Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates

Paige, Ellie; Clément, Marc; Lareyre, Fabien; Sweeting, Michael; Raffort, Juliette; Grenier, Céline; Finigan, Alison; Harrison, James; Peters, James E.; Sun, Benjamin B.; Butterworth, Adam S.; Harrison, Seamus C.; Bown, Matthew J.; Lindholt, Jes Sanddal; Badger, Stephen A.; Kullo, Iftikhar J.; Powell, Janet T.; Norman, Paul; Scott, Daniel; Bailey, Marc A.; Rose–John, Stefan; Danesh, John; Freitag, Daniel F.; Paul, Dirk S.; Mallat, Ziad

doi:10.1161/circgen.118.002413

Cited by 51 publications

(44 citation statements)

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“…The discovery that the pro-inflammatory activities of IL-6 are mediated by IL-6 trans-signalling whereas the protective and regenerative activities of IL-6 rely on classic signalling via the membrane-bound IL-6R suggested that the sgp130Fc protein might be an ideal candidate for a more specific mode of cytokine blockade as opposed to global cytokine inhibition 20 . It was shown in appropriate animal models that blockade of IL-6 trans-signalling was indeed superior to global IL-6 blockade in a bone healing model 44,45 , in a sepsis model 42 , in abdominal aortic aneurysm models 43 , and in bacterial infection models 40,41 . The sgp130Fc protein was expressed and purified according to GMP regulations.…”

Section: Discussionmentioning

confidence: 99%

“…With the help of the sgp130Fc protein and of neutralising monoclonal antibodies, it was possible to selectively block IL-6 trans-signalling or to block all IL-6 signalling, respectively. Using this approach, it was shown that classic IL-6 signalling via the membrane-bound IL-6R was responsible for the defence of the body against bacteria 40 , 41 , intestinal regeneration upon polymicrobial sepsis 42 , prevention of aortic rupture in animal models of abdominal aortic aneurysm 43 , and healing of bone fractures 44 , 45 , indicating that these important processes are severely compromised under blockade of global IL-6 activity 46 . It has been hypothesised that the same might apply for the treatment of COVID-19 patients 46 ( Figure 4 ).…”

Section: Physiologic and Pathophysiologic Functions Of Interleukin-6mentioning

confidence: 99%

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Interleukin-6 signalling in health and disease

Rose–John

2020

F1000Res

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Biochemically, interleukin-6 belongs to the class of four-helical cytokines. The cytokine can be synthesised and secreted by many cells. It acts via a cell surface-expressed interleukin-6 receptor, which is not signalling competent. This receptor, when complexed with interleukin-6, associates with the signalling receptor glycoprotein 130 kDa (gp130), which becomes dimerised and initiates intracellular signalling via the Janus kinase/signal transducer and activator of transcription and rat sarcoma proto oncogene/mitogen-activated protein kinase/phosphoinositide-3 kinase pathways. Physiologically, interleukin-6 is involved in the regulation of haematopoiesis and the coordination of the innate and acquired immune systems. Additionally, interleukin-6 plays an important role in the regulation of metabolism, in neural development and survival, and in the development and maintenance of various cancers. Although interleukin-6 is mostly regarded as a pro-inflammatory cytokine, there are numerous examples of protective and regenerative functions of this cytokine. This review will explain the molecular mechanisms of the, in part opposing, activities of the cytokine interleukin-6.

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Section: Discussionmentioning

confidence: 99%

Section: Physiologic and Pathophysiologic Functions Of Interleukin-6mentioning

confidence: 99%

Interleukin-6 signalling in health and disease

Rose–John

2020

F1000Res

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“…In our study, sgp130 displayed a non-linear association and in previous observational studies, sgp130 has been associated with both protective and detrimental properties (114,151,153,154). While administering supra-physiological doses of recombinant sgp130Fc resulted in dampened atherosclerosis and fewer ruptures of abdominal aortic aneurysms in two murine models of atherosclerosis (138,140). Considering the above, physiological sgp130 levels possibly mirrors the activity in the pathway rather than the level of IL6 trans-signalling inhibition.…”

Section: Study Imentioning

confidence: 98%

The predictive role of interleukin 6 trans-signalling in middle-aged men and women at low-intermediate risk of cardiovascular events

