Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice.
Interleukin (IL)-10 is an anti-inflammatory cytokine that may play a protective role in atherosclerosis. The aim of this study was to assess the effect of IL-10 deficiency in the apolipoprotein E knockout mouse. Apolipoprotein E deficient (E-/-) and IL-10 deficient (-/-) mice were crossed to generate E-/- x IL-10-/- double knockout mice. By 16 wk, cholesterol and triglycerides were similar in double and single knockouts but the lack of IL-10 led to increased low-density lipoprotein cholesterol whereas very-low-density lipoprotein was reduced. In parallel, T-helper 1 responses and lesion size were dramatically increased in double knockout compared with E-/- controls. At 48 wk, matrix metalloproteinases and tissue factor activities were increased in lesions of double-knockout mice. Furthermore, markers of systemic coagulation were increased, and vascular thrombosis in response to i.v. thrombin occurred more frequently in E-/- x IL-10-/- than in E-/- mice. Our findings suggest that IL-10 deficiency plays a deleterious role in atherosclerosis. The early phase of lesion development was increased, and the proteolytic and procoagulant activity was elevated in advanced lesions. These data show that IL-10 may reduce atherogenesis and improve the stability of plaques.
Caligiuri
Giuseppina
G
INSERM U460, Paris, France. caligiuri@necker.fr
Rudling
Mats
M
Ollivier
Véronique
V
Jacob
Marie-Paule
MP
Michel
Jean-Baptiste
JB
Hansson
Göran K
GK
Nicoletti
Antonino
A
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology*; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D001777:Blood Coagulation / Q000502:physiology; D003433:Crosses, Genetic; D004036:Diet, Atherogenic; D016753:Interleukin-10 / Q000172:deficiency / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011973:Receptors, LDL / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013927:Thrombosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D016753:Interleukin-10; D020782:Matrix Metalloproteinases