SIGNALLING PATHWAYS UNDERLYING INTERFERON-γ ACTIONS IN ATHEROSCLEROSIS
Na Li, James E. McLaren and Dipak P. Ramji
Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK
Interferon-γ (IFN-γ) is a major pro-atherogenic cytokine that affects several steps in this disease, including foam cell formation and regulation of plaque stability. A critical role of IFN-γ in atherosclerosis has been revealed from numerous in vitro and in vivo studies. For example, deficiency of this cytokine or its receptors limits the development of atherosclerosis in mouse model systems whereas in vivo administration of IFN-γ potentiates this disease. In addition, neutralisation of this cytokine by repeated injections of a plasmid specifying for a mutant form of the IFN-γ receptor reduces plaque burden and produces a more stable phenotype in mouse models of this disease. Furthermore, the anti-atherogenic effects of lipid-lowering drugs are in part due to the inhibition of IFN-γ actions. It is therefore important to understand the molecular mechanisms underlying IFN-γ actions in atherosclerosis and have therefore been the focus of recent studies in my laboratory. The actions of IFN-γ are mainly mediated via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-1 pathway. In this pathway, binding of IFN-γ to its receptors initiates a signalling pathway that results in the phosphorylation of STAT1 on tyrosine 701 (Y701). STAT1 then dimerises, translocates to the nucleus and regulates gene transcription. In addition to Y701, STAT1 phosphorylation on serine 727 (S727) is required for maximal activity. IFN-γ also activates a number of other signalling pathways though their roles remain poorly understood. Our previous studies have provided new insights into IFN-γ signalling, particularly transcriptional inhibition through Sp1/Sp3 and the roles of casein kinase 2 (CK2) and phosphoinositide 3’-kinase (PI3K) signalling. A major action of CK2 and PI3K was mediated through the control of STAT1 phosphorylation on S727. More recently, we have shown that extracellular signal-regulated kinase (ERK)1/2 is integral to the IFN-γ-mediated activation of STAT1 via S727 phosphorylation, the expression of key genes implicated in atherosclerosis and the uptake of modified lipoproteins in human macrophages. We have also found that lipid-lowering drugs inhibit the trans-activation potential of STAT1. These studies provide novel insights into IFN-γ signalling in atherosclerosis.