Ziegler

Frumento

Wallén

et al. 2019

Eur J Prev Cardiolog

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Background Interleukin 6 trans-signalling is independently associated with the risk of cardiovascular events. The aim of this study was to investigate if interleukin 6 trans-signalling can identify individuals at risk for cardiovascular events (coronary artery disease and ischaemic stroke) among those at-low–intermediate risk. Methods In a cohort of 60-year-olds ( n = 4232, incident cardiovascular events n = 525), interleukin 6 trans-signalling was estimated by a ratio between the pro-inflammatory interleukin 6: soluble interleukin 6 receptor binary receptor complex and the inactivated interleukin 6: soluble interleukin 6 receptor: sgp130 ternary complex (B/T ratio). Risk associated with B/T ratio >median was investigated in individuals with low-density lipoprotein cholesterol ≤4.0 (mmol/l) and in those at low-intermediate risk according to the Framingham risk score (FRS) using Cox regression and expressed as hazard ratio and 95% confidence interval. Difference in time to event (years; 95% confidence interval) was analysed with quantile regression. The interaction between low-density lipoprotein cholesterol and B/T ratio was estimated on the additive scale. Incremental discriminatory value of the B/T ratio if low-density lipoprotein cholesterol ≤4.0 was compared to that of the FRS and interleukin 6. Results B/T ratio >median was associated with increased cardiovascular event risk when low-density lipoprotein cholesterol ≤4.0 (hazard ratio 1.59; 95% confidence interval 1.24–2.05) or FRS ≤ 10%, >10–≤20% (hazard ratio 1.27; 95% confidence interval 1.00–1.61 and hazard ratio 1.78; 95% confidence interval 1.36–2.34, respectively). B/T ratio >median and low-density lipoprotein cholesterol ≤4.0 were associated with early cardiovascular events, particularly ischaemic stroke. No interaction was observed between low-density lipoprotein cholesterol and the B/T ratio, both factors increasing cardiovascular event risk by 60%. In the presence of low-density lipoprotein cholesterol ≤4.0, the B/T ratio slightly improved discrimination measures. Conclusions Interleukin 6 trans-signalling increases cardiovascular event risk in middle-aged men and women otherwise classified at low-intermediate cardiovascular risk.

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“…Moreover, patients with the rs2228145 SNP showed a significant lower risk of Crohn’s disease and ulcerative colitis as compared to control individuals [29]. Furthermore, growth rates of abdominal aortic aneurisms in patients were smaller with the Ala358 variant of the IL-6R [30]. These results can be explained by a higher capacity of the IL-6 buffer in the blood, which is caused by the higher circulating sIL-6R levels [20,23].…”

Section: Introductionmentioning

confidence: 99%

ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer

Schumacher

Rose–John

2019

Cancers

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All ligands of the epidermal growth factor receptor (EGF-R) are transmembrane proteins, which need to be proteolytically cleaved in order to be systemically active. The major protease responsible for this cleavage is the membrane metalloprotease ADAM17, which also has been implicated in cleavage of TNFα and interleukin-6 (IL-6) receptor. It has been recently shown that in the absence of ADAM17, the main protease for EGF-R ligand processing, colon cancer formation is largely abrogated. Intriguingly, colon cancer formation depends on EGF-R activity on myeloid cells rather than on intestinal epithelial cells. A major activity of EGF-R on myeloid cells is the stimulation of IL-6 synthesis. Subsequently, IL-6 together with the ADAM17 shed soluble IL-6 receptor acts on intestinal epithelial cells via IL-6 trans-signaling to induce colon cancer formation, which can be blocked by the inhibitor of IL-6 trans-signaling, sgp130Fc. Blockade of IL-6 trans-signaling therefore offers a new therapeutic window downstream of the EGF-R for the treatment of colon cancer and possibly of other EGF-R related neoplastic diseases.

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Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates

Abstract: Supplemental Digital Content is available in the text.

Cited by 51 publications

References 46 publications

Interleukin-6 signalling in health and disease

Interleukin-6 signalling in health and disease

The predictive role of interleukin 6 trans-signalling in middle-aged men and women at low-intermediate risk of cardiovascular events

ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer

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