title: Interleukin-18-induced atherosclerosis involves CD36 and NF-κB crosstalk in Apo E-/- mice.
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 (2mo); Gp II, recombinant (r)IL-18 (1mo) followed by PBS (1mo); Gp III, rIL-18 (1mo) followed by PDTC (1mo).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
authors.forename: Owais Mohammad
authors.initials: OM
authors.lastname: Bhat
authors.affiliation: National Centre for Laboratory Animal Sciences (NCLAS), Hyderabad, Department of Histopathology, National Institute of Nutrition (NIN), Hyderabad, India.
authors.forename: P Uday
authors.initials: PU
authors.lastname: Kumar
authors.affiliation: Amrita School of Nanosciences & Molecular Medicine, Amrita Institute of Medical Sciences, Amrita Viswavidyapeedham, Kochi, Kerala, India.
authors.forename: N V
authors.initials: NV
authors.lastname: Giridharan
authors.affiliation: Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaul
authors.affiliation: Animal House, Centre for Cellular and Molecular Biology (CCMB), Hyderabad, India.
authors.forename: M J Mahesh
authors.initials: MJ
authors.lastname: Kumar
authors.affiliation: Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Electronic address: veenad2001@yahoo.com.
authors.forename: Veena
authors.initials: V
authors.lastname: Dhawan
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D007249:Inflammation / Q000517:prevention & control*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D013859:Thiocarbamates / Q000494:pharmacology*
chemical_list: D018955:CD36 Antigens; D020382:Interleukin-18; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D020780:Matrix Metalloproteinase 9
keywords: Atherosclerosis; CD36; Liver X receptor alpha; Nuclear factor kappa-B; Recombinant interleukin-18