The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: The Caerphilly Study

Abstract

a b s t r a c tObjectives: Interleukin-6 (IL-6) is a key pro-inflammatory cytokine which mediates expression of several 'downstream' inflammatory markers and may play a role in atherothrombosis. However, it is not yet known whether IL-6 plays a role in mediating the associations of each marker with risk of coronary heart disease (CHD) or ischaemic stroke (IS). Methods and results:We examined the role of IL-6 and several "downstream" markers of inflammation (leucocyte counts, plasma and serum viscosity, fibrinogen, C-reactive protein, ␣1-antitrypsin and ␣2-macroglobulin) with risk of subsequent CHD, IS, and a combined endpoint (CHD/IS) in a population of British men. 2208 men aged 45-64 years were followed for a median of 13.4 years and 486 men had experienced a cardiovascular event. In age-adjusted analyses, most inflammatory markers were significantly associated with risk of CHD or CHD/IS, but for IS associations were weaker. On multivariable analyses, including conventional risk factors, associations of serum viscosity, ␣2-macroglobulin and leucocyte count became non-significant for CHD and CHD/IS, while no inflammatory marker retained a significant association with risk of IS. In contrast, IL-6 retained a significant association with CHD and CHD/IS and, after adjustment for IL-6, hazard ratios for downstream inflammatory markers were attenuated to non-significance. Conclusions: These findings suggest that IL-6 may play a role in mediating the associations of circulating inflammatory markers with risk of CHD in men. Further studies are required to assess whether this is also the case for risk of IS, and for CHD/IS in women.

Multiple Biomarkers for the Prediction of Ischemic Stroke

“…Of note, the magnitude of the multivariable association of hs-CRP with ischemic stroke in our study was similar to that from a recent meta-analysis of individual participant data (OR, 1.20 versus hazard ratio, 1.27 per SD increment in the log-transformed variable). 20 The lack of a significant association between IL-6 and ischemic stroke in the present study is consistent with results of the above mentioned Caerphilly Study, 21 but contrasts with findings in older populations. 8,22,23 IL-6 concentration varies with time and, therefore, regression dilution bias may have contributed to the lack of a significant association with ischemic stroke in the present study.…”

Association Between Interleukin-6 Levels and First-Ever Cerebrovascular Events in Patients With Vascular Risk Factors

“…We confirmed that IL-6 levels are investigated with composite CVD incidence, 3,12,13,21,22 stroke incidence [22][23][24] and recurrence, 25,26 mortality, 26 or prognosis after stroke. 27 However, the results of only a few clinical studies on initial stroke incidence remain controversial.…”

“…The Health ABC Study demonstrated that IL-6, but not hsCRP or tumor necrosis factor-α, predict stroke incidence in elderly populations without prior CVD. 23 In contrast, both the PROSPER 24 and Caerphilly 22 studies confirmed that no inflammatory markers, including IL-6, 22,24 hsCRP, 22,24 and IL-18, 24 showed independent associations and discrimination of stroke risk. The significance of inflammation marker in these previous studies has not been consistently shown in terms of discriminatory ability, judged from the C-statistic.…”

“…The significance of inflammation marker in these previous studies has not been consistently shown in terms of discriminatory ability, judged from the C-statistic. 22 Furthermore, prospective data on the combination of inflammatory markers and SLI for stroke are also limited. Only 1 prospective study reported the predictive value of hsCRP with stroke-risk incorporating SLI; meanwhile, higher hsCRP was no longer a significant predictor without SLI.…”

The anti-malarial artemisinin inhibits pro-inflammatory cytokines via the NF-κB canonical signaling pathway in PMA-induced THP-1 monocytes

“…IL-1ß, also produced mainly by macrophages and the action of which overlaps partly with TNF, induces metalloproteinases, nitric oxide synthase, and adhesion molecules. Moreover, IL-6 and TNF-· have been proven to be clinical markers to identify and track inflammation (27)(28)(29)(30). Targeting inflammatory cytokines has been prosperously developed and been proven to successfully protect against atherosclerosis.…”