PMID- 19201478
OWN - NLM
STAT- MEDLINE
DCOM- 20100125
LR  - 20131121
IS  - 1872-9142 (Electronic)
IS  - 0161-5890 (Linking)
VI  - 47
IP  - 1
DP  - 2009 Nov
TI  - Increased atherosclerotic lesions and Th17 in interleukin-18 deficient 
      apolipoprotein E-knockout mice fed high-fat diet.
PG  - 37-45
LID - 10.1016/j.molimm.2008.12.032 [doi]
AB  - Recent reports show T helper 17 (Th17) cells are involved in the pathogenesis of 
      various chronic inflammatory diseases formerly categorized as Th1-mediated 
      disorders. Interleukin-18 (IL-18) induces Th1 cells to produce interferon-gamma 
      (IFN-gamma) which is proatherogenic, while cholesterol causes atherosclerosis and 
      stimulates intact rat aortae to produce prostaglandin E(2) (PGE(2)), a strong 
      regulator of IL-23 that expands Th17. We wanted to test whether Th17 is 
      proatherogenic and whether cholesterol can induce the alternative Th17 pathway in 
      IL-18 deficient apolipoprotein E-knockout (ApoE(-/-)) mice that have reduced Th1 
      cells, if they are fed high-cholesterol diet. IL-18(+/+)ApoE(-/-) and 
      IL-18(-/-)ApoE(-/-) mice aged 5 weeks were fed high-cholesterol diet (HCD) and 
      control littermates of IL-18(-/-)ApoE(-/-) low-cholesterol diet (LCD) for 12 
      weeks. At termination, cryosectioned aortic arches were stained for lesion 
      measurement and immunohistochemistry. We found that serum cholesterol and 
      triglyceride levels were significantly higher in IL-18(-/-)ApoE(-/-) mice on HCD 
      and they also had significantly increased atherosclerosis compared with 
      18(+/+)ApoE(-/-) mice or IL-18(-/-)ApoE(-/-) mice on LCD. Increased 
      atherosclerosis correlates with enhanced Th17-cells, IL-23-producing vascular 
      smooth muscle cells (VSMC) and macrophages, and thin fibrous cap in lesions, the 
      morphology indicative of unstable plaques prone to rupture. In vitro, cholesterol 
      significantly enhances VSMCs explanted from IL-18(-/-)ApoE(-/-) but not 
      IL-18(+/+)ApoE(-/-) aorta to produce IL-23 and homocysteine mediates secretion. 
      This study suggests that in IL-18 deficiency, cholesterol in HCD synergize 
      mechanistically with homocysteine to accelerate atherosclerosis via the 
      alternative IL-23/Th17 pathway, demonstrating a new role for Th17 in 
      atherosclerosis.
FAU - Pejnovic, Nada
AU  - Pejnovic N
AD  - Translational Medicine & Therapeutics, William Harvey Research Institute, Barts 
      and The London School of Medicine, Queen Mary, University of London, Charterhouse 
      Square, London EC1M 6BQ, UK.
FAU - Vratimos, Athanassios
AU  - Vratimos A
FAU - Lee, Sang Hee
AU  - Lee SH
FAU - Popadic, Dusan
AU  - Popadic D
FAU - Takeda, Kiyoshi
AU  - Takeda K
FAU - Akira, Shizuo
AU  - Akira S
FAU - Chan, Woon Ling
AU  - Chan WL
LA  - eng
GR  - British Heart Foundation/United Kingdom
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090208
PL  - England
TA  - Mol Immunol
JT  - Molecular immunology
JID - 7905289
RN  - 0 (Apolipoproteins E)
RN  - 0 (Dietary Fats)
RN  - 0 (Interleukin-17)
RN  - 0 (Interleukin-18)
RN  - 0 (Interleukin-23)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Aorta/pathology
MH  - Apolipoproteins E/deficiency
MH  - Atherosclerosis/*etiology/metabolism/pathology
MH  - Cholesterol/administration & dosage/pharmacology
MH  - Dietary Fats/administration & dosage/*pharmacology
MH  - Homocysteine
MH  - *Interleukin-17
MH  - Interleukin-18/*deficiency
MH  - Interleukin-23/*biosynthesis/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle, Smooth, Vascular/pathology
MH  - T-Lymphocytes, Helper-Inducer/*pathology
EDAT- 2009/02/10 09:00
MHDA- 2010/01/26 06:00
CRDT- 2009/02/10 09:00
PHST- 2008/11/14 00:00 [received]
PHST- 2008/12/24 00:00 [accepted]
PHST- 2009/02/10 09:00 [entrez]
PHST- 2009/02/10 09:00 [pubmed]
PHST- 2010/01/26 06:00 [medline]
AID - S0161-5890(09)00010-8 [pii]
AID - 10.1016/j.molimm.2008.12.032 [doi]
PST - ppublish
SO  - Mol Immunol. 2009 Nov;47(1):37-45. doi: 10.1016/j.molimm.2008.12.032. Epub 2009 
      Feb 8.