Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex

Lacroix, Marine; Rousseau, François; Guilhot, Joëlle; Malinge, Pauline; Magistrelli, Giovanni; Herren, Suzanne; Jones, Simon A.; Jones, Gareth Wyn; Scheller, Jürgen; Lissilaa, Rami; Kosco‐Vilbois, Marie H.; Johnson, Zoë; Buatois, Vanessa; Ferlin, Walter

doi:10.1074/jbc.m115.682138

Cited by 55 publications

(56 citation statements)

References 30 publications

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“…35,36). The treatment of gp130 F/F :Kras G12D mice with either 25F10 or 1F7 significantly suppressed the identical exacerbated lung adenocarcinoma phenotype observed in both isotype control antibody-treated and untreated gp130 F/F :Kras G12D mice ( Fig.…”

Section: Il6 Trans-signaling Exacerbates Lung Carcinogenesis In Gp130mentioning

confidence: 71%

“…8) or, as a control, equivalent volume (125 mL) of PBS, by intranasal inhalation, and were observed for a further 6 weeks. The anti-IL6R mAbs 25F10 and 1F7, and IgG control (35,36), were administrated to mice at 10 mg/kg by intraperitoneal injection twice weekly for 6 weeks, with the initial injection given the day after Cre inhalation.…”

Section: Mouse Treatmentsmentioning

confidence: 99%

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IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis

et al. 2016

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Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130 F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRASdriven lung tumorigenesis. Malignant growths in the gp130 F/F : Kras G12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental Kras G12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 transsignaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma.Cancer Res; 76(4); 866-76. Ó2016 AACR.

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Section: Il6 Trans-signaling Exacerbates Lung Carcinogenesis In Gp130mentioning

confidence: 71%

Section: Mouse Treatmentsmentioning

confidence: 99%

IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis

et al. 2016

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“…However, there is evidence that cis -signaling through the membrane-bound IL-6R is anti-inflammatory, whereas trans -signaling though the soluble IL-6R is proinflammatory (18). For example, cis -signaling in hepatocytes leads to decreased inflammation, but increased trans -signaling is ineffective (23).…”

Section: Discussionmentioning

confidence: 99%

“…The IL-6 receptor has no independent signaling properties and instead relies on heterodimerization with another membrane protein, gp130, which is expressed almost ubiquitously (18). Gp130 has no affinity for free IL-6 and only binds to the IL-6:IL-6R receptor complex (18). IL-6 receptors are either membrane-bound or soluble; membrane-bound IL-6 receptor expression is limited to liver, leukocytes, and some epithelial barrier cells (18).…”

Section: Introductionmentioning

confidence: 99%

“…Gp130 has no affinity for free IL-6 and only binds to the IL-6:IL-6R receptor complex (18). IL-6 receptors are either membrane-bound or soluble; membrane-bound IL-6 receptor expression is limited to liver, leukocytes, and some epithelial barrier cells (18). However, tissues without membrane bound IL-6 receptor are still responsive to the IL-6:IL-6R complex because gp130 can bind to either the membrane-bound or free version of the IL-6R (18).…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-6 derived from cutaneous deficiency of stearoyl-CoA desaturase- 1 may mediate metabolic organ crosstalk among skin, adipose tissue and liver

Dumas

Guo

Kim

et al. 2019

Biochemical and Biophysical Research Communications

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Stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme that adds a double bond at the delta 9 position of stearate (C18: 0) and palmitate (C16: 0), has been proven to be important in the development of obesity. Mice with skin-specific deficiency of SCD1 (SKO) display increased whole-body energy expenditure, which is protective against adiposity from a high-fat diet because it improves glucose clearance, insulin sensitivity, and hepatic steatosis. Of note, these mice also display elevated levels of the “pro- inflammatory” plasma interleukin-6 (IL-6). In whole skin of SKO mice, IL-6 mRNA levels are increased, and protein expression is evident in hair follicle cells and in keratinocytes. Recently, the well-known role of IL-6 in causing white adipose tissue lipolysis has been linked to indirectly activating the gluconeogenic enzyme pyruvate carboxylase 1 in the liver, thereby increasing hepatic glucose production. In this study, we suggest that skin-derived IL-6 leads to white adipose tissue lipolysis, which contributes to the lean phenotype of SKO mice without the incidence of meta- inflammation that is associated with IL-6 signaling.

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Immunological analysis of the murine anti‐CD3‐induced cytokine release syndrome model and therapeutic efficacy of anti‐cytokine antibodies

et al. 2021

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The aberrant release of inflammatory mediators often referred to as a cytokine storm or cytokine release syndrome (CRS), is a common and sometimes fatal complication in acute infectious diseases including Ebola, dengue, COVID‐19, and influenza. Fatal CRS occurrences have also plagued the development of highly promising cancer therapies based on T‐cell engagers and chimeric antigen receptor (CAR) T cells. CRS is intimately linked with dysregulated and excessive cytokine release, including IFN‐γ, TNF‐α, IL 1, IL‐6, and IL‐10, resulting in a systemic inflammatory response leading to multiple organ failure. Here, we show that mice intravenously administered the agonistic hamster anti‐mouse CD3ε monoclonal antibody 145‐2C11 develop clinical and laboratory manifestations seen in patients afflicted with CRS, including body weight loss, hepatosplenomegaly, thrombocytopenia, increased vascular permeability, lung inflammation, and hypercytokinemia. Blood cytokine levels and gene expression analysis from lung, liver, and spleen demonstrated a hierarchy of inflammatory cytokine production and infiltrating immune cells with differentiating organ‐dependent kinetics. IL‐2, IFN‐γ, TNF‐α, and IL‐6 up‐regulation preceded clinical signs of CRS. The co‐treatment of mice with a neutralizing anti‐cytokine antibody cocktail transiently improved early clinical and laboratory features of CRS. We discuss the predictive use of this model in the context of new anti‐cytokine strategies to treat human CRS.

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Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex

Cited by 55 publications

References 30 publications

IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis

IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis

Interleukin-6 derived from cutaneous deficiency of stearoyl-CoA desaturase- 1 may mediate metabolic organ crosstalk among skin, adipose tissue and liver

Immunological analysis of the murine anti‐CD3‐induced cytokine release syndrome model and therapeutic efficacy of anti‐cytokine antibodies

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