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

Li, Na, McLaren, James Edward ORCID: https://orcid.org/0000-0002-7021-5934, Michael, Daryn Robert, Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Fielding, Ceri Alan ORCID: https://orcid.org/0000-0002-5817-3153 and Ramji, Dipak Purshottam ORCID: https://orcid.org/0000-0002-6419-5578 2010. 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. The Journal of Immunology 185 (5) , pp. 3041-3048. 10.4049/jimmunol.1000993

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	Q Science > QH Natural history > QH426 Genetics Q Science > QR Microbiology > QR180 Immunology
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Last Modified:	27 Jul 2023 01:07
URI:	https://orca.cardiff.ac.uk/id/eprint/24210

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