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Differential role and tissue specificity of interleukin-1α gene expression in atherogenesis and lipid metabolism

  • Author Footnotes
    1 These authors contributed equally to this work.
    Yehuda Kamari
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel

    Hypertension Unit, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Rachel Werman-Venkert
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Microbiology and Immunology, Ben-Gurion University, Beer-Sheva, Israel
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  • Aviv Shaish
    Affiliations
    Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
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  • Ariel Werman
    Affiliations
    Department of Microbiology and Immunology, Ben-Gurion University, Beer-Sheva, Israel
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  • Ayelet Harari
    Affiliations
    Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
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  • Ayelet Gonen
    Affiliations
    Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
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  • Elena Voronov
    Affiliations
    Department of Microbiology and Immunology, Ben-Gurion University, Beer-Sheva, Israel
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  • Itamar Grosskopf
    Affiliations
    Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
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  • Yehonatan Sharabi
    Affiliations
    Hypertension Unit, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
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  • Ehud Grossman
    Affiliations
    Hypertension Unit, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
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  • Yoichiro Iwakura
    Affiliations
    Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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  • Charles A. Dinarello
    Affiliations
    Department of Medicine, University of Colorado Health Science Center, Denver, United States
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Ron N. Apte
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Microbiology and Immunology, Ben-Gurion University, Beer-Sheva, Israel
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Dror Harats
    Correspondence
    Corresponding author. Tel.: +972 3 5302940; fax: +972 3 5343521.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Abstract

      Objective

      We examined the role of IL-1α and IL-1β expressed by bone marrow-derived cells in atherogenesis and lipid metabolism.

      Methods and results

      We first studied the effect of atherogenic diet on wild-type C57BL/6 IL-1α or IL-1β deficient mice. IL-1α KO resulted in a comparatively higher total cholesterol levels, compared to WT and IL-1β KO mice (398 ± 10; 266 ± 19; 223 ± 13 mg/dl, respectively, p < 0.001), due to higher non-HDL cholesterol. Nevertheless, aortic sinus lesion area was 56% lower in IL-1α KO (p < 0.05) and 50% lower in IL-1β KO (p = 0.08), compared to WT mice. Likewise, SAA levels in IL-1α KO mice were markedly lower compared to WT and IL-1β KO mice (31 ± 14; 220 ± 33 and 106 ± 39 μg/ml, respectively, p < 0.001).
      To study the specific role of bone marrow-derived IL-1, irradiated C57BL/6 mice were transplanted with either IL-1+/+, IL-1α−/− or IL-1β−/− bone marrow cells. Despite similar lipoprotein levels, aortic sinus lesion area was 59% lower in IL-1α−/− transplanted (p < 0.05) compared to IL-1+/+ transplanted mice. Lesion area in IL-1β -/- was 33% lower than in IL-1+/+ recipient mice, but it was not statistically significant.

      Conclusion

      We demonstrated that early lesion formation is accelerated specifically by bone marrow-derived IL-1α. Furthermore, we showed that the expression of IL-1α in cells other than the bone marrow plays a significant role in non-HDL cholesterol metabolism.

      Keywords

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