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Interleukin-10 Deficiency Increases Atherosclerosis, Thrombosis, and Low-density Lipoproteins in Apolipoprotein E Knockout Mice

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Abstract

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−/− × 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−/− × 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.

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Acknowledgments

We thank Inger Bodin, Liliane Louedec, Chantal Mandet, Mirre Mikkola, Ingrid Törnberg, and Kristina Edwardsson for excellent technical assistance. GC is the recipient of a Marie Curie TMR grant (BMH4CT98-5108). This work was in part supported by an INSERM-MFR (France-Sweden) collaboration grant and by the Swedish Medical Research Council (6816,13571,14053), Heart & Lung Foundation, the Karolinska Institute and Söderberg Foundation.

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Authors and Affiliations

  1. Faculté de Necker, INSERM U460, EMI 00-16, 156, rue de Vaugirard, 75015, Paris, France

    Giuseppina Caligiuri, Marie-Paule Jacob & Jean-Baptiste Michel

  2. INSERM U430, Paris, France

    Antonino Nicoletti

  3. INSERM U479, Paris, France

    Véronique Ollivier

  4. Centers for Molecular Medicine, Karolinska Institute, Stockholm, Sweden

    Göran K. Hansson

  5. Karolinska Institute, Center for Nutrition and Toxicology at Huddinge University Hospital, Stockholm, Sweden

    Mats Rudling

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  1. Giuseppina Caligiuri
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Correspondence to Giuseppina Caligiuri.

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Caligiuri, G., Rudling, M., Ollivier, V. et al. Interleukin-10 Deficiency Increases Atherosclerosis, Thrombosis, and Low-density Lipoproteins in Apolipoprotein E Knockout Mice. Mol Med 9, 10–17 (2003). https://doi.org/10.1007/BF03402102

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