Abstract
Interleukin (IL) 6 contributes to atherosclerotic plaque development through IL6 membrane-bound (IL6R and gp130) and soluble (sIL6R and sgp130) receptors. We investigated IL6 receptor expression in carotid plaques and its correlation with circulating IL6 and soluble receptor levels. Plasma samples and carotid plaques were obtained from 78 patients in the Biobank of Karolinska Endarterectomies study. IL6, sIL6R, and sgp130 were measured in plasma and IL6, IL6R, sIL6R, GP130, and sGP130-RAPS (sGP130) gene expression assessed in carotid plaques. Correlations between plaque IL6 signaling gene expression and plasma levels were determined by Spearman’s correlation. Differences in plasma and gene expression levels between patients with (n = 53) and without (n = 25) a history of a cerebral event and statin-treated (n = 65) and non-treated (n = 11), were estimated by Kruskal–Wallis. IL6 and its receptors were all expressed in carotid plaques. There was a positive, borderline significant, moderate correlation between plasma IL6 and sIL6R and the respective gene expression levels (rho 0.23 and 0.22, both p = 0.05). IL6R expression was higher in patients with a history of a cerebrovascular event compared to those without (p = 0.007). Statin-treated had higher IL6R, sIL6R, and sGP130 expression levels and plasma sIL6R compared to non-treated patients (all p < 0.05). In conclusion, all components of the IL6 signaling pathways are expressed in carotid artery plaques and IL6 and sIL6R plasma levels correlate moderately with IL6 and sIL6R. Our data suggest that IL6 signaling in the circulation might mirror the system activity in the plaque, thus adding novel perspectives to the role of IL6 signaling in atherosclerosis.
Highlights
Inflammation is the hotbed for atherosclerosis and the proinflammatory interleukin (IL) 1β-interleukin 6 (IL6)-C-reactive protein (CRP) pathway is the central axis
We previously demonstrated that IL6 trans-signaling, estimated by high values of the ratio between the circulating active IL6:soluble isoform of IL6R (sIL6R) and inactive IL6:sIL6R:sgp[130] complex, was associated with an increased risk of future cardiovascular events (CVE)[8] and early ischemic stroke in middle-aged individuals without prevalent cardiovascular
We found that IL6 receptor (IL6R), sIL6R, GP130, and Exploratory analyses of the IL6 signaling pathway gene expression and plasma levels in clinically relevant subgroups of patients
Summary
Inflammation is the hotbed for atherosclerosis and the proinflammatory interleukin (IL) 1β-IL6-C-reactive protein (CRP) pathway is the central axis. IL6 governs pivotal physiological processes (e.g. immunological and regenerative) through the binding to the membrane-bound IL6 receptor (IL6R), a signaling moiety known as classical signaling. IL6 elicits pro-inflammatory signals in target tissues when bound to the soluble isoform of IL6R (sIL6R),[4] in the so-called IL6 trans-signaling. Both signaling moieties need the ubiquitously expressed co-receptor gp[130] to transduce the IL6 signal. To avoid systemic uncontrolled inflammation, the circulating IL6:sIL6R complex is buffered by a soluble gp[130] isoform (sgp130).[5] The sIL6R and sgp[130] are produced either through limited proteolytic cleavage of the membrane-bound receptor (main mechanism for sIL6R) or by alternative splicing of the gene coding the transmembrane receptor (main mechanism for sgp130).[6,7]
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