The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation

Abstract

Vascular inflammation is a common pathophysiological response to diverse cardiovascular disease processes, including atherosclerosis, myocardial infarction, congestive heart failure, and aortic aneurysms/dissection. Inflammation is an ordered process initiated by vascular injury that produces enhanced leucocyte adherence, chemotaxis, and finally activation in situ. This process is coordinated by local secretion of adhesion molecules, chemotactic factors, and cytokines whose expression is the result of vascular injury-induced signal transduction networks. A wide variety of mediators of the vascular injury response have been identified; these factors include vasoactive peptides (angiotensin II, Ang II), CD40 ligands, oxidized cholesterol, and advanced glycation end-products. Downstream, the nuclear factor-kappaB (NF-kappaB) transcription factor performs an important signal integration step, responding to mediators of vascular injury in a stimulus-dependent and cell type-specific manner. The ultimate consequence of NF-kappaB signalling is the activation of inflammatory genes including adhesion molecules and chemotaxins. However, clinically, the hallmark of vascular NF-kappaB activation is the production of interleukin-6 (IL-6), whose local role in vascular inflammation is relatively unknown. The recent elucidation for the role of the IL-6 signalling pathway in Ang II-induced vascular inflammation as one that controls monocyte activation as well as its diverse signalling mechanism will be reviewed. These new discoveries further our understanding for the important role of the NF-kappaB-IL-6 signalling pathway in the process of vascular inflammation.

Figure 1

NF-κB activation pathways. Schematic view of the canonical (left) and non-canonical (right) NF-κB activation pathways. The canonical pathway is activated by activated TNF receptor via the IKK signalsome, composed of the catalytic kinases IKKα and -β, and the regulatory subunit IKKγ. Activated IKK is responsible for NF-κB translocation by proteolysis of the IκBα inhibitor. NF-κB activation is mediated by the PKAc phosphorylating Ser residue 276 of the RelA subunit. In contrast, Ang II activates the canonical pathway by inducing the Carma3·Bcl10·MALT1 complex, known as the ‘CBM signalsome’ upstream of IKK. Activated IKK liberates NF-κB for translocation. NF-κB activation is mediated by the RhoA-NIK signalling pathway converging on phosphorylation of RelA on Ser residue 536. The non-canonical pathway is controlled by the IKK complex composed of IKKα and NIK. Activated IKKα·NIK phosphorylates the COOH terminus of 100 kDa precursor of NF-κB2 DNA-binding subunit. Liberated NF-κB2 associates with RelA (forming the cross-talk pathway), and RelB, with the latter complex activating CCL19 and other unique genes. IKK, IκB kinase; TNF, tumour necrosis factor; NIK, NF-κB-inducing kinase; PKAc, catalytic subunit of protein kinase A; Pol II, RNA polymerase II.

Figure 2

Overview of NF-κB–IL-6 in the major regulated steps in vascular inflammation. A variety of pro-inflammatory agonists activate resident VSMCs, fibroblasts, and endothelial cells via the NF-κB transcription factor, including TNF, local and systemic Ang II production, and CD40 ligands, sCD40 and CD145, advanced glycation end-products, and oxidized LDL. Downstream, activated NF-κB coordinates the expression of monocyte adhesion proteins, including VCAM-1 and ICAM-1. Circulating monocytes enter the vessel wall either from ‘inside-out’ via endothelial cell interaction, or from ‘outside-in’ via the adventitial vaso vasorum. Monocyte chemotaxis is controlled by NF-κB-inducing expression of MCP-1, GM-CSF, and other chemokines. Monocyte activation is controlled by local IL-6 production. IL-6 acts through trans-signalling and trans-membrane signalling result in monocyte activation (MMP expression) and ROS resistance. Enhanced monocytic interaction with adventitial fibroblasts produce an amplification loop, enhancing MCP-1 and IL-6 production. Activated monocyte/macrophages oxidize cholesterol, release ROS, and matrix metalloproteinases to produce ECM remodelling that contribute to vascular pathology.