Interleukin-1 Beta as a Target for Atherosclerosis Therapy: Biological Basis of CANTOS and Beyond

Abstract

Inflammatory pathways drive atherogenesis and link conventional risk factors to atherosclerosis and its complications. One inflammatory mediator has come to the fore as a therapeutic target in cardiovascular disease. The experimental and clinical evidence reviewed here support interleukin-1 beta (IL-1β) as both a local vascular and systemic contributor in this regard. Intrinsic vascular wall cells and lesional leukocytes alike can produce this cytokine. Local stimuli in the plaque favor the generation of active IL-1β through the action of a molecular assembly known as the inflammasome. Clinically applicable interventions that interfere with IL-1 action can improve cardiovascular outcomes, ushering in a new era of anti-inflammatory therapies for atherosclerosis. The translational path described here illustrates how advances in basic vascular biology may transform therapy. Biomarker-directed application of anti-inflammatory interventions promises to help us achieve a more precise and personalized allocation of therapy for our cardiovascular patients.

Keywords: acute coronary syndromes; high-sensitivity C-reactive protein; interleukin-1; myocardial infarction.

Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Selected actions of IL-1 related to atherosclerosis

IL-1β acts on many cell types and organs, including those involved in atherogenesis such as vascular endothelial and smooth muscle cells, and macrophages. IL-1β elicits the functions shown, among many others. Blockade of IL-1 induced MMP-2 (Type IV collagenase) may contribute to the marked drop in cancer incidence and mortality seen in CANTOS by impeding tumor invasion through the collagen IV-rich basement membrane and thus limiting metastasis. MMP: matrix metalloproteinase, WBC: White blood cell.

Figure 1. Selected actions of IL-1 related to atherosclerosis

IL-1β acts on many cell types and organs, including those involved in atherogenesis such as vascular endothelial and smooth muscle cells, and macrophages. IL-1β elicits the functions shown, among many others. Blockade of IL-1 induced MMP-2 (Type IV collagenase) may contribute to the marked drop in cancer incidence and mortality seen in CANTOS by impeding tumor invasion through the collagen IV-rich basement membrane and thus limiting metastasis. MMP: matrix metalloproteinase, WBC: White blood cell.

Figure 2. IL-1 activates human vascular wall cells. A: Human endothelial cells express IL-1β after exposure to bacterial endotoxin

Cultured human endothelial cells were exposed to E. coli endotoxin (LPS) for 24 hours. IL-1β mRNA was evaluated by Northern blotting (42). B: IL-1 induces IL-1 in human vascular cells. Cultured human endothelial cells were exposed to recombinant IL-1α at the concentrations noted for six hours. IL-1β messenger RNA was visualized by Northern blotting.(25) Such auto induction of interleukin one isoforms occurs in human vascular smooth muscle cells and in macrophages as well (24,120). Either IL-1 isoform can induce the other or itself. C. IL-1 induces IL-6 expression in human vascular school muscle cells (VSMC.) Human the SMC were exposed to IL-1α at the concentration shown for 24 hours. IL-6 activity released by the cells is reported in arbitrary units on a logarithmic scale. IL-1 also induces IL-6 in human endothelial cells.(121). D. Caspase-1 activates IL-1β in human VSMC stimulated with recombinant CD40 ligand (rCD40L.) The 33 kD pro-IL-1β concentration declines as the active 17 kD mature form accumulates. The conversion depends on caspase-1 as shown by treatment with the caspase-1/IL-1β converting enzyme (ICE) inhibitor ZVAD (122). E. Foam cells in a human atheroma expresses caspase-1. This representative view of typical human atherosclerotic plaque shows immunohistochemical staining for caspase-1, the IL-1β converting enzyme (pink reaction product.)(27) (Republished with permission from the following sources: 1) Libby P, Ordovàs JM, Auger KR, Robbins H, Birinyi LK, Dinarello CA. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Path 1986;124:179–186. 2) Geng Y-J, Libby P. Evidence for apoptosis in advanced human atheroma. Co-localization with interleukin-1 b-converting enzyme. Am J Pathol 1995;147:251–266. 3) Loppnow H, Libby P. Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1. Cell Immunol 1989;122:493–503. 4)Warner SJC, Auger KR, Libby P. Interleukin-1 induces interleukin-1. II. Recombinant human interleukin-1 induces interleukin-1 production by adult human vascular endothelial cells. J Immunol 1987;139:1911–1917. Copyright © [1987] The American Association of Immunologists, Inc. 5)Dinarello CA, Ikejima T, Warner SJC et al. Interleukin-1 induces interleukin-1. I. Induction of circulating interleukin-1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol 1987;139:1902–1910. Copyright © [1987] The American Association of Immunologists, Inc. 6)Warner SJC, Auger KR, Libby P. Human interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cells. J Exp Med 1987;165:1316–1331. 7)Schoenbeck U, Mach F, Bonnefoy JY, Loppnow H, Flad HD, Libby P. Ligation of CD40 activates interleukin 1beta-converting enzyme (caspase-1) activity in vascular smooth muscle and endothelial cells and promotes elaboration of active interleukin 1beta. Journal of Biological Chemistry 1997;272:19569–19574. © the American Society for Biochemistry and Molecular Biology.)

Figure 3. The inflammasome senses danger signals and activates IL-1 beta by proteolytic processing to the mature form by caspase 1

Transcription of the interleukin-1 (IL-1) beta (β) gene produces pro-IL-1β, a 33 kiloDalton (kD) protein that lacks biological activity. This precursor undergoes cleavage by an enzyme known as IL-1β converting enzyme (ICE) or caspase-1, to produce the active form of the cytokine with a molecular weight of 17 kD. The activity of caspase 1 depends on the NLRP3 inflammasome that senses danger signals such as those shown.

Figure 4. Amplification cascades boost IL-1 actions implicated in atherothrombosis

nterleukin-1 (IL-1) can induce its own gene expression in many cell types, including those implicated in atherosclerosis. This property provides a positive feedback amplification loop for boosting IL-1 levels at sites of inflammation. IL-1 also strongly augments the production of IL-6 by various cell types. IL-6 mediates the acute phase response through which the liver produces proteins that participate in host defenses, but that also augments thrombosis and inhibits fibrinolysis as explained in the text.

Central Illustration. Some Effects of Interleukin-1 Blockade on Cellular Functions

Interleukin-1 exerts many actions on cells that can contribute to pathogenesis diseases including atherosclerosis, thrombosis, oncogenesis, and invasion and metastasis of tumors. Many of the effects of interleukin-1 on hepatocytes, including the induction of the acute phase response, depend on the intermediary of interleukin 6 (IL-6), a cytokine potently induced by interleukin 1. Strong human genetic evidence implicates IL-6 as a causal factor for atherothrombosis.