Abstract
Atherosclerosis, a chronic inflammatory disorder of the walls of arteries, causes more deaths worldwide than any other disease. Cytokines, which are present at high levels in atherosclerotic plaques, play important roles in regulating the initiation and the progression of the disease. Previous studies using animal and cell culture model systems revealed protective, anti-atherogenic effects of the cytokine interleukin-33 (IL-33). The action of this cytokine involves both the induction and suppression of expression of many genes. Unfortunately, the signaling pathways that are responsible for the inhibition of gene expression by this cytokine are poorly understood. Further studies are required given the important roles of genes whose expression is inhibited by IL-33 in key cellular processes associated with atherosclerosis such as monocyte recruitment, foam cell formation and lipoprotein metabolism. We have investigated here the roles of various known IL-33 activated signaling pathways in such inhibitory actions using RNA interference-mediated knockdown assays and monocyte chemotactic protein-1 and intercellular adhesion molecule-1 as model genes. Key roles were identified for extracellular signal-regulated kinase-1/2, p38α kinase, c-Jun N-terminal kinase-1/2, phosphoinositide 3-kinase-γ, and p50 and p65 nuclear factor-κB in such inhibitory action of IL-33. These studies provide new insights on the signaling pathways through which IL-33 inhibits the macrophage expression of key atherosclerosis-associated genes.
Highlights
Atherosclerosis, a major underlying cause of coronary heart disease (CHD), is associated with inflammation of the arterial wall[1,2]
In contrast to activation, the signaling pathways involved in the suppression of gene expression by IL-33 are poorly understood mainly due to limited previous research and formed the focus of our current study on human macrophages using monocyte chemotactic protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) as model genes
The action of IL-33 was conserved between human THP-1 macrophages, which have been used in numerous studies on macrophages in relation to atherosclerosis[22], and primary cultures of human monocyte-derived macrophages (HMDM) and mouse bone marrow-derived macrophages (BMDM), and extended to the in vivo context[10]
Summary
Atherosclerosis, a major underlying cause of coronary heart disease (CHD), is associated with inflammation of the arterial wall[1,2]. The disease is initiated by endothelial cell dysfunction or activation in response to pro-inflammatory stimuli, such as modified low-density lipoproteins (LDL). This results in increased secretion of chemokines [e.g. monocyte chemotactic protein-1 (MCP-1)] by the endothelial cells along with the expression of cell surface adhesion molecules [e.g. intercellular adhesion molecule-1 (ICAM-1)], which together facilitate the recruitment, attachment and infiltration of circulating leukocytes into the subendothelial space[1,2]. Subsequent studies have confirmed the requirement of the ST2 receptor in the IL-33-mediated regulation of expression of other genes in human macrophages together with its anti-foam cell action[11,13]. IL-33 inhibited macropinocytosis[5], which contributes to the disease via the macrophage uptake of LDL particles[1] Both the up- and down-regulation of gene expression is associated with the cellular actions of IL-33. We show key roles for extracellular signal-regulated kinase (ERK)-1/2, p38α MAPK, c-Jun N-terminal kinase (JNK)-1/2, PI3K-γ, and p50 and p65 NF-κB
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