Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice.
OBJECTIVE
Atherosclerosis is an inflammatory disease in which T helper 1 (Th1) immunity has been proposed to play an important role. Nai;ve CD4+ T cells differentiate into interferon-gamma (IFN-gamma) producing Th1 effector cells when stimulated by interleukin-18 (IL-18) and IL-12. We wanted to directly test whether the Th1 pathway is proatherogenic.


METHODS
We bred IL-18(-/-) mice with apolipoprotein E(-/-) (apoE(-/-)) mice and assessed atherosclerosis in the aortic root of the offspring.


RESULTS
24-week-old IL-18 deficient apoE(-/-) mice exhibited substantially reduced lesion size (93,866+/-11273 vs. 144,019+/-9667 microm(2) in IL-18(+/+)xapoE(-/-) mice, P=0.005). Lesion cells in compound knockout mice displayed reduced I-A(b) expression, implying reduced local IFN-gamma stimulation. These mice also had an increased proportion of alpha-SM-actin+ smooth muscle cells, compatible with a more stable lesion phenotype. Immunoglobulin G (IgG) subclass analysis of antibodies to malondialdehyde-modified low density lipoprotein indicated increased Th2 and reduced Th1 helper to B cell antibody production. Surprisingly, serum cholesterol and triglyceride levels were significantly higher in IL-18(-/-)xapoE(-/-) mice in spite of their reduced atherosclerosis. However, no changes in lipoprotein cholesterol patterns were registered.


CONCLUSIONS
These data show reduced atherosclerosis and Th1 activity in spite of increased serum cholesterol in IL-18 deficient apoE(-/-) mice. They support a proatherogenic role for IL-18.
Elhage
Rima
R
Department of Medicine at Karolinska Hospital and Center for Molecular Medicine L8:03, Karolinska Institute, SE-17176 Stockholm, Sweden.
Jawien
Jacek
J
Rudling
Mats
M
Ljunggren
Hans-Gustaf
HG
Takeda
Kiyoshi
K
Akira
Shizuo
S
Bayard
Francis
F
Hansson
Göran K
GK
D000199:Actins / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D015870:Gene Expression; D007074:Immunoglobulin G / Q000032:analysis; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*; D014280:Triglycerides / Q000097:blood
D000199:Actins; D001057:Apolipoproteins E; D001323:Autoantibodies; D007074:Immunoglobulin G; D020382:Interleukin-18; D008077:Lipoproteins, LDL; D014280:Triglycerides; D007371:Interferon-gamma; D002784:Cholesterol