Interleukin-18-induced atherosclerosis involves CD36 and NF-κB crosstalk in Apo E-/- mice

Objective: Interleukin (IL)-18 is a pleotropic cytokine involved in various inflammatory disorders. The transcription factor, nuclear factor kappa-B (NF-kappa B), is thought to play an important role in IL-18 signaling. The present study proposes a novel role for 1L-18 in cholesterol efflux and plaque stability and demonstrates that pyrrolidine dithiocarbamate (PDTC), a NF-kappa B 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)alpha 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-kappa B was observed in Gp II but liver X receptor alpha (LXR-alpha) 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 R alpha via NF-kappa B which is involved in progression and destabilization of atherosclerotic plaques in Apo E-/- mice. This study also reveals that NF-kappa B blockade with PDTC, blocks IL-18 signaling through down-regulation of IL-18, IL-18 R alpha, CD36, and MMP-9, thus reducing inflammation and restoring plaque instability via upregulation of LXR-alpha. (C) 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.