From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection
Open accessAbstract
Plasma levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or high-density lipoprotein cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of low-density lipoprotein cholesterol. Yet, although hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to interleukin (IL)-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β-producing NOD-like receptor family pyrin domain containing 3 inflammasome. Cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker for upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute-phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10 065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials using alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis, including low-dose methotrexate and colchicine, are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.
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CRP is an established biomarker of inflammation and is commonly elevated in people with overweight/obesity.
“C-reactive protein (CRP), an established biomarker of inflammation, is commonly elevated in people with overweight/obesity.”
From Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials (2023) · cites this paper as [3]
In “The Evidence for C-Reactive Protein (CRP)” (page unavailable), the paper describes CRP as an acute-phase reactant and hsCRP as a biomarker, supporting its role as an inflammation marker. It notes that human adipocytes can produce CRP, but does not say that CRP is commonly elevated in people with overweight or obesity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCRP concentrations of <1 mg/L, 1-3 mg/L, and >3 mg/L indicate low, intermediate, and high relative cardiovascular risk.
“CRP concentrations of <1 mg/L, 1–3 mg/L, and >3 mg/L indicate low, intermediate, and high relative cardiovascular risk, in the context of traditional risk factors.2,3”
Inflammatory cascades of CRP to IL-6 to IL-1 make inflammation key to atherosclerotic disease processes.
“Ridker (2016) follows the path of inflammatory cascades of CRP to IL-6 to IL-1, making inflammation the key to atherosclerotic disease processes.”
From Strong Enough to Suffer: Emotional Suppression, Stress Exposure, and Physiological Health Among Men Across the Life Course (2026) · cites this paper as Ridker, 2016
The interleukin-1β to interleukin-6 to C-reactive protein pathway of innate immunity is important for atherosclerosis development.
“particularly inhibition of the central interleukin-1β to interleukin-6 to C-reactive protein pathway of innate immunity that is important for atherosclerosis development 4,5”
From Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy (2022) · cites this paper as [4]
Targeting individual cytokines of the pro-inflammatory cascade may not fully address the effects of various other pro-inflammatory elements.
“Furthermore, targeting individual cytokines of the pro-inflammatory cascade may not fully address the effects of various other pro-inflammatory elements.5”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [5]
Strategies to target upstream effectors in the inflammatory signalling cascade may provide a solution for the limitations of current anti-inflammatory approaches.
“Strategies to target upstream effectors in the inflammatory signalling cascade may provide a solution for these issues.5”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [5]
CRP is a predictive biomarker for cardiovascular disease but is not causally related to atherothrombosis.
“other mechanistic studies and Mendelian randomization analyses in large populations suggest that CRP is a predictive biomarker that is not causally related to atherothrombosis”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [163]
IL-6 and IL-1 contribute to atherosclerosis and are considered therapeutic targets.
“IL-6 and IL-1 contribute to atherosclerosis and should be considered to be therapeutic targets”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [163]
Consistent SASP elements in the majority of senescent cells are IL-1α, IL-1β, IL-6, IL-8, IL-18, and TNF-α, all of which are clinically validated CVD risk factors.
“Consistent SASP elements in the majority of senescent cells are IL-1α, IL-1β, IL-6, IL-8, IL-18, and TNF-α,15,105,110 all of which are clinically validated CVD risk factors.1,5”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [5]
Elevated CRP has been well established as a clinically useful marker for cardiovascular risk prediction.
“elevated CRP has been well established as a clinically useful marker for cardiovascular risk prediction”
From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [470]
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Inflammation and Cardiovascular Disease
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Self-citationC-reactive protein is a mediator of cardiovascular disease
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Interleukin-1 Receptor Antagonist Expression in Human Endothelial Cells and Atherosclerosis
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Interleukin-1 Receptor Antagonist Gene Polymorphism and Coronary Artery Disease
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Monocyte Fate in Atherosclerosis
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Self-citationTransgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice
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C-Reactive Protein Decreases Prostacyclin Release From Human Aortic Endothelial Cells
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Moderate Hypoxia Potentiates Interleukin-1β Production in Activated Human Macrophages
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C-Reactive Protein Decreases Tissue Plasminogen Activator Activity in Human Aortic Endothelial Cells
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Neutrophil-macrophage communication in inflammation and atherosclerosis
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THE OCCURRENCE DURING ACUTE INFECTIONS OF A PROTEIN NOT NORMALLY PRESENT IN THE BLOOD
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Temporal and spatial distribution of interleukin-1β in balloon injured porcine coronary arteries
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C-reactive protein is a bystander of cardiovascular disease
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“processes leading to acute rupture and subsequent vascular hypoxia.(52,53) Several pharmacological agents are available”
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- Authors
- Ridker, P. M.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Ridker, Paul M
- ORCID
- Ridker, Paul M
- Venue
- Circulation Research
- Published
- 2016-01-08
- Volume
- 118
- Issue
- 1
- Pages
- 145-156
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4793711
- OpenAlex
- W2222665820
- Cited by
- 1,002
- References
- 112
- Citations by year
- 2026: 127 · 2025: 105 · 2024: 86 · 2023: 115 · 2022: 85 · 2021: 101 · 2020: 99 · 2019: 90 · 2018: 81 · 2017: 78 · 2016: 35
- FWCI
- 18.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U01HL101422, HL101422-03)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- high-sensitivity C-reactive protein, interleukin-6, IL-1β, NLRP3 inflammasome, atherosclerosis, inflammation, cardiovascular risk prediction, statin therapy, residual cardiovascular risk, canakinumab, anakinra, tocilizumab, methotrexate, colchicine, cholesterol crystals, neutrophil extracellular traps, fibrinogen, diabetic patients, myocardial infarction
- MeSH terms
- Interleukin-6 Inhibitors, Animals, Anti-Inflammatory Agents, C-Reactive Protein, Humans, Interleukin-1, Biomarkers, Interleukin-6, Drug Delivery Systems, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Atherosclerosis
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