Atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors
Highlights
► TNF-α and IL-6 each promoted foam cell formation, a pivotal process of oxLDL-mediated atherogenesis. ► αIL-6R Ab partially inhibited TNF-α-induced oxLDL accumulation. ► Serum from RA patients, but not serum of healthy subjects, induced foam cell formation. ► Foam cell formation induced by serum from RA serum was partially reverse by either αIL-6R Ab or TNF-α receptor (p75)-Fc. ► TNF-α, IL-6 and serum from RA patients each up-regulated the expression of SR-A, LOX-1 which uptake oxLDL.
Introduction
In patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus, the risk of cardiovascular disease (CVD) is increased [1], [2]. Inflammatory cytokines are considered of fundamental importance in the development of CVD. The greatest advance in the therapy of RA has been the identification of the key pathogenic roles played by TNF-α and IL-6. Interestingly, one recent study showed that TNF-α blockade also has a beneficial effect on the risk for mortality from CVD in RA patients [3]. However, the mechanisms underlying this preventive effect of TNF-α blockade on CVD are not yet fully clear. Mortality due to CVD is increased in inflammatory diseases [4], [5], but this elevated risk is not explained by traditional risk factors for CVD such as elevated LDL cholesterol, smoking, high fat diet, or heredity [6], [7], [8]. Paradoxically, although TNF-α blockade therapy significantly increases serum levels of cholesterol and LDL, it nevertheless decreases the onset of CVD.
The pathway leading to atherosclerotic plaque and cardiovascular events begins with fatty streak formation and macrophage infiltration. Macrophages are dedicated phagocytes and their sole function is to remove small particles like lipoproteins as well as pathogens and dead or damaged cells. After phagocytosis, lipoproteins are efficiently delivered to lysozymes for degradation [9]. However, oxidized low density lipoprotein (oxLDL) protein is resistant to lysosomal degradation and accumulates along with oxLDL cholesterol [10]. This accumulation results in the transformation of macrophages into foam cells, resulting in the formation of plaque. oxLDL and its scavenger receptors participate in all of these processes. Therefore, in this study, we evaluated the effect of TNF-α and IL-6 on the pivotal process of oxLDL-mediated atherogenesis, and thus, foam cell formation.
We demonstrated that TNF-α and IL-6 were each able to promote oxLDL accumulation and foam cell formation by up-regulating the expressions of scavenger receptors: human scavenger receptor-A (SR-A) and lectin-like oxidized LDL receptor-1 (LOX-1). In addition, IL-6 induced by TNF-α at least partially mediated the foam cell formation by TNF-α. Finally, we found that foam cell formation and the expression of scavenger receptors were significantly augmented by the serum of RA patients, but not by the serum of healthy subjects.
Section snippets
Reagents and cells
A humanized anti-human IL-6R antibody (tocilizumab, αIL-6R Ab, [11]) was prepared in our laboratories. Recombinant human TNF-α and human IL-6 were purchased from PeproTech (Rocky Hill, NJ, USA). A recombinant TNF-α-receptor (p75)-Fc-fusion protein (etanercept, αTNF-α Ab) was purchased from Wyeth (Munster, Germany). Human IgG and recombinant human IFN-γ were purchased from Sigma–Aldrich (St Louis, MO, USA). The human monocyte cell line THP-1 was obtained from ATCC (Manassas, VA, USA) and
IL-6 and TNF-α induced foam cell formation in THP-1/macrophages
The THP-1/macrophage assay system for oxLDL accumulation was widely used in evaluation of the effects of cytokines or drugs on foam cell formation. We used the THP-1/macrophage assay system for oxLDL accumulation based on a system reported previously [13]. As previously reported, IFN-γ stimulation accelerated the uptake of oxLDL in our system. TNF-α and IL-6 also increased intracellular oxLDL accumulation in THP-1/macrophages. αTNF-α and αIL-6R Ab inhibited intracellular oxLDL accumulation
Discussion
We examined the effects of TNF-α and IL-6 on foam cell formation by measuring the accumulation of oxLDL in THP-1/macrophages, which is a well-characterized experimental system to study the transformation of macrophages to foam cells [16]. Briefly, human THP-1 monocytic cells are differentiated into macrophages by stimulation with PMA, and these macrophages become foam cells by the uptake of modified LDLs, such as oxLDL or acetylated LDL [17]. In this study, we confirmed that IFN-γ promoted foam
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