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Immunotropic Effects and Proposed Mechanism of Action for 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors (Statins)

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Abstract

Inhibitors of HMG-CoA reductase (statins) are the major group of lipid-lowering drugs. Along with hypocholesterolemic activity, statins exhibit anti-inflammatory and immunomodulatory properties that expand their clinical use, particularly, in the treatment of chronic inflammatory and autoimmune disorders. In this review, we critically analyze the data of statin effects on immune cells (e.g., monocytes and T cells) involved in the development of atherosclerosis and other chronic inflammatory diseases. We (i) discuss the properties of statins and routes of cell entry, as well as their major intracellular targets; (ii) evaluate the data on the effects of statins on the subset composition of circulatory monocytes, ability of monocytes to migrate to the site of inflammation (cell motility and expression of adhesion molecules and chemokine receptors), production of cytokines, matrix metalloproteinases, and reactive oxygen species by monocytes/macrophages, and antigen-presenting activity in peripheral blood monocyte-derived dendritic cells; and (iii) summarize the data on the regulation of proliferation and differentiation of various CD4+ T cell subsets (type 1/2/17 helper T cells and regulatory T cells) by statins.

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Abbreviations

CD:

cluster of differentiation

CRP:

C–reactive protein

DCs:

dendritic cells

ERK1/2:

extracellular signal–regulated kinase–1/2

FPP:

farnesyl pyrophosphate

GGPP:

geranylgeranyl pyrophosphate

GM–CSF:

granulocyte macrophage colony stimulating factor

GTPase:

guanosine triphosphate hydrolase

HLA–DR:

human leukocyte antigen–antigen D–related

HMG–CoA reductase:

3–hydroxy–3–methylglutaryl–coenzyme A reductase

ICAM–1:

intracellular adhesion molecule 1

IL:

interleukin

INF–γ:

interferon–γ

LFA–1:

lymphocyte function–associated antigen 1, integrin family of adhesion molecules

LPS:

lipopolysaccharide

Mac–1:

macrophage–1 antigen, integrin family of adhesion molecules

MAP kinase:

mitogen–activated protein kinase

MCP–1:

monocyte chemoattractant protein–1

MIP:

macrophage inflammatory protein, cytokine

MMP:

matrix metalloproteinase

mTOR:

mammalian target of rapamycin, protein kinase

PHA:

phytohemagglutinin

RANTES:

regulated on activation, normal T–cell expressed and secreted (chemokine)

TGFβ:

transforming growth factor–β

Th1/2/17:

type 1/2/17 helper T cells

TIMP:

tissue inhibitor of metalloproteinase

TLR4:

Toll–like receptor 4

TNF:

tumor necrosis factor

Treg:

regulatory T lymphocytes

VLA–4:

very late antigen–4, integrin family of adhesion molecules

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Authors and Affiliations

  1. National Medical Research Center of Cardiology, Ministry of Health of the Russian Federation, 121552, Moscow, Russia

    T. I. Arefieva, A. Yu. Filatova, A. V. Potekhina & A. M. Shchinova

  2. Kurchatov Institute National Research Center Complex, 123182, Moscow, Russia

    T. I. Arefieva

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Original Russian Text © T. I. Arefieva, A. Yu. Filatova, A. V. Potekhina, A. M. Shchinova, 2018, published in Biokhimiya, 2018, Vol. 83, No. 8, pp. 1111–1129.

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Arefieva, T.I., Filatova, A.Y., Potekhina, A.V. et al. Immunotropic Effects and Proposed Mechanism of Action for 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors (Statins). Biochemistry Moscow 83, 874–889 (2018). https://doi.org/10.1134/S0006297918080023

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