Interleukin-18-induced atherosclerosis involves CD36 and NF-κB crosstalk in Apo E-/- mice
Publication Type:Journal Article
Source:Journal of Cardiology, Japanese College of Cardiology (Nippon-Sinzobyo-Gakkai), Volume 66, Number 1, p.28-35 (2015)
Keywords:animal cell, animal model, animal tissue, apolipoprotein E, article, atherosclerosis, atherosclerotic plaque, capillary endothelial cell, CD36 antigen, cholesterol, cholesterol blood level, controlled study, down regulation, enzyme linked immunosorbent assay, fluorescence activated cell sorting, gelatinase B, gene expression, heart muscle cell, high density lipoprotein cholesterol, histopathology, immunoglobulin enhancer binding protein, immunohistochemistry, interleukin 18, interleukin 18 receptor alpha, liver X receptor alpha, low density lipoprotein cholesterol, male, messenger RNA, mouse, nonhuman, peripheral blood mononuclear cell, protein blood level, protein expression, pyrrolidine dithiocarbamate, real time polymerase chain reaction, recombinant interleukin 18, tissue section, triacylglycerol, triacylglycerol blood level, upregulation, very low density lipoprotein cholesterol
Objective: Interleukin (IL)-18 is a pleotropic cytokine involved in various inflammatory disorders. The transcription factor, nuclear factor kappa-B (NF-κB), is thought to play an important role in IL-18 signaling. The present study proposes a novel role for IL-18 in cholesterol efflux and plaque stability and demonstrates that pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor blocks IL-18 signaling in apolipoprotein (Apo) E-/- mice. Methods: Three groups of normal chow-diet-fed, male Apo E-/- mice, aged 12 weeks (n = 6/group) were employed: Gp I, PBS (2 mo); Gp II, recombinant (r)IL-18 (1 mo) followed by PBS (1 mo); Gp III, rIL-18 (1 mo) followed by PDTC (1 mo). Results: Significantly augmented expression of IL-18 receptor (R)α by fluorescence-activated cell sorting analysis and plasma IL-18 was observed in Gp II. There was a significant increase in total cholesterol and low-density lipoprotein cholesterol whereas high-density lipoprotein cholesterol was significantly decreased in Gp II. However, this pattern was reversed in Gp III. Significantly augmented mRNA expression of IL-18, CD36, matrix metalloproteinase (MMP)-9, and NF-κB was observed in Gp II but liver X receptor alpha (LXR-α) gene was significantly reduced. A significant increase in frequency of atherosclerotic lesions was observed in Gp II animals, whereas there was a significant decrease in the Gp III. Conclusion: IL-18 administration initiates inflammatory cascade by binding with IL-18 Rα via NF-κB which is involved in progression and destabilization of atherosclerotic plaques in Apo E-/- mice. This study also reveals that NF-κB blockade with PDTC, blocks IL-18 signaling through down-regulation of IL-18, IL-18 Rα, CD36, and MMP-9, thus reducing inflammation and restoring plaque instability via upregulation of LXR-α © 2014 Japanese College of Cardiology.
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