ERK Is Integral to the IFN-γ–Mediated Activation of STAT1, the Expression of Key Genes Implicated in Atherosclerosis, and the Uptake of Modified Lipoproteins by Human Macrophages

Abstract

The proinflammatory cytokine IFN-γ is a master regulator of atherosclerosis and mediates its cellular actions mainly through STAT1. Unfortunately, the impact of other IFN-γ inducible pathways on STAT1 activation and the regulation of downstream responses associated with atherosclerosis in human macrophages are poorly understood and were therefore investigated. In this study, we demonstrate that the IFN-γ–mediated phosphorylation of STAT1 on Ser727, crucial for its maximal activity, was attenuated in human macrophages by pharmacological inhibition of ERK. In these cells, IFN-γ induced changes in the expression of several key genes implicated in atherosclerosis, such as MCP-1, through an ERK-dependent mechanism. Additionally, the IFN-γ–induced activity of STAT1-responsive promoters was attenuated by transfection of dominant-negative forms of ERK and other key components of this pathway. Furthermore, the IFN-γ–induced uptake of acetylated and oxidized low-density lipoprotein by human macrophages was attenuated by pharmacological inhibition or RNA interference–mediated knockdown of ERK. These studies suggest a critical role for ERK signaling in the IFN-γ–mediated changes in macrophage cholesterol homeostasis and gene expression during atherosclerosis.

Silence of lncRNA UCA1 Represses the Growth and Tube Formation of Human Microvascular Endothelial Cells Through miR-195

“…MEK activation is the upstream signaling event that leads to the activation of ERK. During atherosclerosis, ERK modulates macrophage cholesterol homeostasis and key genes implicated in atherosclerosis [35]. Besides, multiple researchers have suggested that mTOR may offer new avenues in the regression of atherosclerotic plaques [36,37].…”

Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

“…Several cytokines were previously shown to modulate the formation of foamy macrophages generated in the presence of aggregated, acetylated or oxidized LDL. IFN-␥ , IL-1 ␤ , and TNF-␣ promote macrophage foam cell formation (25)(26)(27)(28), while IL-6, TGF-␤ 1, and IL-33 (29)(30)(31) have been described as anti-foam cell cytokines in humans and IL-10 facilitates both cholesterol uptake and effl ux in macrophages ( 32 ). Only IL-1 ␤ expression was weakly affected by IL-17A treatment, suggesting a role for this models.…”

Immunization With a Combination of 2 Peptides Derived From the C5a Receptor Significantly Reduces Early Atherosclerotic Lesion in Ldlr tm1Her Apob tm2Sgy J Mice

“…30,31 On the basis of the cytokine profiles from either plasma or spleen cells in immunized mice, TNF-α and IFN-γ secretion may well be linked to the ability of the immune animals to release these cytokines from preprimed cells, leading to a decrease in the need to synthesize significant amounts of new TNF-α and IFN-γ. Our results show that vaccination with peptides promoted a major shift away from proinflammatory cytokines (ie, TNF-α and IFN-γ) toward antiinflammatory cytokines (IL-10 and TGF-β), which is evident not only in the plaque but also systemically.…”