Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases

Abstract

Cardio-Cerebrovascular Disease is a collective term for cardiovascular disease and cerebrovascular disease, being a serious threat to human health. A growing number of studies have proved that the content of inflammatory factors or mediators determines the stability of vascular plaque and the incidence of cardio-cerebrovascular event, and involves in the process of Cardio-Cerebrovascular Diseases. Interleukin-6 is a widely used cytokine that causes inflammation and oxidative stress, which would further result in cardiac and cerebral injury. The increased expression of interleukin-6 is closely related to atherosclerosis, myocardial infarction, heart failure and ischemic stroke. It is a key risk factor for these diseases by triggering inflammatory reaction and inducing other molecules release. Therefore, interleukin-6 may become a potential target for Cardio-Cerebrovascular Diseases in the future. This paper is aimed to discuss the expression changes and pathological mechanisms of interleukin-6 in Cardio-Cerebrovascular Diseases, and to provide a novel strategy for the prevention and treatment of Cardio-Cerebrovascular Diseases.

Keywords: IL-6Rα; atherosclerosis; inflammation; interleukin-6; ischemic stroke; target.

FIGURE 1

Schematic representation of IL-6 signal transduction. On target cells, IL-6 first binds to IL-6Rα, and subsequently associates with cellular membrane bound gp130, in turn inducing gp130 dimerization and initiation of IL-6 intracellular signalling. Formation of the IL-6/IL-6Rα/gp130 complex induces autophosphorylation and activation of the gp130-associated JAKs. These activated JAKs phosphorylate tyrosine residues within the cytoplasmic portion of gp130. Phosphorylation of the membrane-proximal tyrosine residue, leads to the recruitment of SHP2, which then stimulates the activation of MAPK and PI3K pathways. After the activation of JAKs, STAT molecules are recruited and then phosphorylated by the JAKs. The related down-stream proteins translocate afterwards into the nucleus to activate gene transcription, thereby playing the corresponding roles.

FIGURE 2

Schematic representation of IL-6 accelerating atherosclerosis. Through five pathways including liver, macrophages, smooth muscle cells, endothelial cells and T lymphocytes, IL-6 promotes inflammatory response and oxidative stress, and accelerates lipid deposition and foam cell formation, thereby participating in thrombosis and plaque formation and predisposing plaques to rupture. Ultimately, IL-6 exacerbates the progression of atherosclerosis.

FIGURE 3

IL-6 in Diabetic cardiomyopathy and Atrial fibrillation. In diabetic cardiomyopathy and atrial fibrillation, on the one hand, IL-6 promotes the development of diabetic myocardial fibrosis by enhancing TGF-β1 and inhibiting the expression of miRNA-29 in cardiac fibroblasts, which increases collagen synthesis. On the other hand, IL-6 promotes the secretion of MMP-2 from cardiomyocytes, which causes atrial fibrillation due to enlargement and remodeling of the left atrium.

FIGURE 4

Schematic representation of risk factor inducing IL-6 in Cardio-Cerebrovascular Disease. In response to stimulation by ischemia and hypoxia, oxidative stress, inflammation and vascular occlusion, IL-6 levels are elevated, which partly leads to the production of the acute phase protein CRP in the liver, thereby stimulating leukocyte recruitment and thrombosis, ultimately causing multiple cardio-cerebrovascular diseases.