkpoint molecules [10,11]; depletion of metabolites critical for lymphocyte functions [12,13]; and through their secretion of growth, angio-lymph-angiogenic factors and inflammatory mediators [13], that are crucial for tissue remodeling and tumor development.Recent insights into this inflammatory milieu, specifically in breast (BC) and prostate (PC) cancers, have unveiled a role for the novel immunoregulatory mediator Interleukin(IL)-30/IL-27p28 [14] in the TME and in the intricate relationship between cancer and myeloid cells, which orchestrates tumor-promoting events with evident clinical implications [15,16].

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Interleukin (IL)-6 Inhibits IL-27- and IL-30-Mediated Inflammatory Responses in Human Monocytes

Cited by 33 publications

References 44 publications

egc Superantigens Impair Monocytes/Macrophages Inducing Cell Death and Inefficient Activation

egc Superantigens Impair Monocytes/Macrophages Inducing Cell Death and Inefficient Activation

IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review

Decoding the Role of Interleukin-30 in the Crosstalk between Cancer and Myeloid Cells

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