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.

Keywords: IL-6/ gp-130/ angiotensin II/ STAT3/ vascular inflammation..

Fig. (1).

IL-6 induced classical and trans-signaling pathways. Shown is a schematic view of classical IL-6 signaling via the IL-6Rα receptor and gp130 for a representative hepatocyte. IL-6Rα bound to the IL-6 ligand results in complex formation with gp130, activating tyrosine kinase activity, including and culminating in tyrosine phosphorylation of STAT3. The IL-6 trans-signaling pathway is diagrammed at top, using a representative endothelial cell. Circulating IL-6∙IL-6Rα engages with gp130 expressed on cells, enabling activation of the IL-6 signaling pathway in cells lacking IL-6Rα. See text for further details.

Fig. (2).

Discrete mechanisms for IL-6 induction of target genes. Top, coactivator recruitment mechanism. Tyrosine phosphorylated STAT3 binds to p300/CBP, resulting in STAT3 acetylation (Ac) on its NH₂ terminus, and stabilization of the STAT3-p300/CBP complex. The acetylated-phosphorylated STAT3-p300/CBP complex then binds to high affinity IL-6 response elements in the promoters of target genes. This complex induces nucleosomal reorganization via the p300 histone acetylase activity, pre-initiation complex formation, recruiting TATA box binding protein, and enhanced RNA polymerase II activity. Bottom, transcriptional elongation. In a subset of IL-6 responsive promoters, RNA polymerase (Pol) II is engaged with the promoter producing incomplete transcripts. During the process of activation, tyrosine phosphorylated STAT3 complexes with the positive transcriptional elongation factor (PTEF-b), a complex containing CDK9. CDK9 phosphorylates the COOH terminal domain of RNA polymerase II, enabling it to enter productive elongation mode, producing full length RNA transcripts.

Fig. (3).

Negative regulation of the JAK-STAT pathway. Shown are the major negative autoregulatory pathways of IL-6 induced STAT3 signaling. IL-6 activated STAT3 both engages the suppressor of cytokine signaling (SOCS3) gene, inducing its expression and recruits SOC3 to gp130 where it subsequently terminates STAT3 activation via JAK1 inactivation. SHP2 phosphatase activity also inactivates gp130 and JAKs.