Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study

Bonomi, Alice; Veglia, Fabrizio; Baldassarre, Damiano; Strawbridge, Rona J.; Golabkesh, Zahra; Sennblad, Bengt; Leander, Karin; Smit, Andries J.; Giral, Philippe; Humphries, Steve E.; Tremoli, Elena; Hamsten, Anders; Fairé, Ulf dé; Gigante, Bruna

doi:10.1038/s41435-019-0090-z

Cited by 14 publications

(12 citation statements)

References 52 publications

(55 reference statements)

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“…There are three sgp130 isoforms [ 95 ]: sgp130-RAPS [ 96 ], sgp130-E10 [ 97 ], and full-length sgp130 [ 98 ]. Unfortunately, there is no information on the secretion of these isoforms during exercise.…”

Section: Hyper-il-6 and Sgp130 Production During Exercisementioning

confidence: 99%

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Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

Nara

Watanabe

2021

IJMS

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Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver.

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Section: Hyper-il-6 and Sgp130 Production During Exercisementioning

confidence: 99%

“…Unfortunately, there is no information on the secretion of these isoforms during exercise. Additionally, the genes that regulate sgp130 levels are largely unknown [ 95 ].…”

Section: Hyper-il-6 and Sgp130 Production During Exercisementioning

confidence: 99%

Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

Nara

Watanabe

2021

IJMS

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“…The factors inducing sgp130 production through alternative splicing are unknown. We have recently shown that about genetic variants contribute to determine sgp130 circulating levels in serum and explain 11% of the variance (93).…”

Section: The Soluble Glycoprotein 130mentioning

confidence: 99%

“…The sgp130-E10 isoform on the other hand accounts merely for 1-2% of circulating sgp130 (95). The isoform most efficient in inhibiting IL6 trans-signalling is the full length sgp130 with inhibition executed in an autocrine fashion in cells secreting protective sgp130 (92,93). In addition, in an in vitro experimental setting, it was demon strated that monocytes expressed the full-length sgp130 albeit the expression disappeared upon their differentiation into macrophages (92).…”

Section: The Soluble Glycoprotein 130mentioning

confidence: 99%

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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“…A missense variant (Gly148Arg) in exon 5 of the IL6ST gene, rs2228044, that has been associated with higher serum sgp130 levels ( 59 ) is not in LD with rs7731626 ( R 2 = 0.0008 in the European population), ruling out a mechanistic correlation. In light of these current observations, and considering serum sgp130 appears to be a polygenic trait influenced by genomic variants acting in trans ( 60 ), decreased circulating sgp130 levels constitute likely a secondary effect of the major causative link to MS risk conferred by rs7731626, which thus far is understood as upregulation of both ANKRD55 and IL6ST expression in CD4 + T lymphocytes ( 34 , 36 ).…”

Section: Discussionmentioning

confidence: 92%

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

et al. 2022

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Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.

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Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study

Cited by 14 publications

References 52 publications

Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

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

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells

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