Roles of IL-6-gp130 Signaling in Vascular Inflammation

Abstract

Interleukin-6 (IL-6) is a well-established, independent indicator of multiple distinct types of cardiovascular disease and all-cause mortality. In this review, we present current understanding of the multiple roles that IL-6 and its signaling pathways through glycoprotein 130 (gp130) play in cardiovascular homeostasis. IL-6 is highly inducible in vascular tissues through the actions of the angiotensin II (Ang II) peptide, where it acts in a paracrine manner to signal through two distinct mechanisms, the first being a classic membrane receptor initiated pathway and the second, a trans-signaling pathway, being able to induce responses even in tissues lacking the IL-6 receptor. Recent advances and new concepts in how its intracellular signaling pathways operate via the Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) are described. IL-6 has diverse actions in multiple cell types of cardiovascular importance, including endothelial cells, monocytes, platelets, hepatocytes and adipocytes. We discuss central roles of IL-6 in endothelial dysfunction, cellular inflammation by affecting monocyte activation/differentiation, cellular cytoprotective functions from reactive oxygen species (ROS) stress, modulation of pro-coagulant state, myocardial growth control, and its implications in metabolic control and insulin resistance. These multiple actions indicate that IL-6 is not merely a passive biomarker, but actively modulates adaptive and pathological responses to cardiovascular stress. Summary:IL-6 is a multifunctional cytokine whose presence in the circulation is linked with diverse types of cardiovascular disease and is an independent risk factor for atherosclerosis. In this review, we examine the mechanisms by which IL-6 signals and its myriad effects in cardiovascular tissues that modulate the manifestations of vascular inflammation.

Association of Systemic Arterial Properties With Right Ventricular Morphology: The Multi‐Ethnic Study of Atherosclerosis (MESA)‐Right Ventricle Study

“…In the MESA‐RV cohort, higher levels of IL‐6 and CRP have been shown to be associated with lower RV mass and smaller RV volumes 34. IL‐6, and its signaling pathways through glycoprotein 130, mediate the interface between the cardiomyocyte's compensatory remodeling and apoptosis in response to injury, which could explain the reduction in RV size 52, 53. Collectively, these findings imply that systemic arterial health could affect the RV through vasoactive mediators by a direct effect through the coronary flow and microvasculature.…”

Recipient Myd88 Deficiency Promotes Spontaneous Resolution of Kidney Allograft Rejection

“…28 IL-6 is a pleiotropic cytokine that can be induced via MyD88 signaling in response to several stimuli, such as IL-1, TNF-a, and LPS. [29][30][31][32][33][34] Elevated IL-6 in blood and urine was correlated with rejection in transplant recipients. 35,36 IL-6 is produced by a variety of cells, such as APCs, endothelial cells (ECs), and activated T cells.…”

Multifaceted Role of Angiotensin II in Vascular Inflammation and Aortic Aneurysmal Disease

“…Together, these data suggest that NF-κB transcription factor is required for inducible expression of the IL-6 by Ang II. IL-6 is a 26 kDa glycosylated cytokine that acts in a paracrine manner to signal through two distinct mechanisms, termed the classical initiated by membrane receptor binding, and the trans-signaling pathway mediated by soluble IL-6 R (Hou, et al, 2008). Classical IL-6 signaling is mediated via ligand binding to the IL-6R receptor on the cell membrane.…”

“…JAK1 in turn induces tyrosine phosphorylation and activation of STAT isoforms STAT1 and STAT3 (Figure 1). As transcription factors, they then form homoand heterodimers with each other, translocate to the nucleus, bind specific DNA sequences and enhance transcription of target genes via interactions with co-factors and co-activators such as p300/CREB-binding protein (CBP) and Positive Transcription Elongation Factor (PTEF-b) (Hou, et al, 2008). IL-6 plays a major role in inducing systemic responses to the presence of vascular inflammation through the hepatic acute-phase response (Brasier, et al, 2002).…”

“…IL-6 stimulation increases esterase and phagocytic activities and enhances surface expression of Fc receptors, macrophage-colony stimulating factor (M-CSF) receptors, and the mature macrophage marker F4/80. Additionally, IL-6 induces expression of genes important for macrophage differentiation such as c-Jun, jun B, jun D, interferon-regulatory factor 1 (IRF1), JAK3, Egr-1 (Hou, et al, 2008). Moreover, IL-6 up-regulates MCP-1 expression (Biswas, et al, 1998;Tieu, et al, 2009) by vascular monocytic cells.…”