STAT1 As a Novel Therapeutical Target in Pro-atherogenic Signal Integration of IFNγ, TLR4 and IL-6 in Vascular Disease

Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of atherosclerosis. Recruitment of blood leukocytes to the injured vascular endothelium characterizes the initiation and progression of atherosclerosis and involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The pro-inflammatory cytokine, interferon (IFN)-γ derived from T cells, is vital for both innate and adaptive immunity and is also expressed at high levels in atherosclerotic lesions. As such IFN-γ plays a crucial role in the pathology of atherosclerosis through activation of signal transducer and activator of transcription (STAT) 1. Toll-like receptors (TLRs) are innate immune pattern recognition receptors (PRRs) expressed on a variety of cells, and thus initiate and sustain the inflammatory response in atherosclerosis. More recent studies have revealed that STAT1 is involved in the signaling events mediated by TLR4, leading to increased expression of several pro-inflammatory and pro-atherogenic mediators. By upregulating members of the Suppressors Of Cytokine Signaling (SOCS) family that regulate cellular responsiveness to immune signals, IFNγ and TLR4-activated pathways have also shown to inhibit IL-6 STAT3-dependent anti-inflammatory signaling and potentially shift IL-6 to a STAT1 activating pro-inflammatory cytokine. Consequently, STAT1 has been identified as a point of convergence for the cross-talk between the pro-atherogenic IFN-γ, TLR4 and IL-6 activated pathways in immune as well as vascular cells, as such amplifying pro-inflammatory signals. This results in augmented smooth muscle cell (SMC) and leukocyte migration, leukocyte to endothelial cell (EC) adhesion and foam cell formation, and could encompass a novel mechanism involved in the initiation and progression of atherosclerosis. Therefore, application of small inhibitory compounds that specifically interact with the SH2-phosphotyrosine pocket of STAT1, proposed here as a novel working mechanism for the known STAT1 inhibitor fludarabine, could be a promising tool in the development of a therapeutical strategy for atherosclerosis.