IL-1 Cytokines in Cardiovascular Disease: Diagnostic, Prognostic and Therapeutic Implications

Abstract

Interleukins (ILs) are key mediators in the chronic vascular inflammatory response underlying several aspects of cardiovascular disease. Due to their powerful pro-inflammatory potential, and the fact that they are highly expressed by almost all cell types actively implicated in atherosclerosis, members of the IL-1 cytokine family were the first to be investigated in the field of vessel wall inflammation. The IL-1 family is comprised of five proteins that share considerable sequence homology: IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-18 (also known as IFNgamma-inducing factor), and the newly discovered ligand of the ST2L receptor, IL-33. Expression of IL-1s and their receptors has been demonstrated in atheromatous tissue, and serum levels of IL-1-cytokines have been correlated with various aspects of cardiovascular disease and their outcome. In vitro studies have confirmed pro-atherogenic properties of IL-1alpha, IL-1beta and IL-18 such as, up-regulation of endothelial adhesion molecules, the activation of macrophages and smooth muscle cell proliferation. In contrast with this, IL-1Ra, a natural antagonist of IL-1, possesses anti-inflammatory properties, mainly through the endogenous inhibition of IL-1 signaling. IL-33 was identified as a functional ligand of the, till recently, orphan receptor, ST2L. IL-33/ST2L signaling has been reported as a mechanically activated, cardioprotective paracrine system triggered by myocardial overload. As the roles of individual members of the IL-1 family are being revealed, novel therapies aimed at the modulation of interleukin function in several aspects of cardiovascular disease, are being proposed. Several approaches have produced promising results. However, none of these approaches has yet been applied in clinical practice.

Phosphorylation and Acetylation of Histone H3 and Autoregulation by Early Growth Response 1 Mediate Interleukin 1β Induction of Early Growth Response 1 Transcription

“…IL-1␤ and its receptor are expressed in atheromatous tissue; IL-1␤ activates macrophages, stimulates SMC proliferation, and upregulates endothelial adhesion molecule expression. 35 The zinc finger transcription factor EGR-1 is a "master regulator" in that it controls the expression of many pathophysiologically relevant genes. 5,17 EGR-1-dependent genes have been strongly implicated in the initiation and progression of atherosclerosis and postangioplasty restenosis.…”

Pathways Involved in Interleukin-1β–Mediated Murine Cardiomyocyte Apoptosis

“…6,7 In the pathogenesis of cardiovascular diseases, IL-1 signaling promotes the formation of atheromatous lesions, increases vascular inflammation, and triggers plaque destabilization. 8,9 After myocardial infarction, IL-1 signaling critically regulates the inflammatory response and is involved in the development of adverse remodeling by increasing the expression of matrix metalloproteinases. 7,10 Emerging evidence suggests that IL-1 signaling has an essential role in heart failure by suppressing cardiac function, promoting myocardial hypertrophy, and even inducing cardiomyocyte apoptosis.…”

Genetic variability of the distal promoter of the ST2 gene is associated with angiographic severity of coronary artery disease

“…Introduction IL-1 cytokines share a common -trefoil structure and form a complex network of several naturally occurring antagonists and decoy receptors regulating their highly proinflammatory properties [1]. IL-33 is the most recently discovered member of the IL-1 cytokine family.…”