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

https://doi.org/10.1016/j.jjcc.2014.10.012Get rights and content
Under an Elsevier user license
open archive

Abstract

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.

Keywords

Recombinant interleukin-18
Atherosclerosis
CD36
Liver X receptor alpha
Nuclear factor kappa-B

Cited by (0)