Regulation of ADAMTS-1, -4 and -5 expression in human macrophages: differential regulation by key cytokines implicated in atherosclerosis and novel synergism between TL1A and IL-17

Atherosclerosis is an inflammatory disease of the vasculature regulated by cytokines. Macrophages play a crucial role at all stages of this disease, including regulation of foam cell formation, the inflammatory response and stability of atherosclerotic plaques. For example, matrix metalloproteinases produced by macrophages play an important role in modulating plaque stability. More recently, the ADAMTS proteases, which are known to play a key role in the control of cartilage degradation during arthritis, have been found to be expressed in atherosclerotic lesions and suggested to have potentially important functions in the control of plaque stability. Unfortunately, the action of cytokines on the expression of ADAMTS family in macrophages is poorly understood. We have investigated the effect of classical cytokines (IFN-γ and TGF-β) and those that have been recently identified (TL1A and IL-17) on the expression of ADAMTS-1, -4 and -5 in human macrophages. The expression of all three ADAMTS members was induced during differentiation of monocytes into macrophages. TGF-β had a differential action with induction of ADAMTS-1 and -5 expression and attenuation in the levels of ADAMTS-4. In contrast, IFN-γ suppressed the expression of ADAMTS-1 without having an effect on ADAMTS-4 and -5. Although TL-1A or IL-17A alone had little effect on the expression of all the members, they induced their expression synergistically when present together. These studies provide new insight into the regulation of key ADAMTS family members in human macrophages by major cytokines in relation to atherosclerosis

Differential regulation of macropinocytosis in macrophages by cytokines: Implications for foam cell formation and atherosclerosis

A key event during the formation of lipid-rich foam cells during the progression of atherosclerosis is the uptake of modified low-density lipoproteins (LDL) by macrophages in response to atherogenic mediators in the arterial intima. In addition to scavenger receptor-dependent uptake of LDL, macropinocytosis is known to facilitate the uptake of LDL through the constitutive and passive internalization of large quantities of extracellular solute. In this study we confirm the ability of macropinocytosis to facilitate the uptake of modified LDL by human macrophages and show its modulation by TGF-β, IFN-γ, IL-17A and IL-33. Furthermore we show that the TGF-β-mediated inhibition of macropinocytosis is a Smad-2/-3-independent process

Macrophages, lipid metabolism and gene expression in atherogenesis: a therapeutic target of the future?

Cardiovascular disease results in more deaths globally than any other ailment. A major contributing factor to its pathology is atherosclerosis; an inflammatory disorder characterized by the development of fibrotic plaques within the arterial walls. Key to the progression of atherosclerosis are macrophages that contribute to plaque development by transforming into lipid-loaded foam cells upon internalization of modified lipoproteins. Accumulation of such foam cells in the arterial wall initiates the formation of fatty streaks that subsequently develop into advanced plaques that are prone to rupture. Clearly, macrophage lipid metabolism and foam cell biology represent a key avenue of research during the ongoing search for novel therapeutic targets that can be used in the clinical intervention of atherosclerosis. In this article, we aim to summarize the current status of research on macrophages, lipid metabolism and gene expression in relation to atherogenesis and both current and potential future therapies

Liver X receptors, atherosclerosis and inflammation

Liver X receptors (LXRs) belong to the nuclear receptor superfamily of ligand-dependent transcription factors. LXRs are activated by oxysterols, metabolites of cholesterol, and therefore act as intracellular sensors of this lipid. There are two LXR genes (α and β) that display distinct tissue/cell expression profiles. LXRs interact with regulatory sequences in target genes as heterodimers with retinoid X receptor. Such direct targets of LXR actions include important genes implicated in the control of lipid homeostasis, particularly reverse cholesterol transport. In addition, LXRs attenuate the transcription of genes associated with the inflammatory response indirectly by transrepression. In this review, we describe recent evidence that both highlights the key roles of LXRs in atherosclerosis and inflammation and provides novel insights into the mechanisms underlying their actions. In addition, we discuss the major limitations of LXRs as therapeutic targets for the treatment of atherosclerosis and how these are being addressed

Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy

Cardiovascular disease is the biggest killer globally and the principal contributing factor to the pathology is atherosclerosis; a chronic, inflammatory disorder characterized by lipid and cholesterol accumulation and the development of fibrotic plaques within the walls of large and medium arteries. Macrophages are fundamental to the immune response directed to the site of inflammation and their normal, protective function is harnessed, detrimentally, in atherosclerosis. Macrophages contribute to plaque development by internalizing native and modified lipoproteins to convert them into cholesterol-rich foam cells. Foam cells not only help to bridge the innate and adaptive immune response to atherosclerosis but also accumulate to create fatty streaks, which help shape the architecture of advanced plaques. Foam cell formation involves the disruption of normal macrophage cholesterol metabolism, which is governed by a homeostatic mechanism that controls the uptake, intracellular metabolism, and efflux of cholesterol. It has emerged over the last 20 years that an array of cytokines, including interferon-γ, transforming growth factor-β1, interleukin-1β, and interleukin-10, are able to manipulate these processes. Foam cell targeting, anti-inflammatory therapies, such as agonists of nuclear receptors and statins, are known to regulate the actions of pro- and anti-atherogenic cytokines indirectly of their primary pharmacological function. A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis. Abbreviations ABCA-1/G-1, ATP-binding cassette transporter A-1/G-1; ACAT-1, Acyl-CoA:cholesterol acyltransferase-1; AcLDL, acetylated LDL; ADRP, adipocyte differentiation related protein; ApoE/A–I, apolipoprotein E/A–I; BMMs, bone-marrow derived macrophages; CD, cluster of differentiation; CHOP, C/EBP-homologous protein; CPT-1, carnitine palmitoyl transferase-1; CRP, C-reactive protein; CXCL, chemokine (C–X–C motif) ligand; CVD, cardiovasculardisease; DR3, Death Receptor 3; ECM, extracellular matrix; FAs, non-esterified fatty acids; HDL, high-density lipoprotein; HL, hepatic lipase; HMDMs, human monocyte-derived macrophages; HMG CoA, 3-hydroxy-3-methylglutaryl-CoA; ICAM1, intercellular adhesion molecule-1; IDL, intermediate density lipoprotein; IFN, interferon; IL, interleukin; IMT, intima-media thickness; JNK2, c-Jun N-terminal kinase 2; LIGHT, lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells; LDL, low density lipoprotein; LDLr, low density lipoprotein receptor; LPL, lipoprotein lipase; LXR, liver X receptor; MAPK, mitogen activated protein kinase; M1, classically activated macrophage; M2, alternatively activated macrophage; MCP-1, monocyte chemoattractant protein-1; M-CSF, macrophage-colony stimulating factor; MMP, matrix metalloproteinase; MPMs, murine peritoneal macrophages; NPC, Niemann Pick type C; NCEH, neutral cholesteryl ester hydrolase; oxLDL, oxidized LDL; PPAR, peroxisome proliferator-activated receptor; sIFN-γR, soluble interferon-γ receptor; SOCS3, suppressor of cytokine signaling 3; sPLA2, secretory phospholipase A2; SR, scavenger receptor; SR-PSOX, scavenger receptor for phosphatidylserine and oxidized LDL; Th, T-helper; TGF-β1, transforming growth factor-β1; TL1A, TNF-like protein 1A; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TNFSF, tumor necrosis factor superfamily; TWEAK, TNF-like weak inducer of apoptosis; UPR, unfolded protein response; VCAM-1, vascular cell adhesion molecule-1; VLDL, very low-density lipoprotein; VSMC, vascular smooth muscle cell

The expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 in human macrophages is inhibited by the anti-atherogenic cytokine transforming growth factor-β and requires Smads, p38 mitogen-activated protein kinase and c-Jun

Atherosclerosis is an inflammatory disorder of the vasculature that is orchestrated by the action of cytokines. Macrophages play a prominent role in all stages of this disease, including foam cell formation, production of reactive oxygen species, modulation of the inflammatory response and the regulation of the stability of atherosclerotic plaques. The role of the matrix metalloproteinase family in the control of plaque stability is well established. A disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) family has been implicated in several diseases and the expression of ADAMTS-4 in macrophages of atherosclerotic lesions has suggested a potential role for this protease in atherosclerosis. However, the action of cytokines on the expression of ADAMTS-4 in macrophages is poorly understood. We have investigated here the effect of transforming growth factor-β (TGF-β) on ADAMTS-4 expression in macrophages along with the regulatory mechanisms underlying its actions. Consistent with the anti-atherogenic role of TGF-β, this cytokine decreased the expression of ADAMTS-4 mRNA and protein in human macrophages. Transient transfection assays showed that the −100 to +10 promoter region contained the minimal TGF-β response elements. Small-interfering RNA-mediated knockdown revealed a critical role for Smads, p38 mitogen-activated protein kinase and c-Jun in the action of TGF-β on ADAMTS-4 mRNA expression. These studies show for the first time that TGF-β inhibits the expression of ADAMTS-4 in human macrophages and identifies the signalling pathways underlying this response. The inhibition of macrophage ADAMTS-4 expression is likely to contribute to the anti-atherogenic, plaque stabilisation action of TGF-β