Atherosclerosis
Volume 197, Issue 2 , Pages 504-514, April 2008

Atheroprotective role of interleukin-6 in diet- and/or pathogen-associated atherosclerosis using an ApoE heterozygote murine model

Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University, 700 Albany Street, W201E, Boston, MA 02118, USA

Received 3 November 2006; received in revised form 1 February 2007; accepted 21 February 2007. published online 05 April 2007.

Abstract 

Background

Pathogens have been implicated in the pathogenesis of inflammatory atherosclerosis. Given the pleiotropic role of interleukin-6 in the regulation of cytokines, lipid homeostasis, vascular remodeling, and apoptosis we hypothesized that IL-6 plays an important role in development and progression to inflammatory atherosclerosis.

Methods and results

To explore the role of IL-6 in inflammation- and infection-associated atherosclerosis, 10-week-old ApoE+/−-IL-6+/− and ApoE+/−-IL-6−/− mice fed either high fat diet or regular chow diet were inoculated intravenously, once per week for 14 or 24 consecutive weeks with 50μl live Porphyromonas gingivalis (P.g.) (107CFU) or vehicle (normal saline). Animals were euthanized at 24 weeks of age (14 weeks injection) or 34 weeks of age (24 weeks injection). Histomorphometric analysis of atheromatous lesions, en face analysis over the aortic tree, immunohistochemistry for macrophages and smooth muscle cell, TUNEL staining for apoptotic cells, serum amyloid A (SAA) levels, serum lipids and glucose level, serum cytokines were obtained. ApoE+/−-IL-6−/− mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE+/−-IL-6+/− mice for all conditions (chow diet and P.g.-inoculated, high fat diet and P.g.-inoculated, high fat diet and vehicle-inoculated) at 14 weeks and greater at 24 weeks. SAA levels from ApoE+/−-IL-6−/− mice were significantly higher than ApoE+/−-IL-6+/− mice. IL-6 deficiency led to profound changes in plaque composition evidenced by increased macrophage infiltration, apoptosis, lipid content and decreased smooth muscle cell mass reflecting an unstable plaque phenotype. Array analysis revealed increased levels of proinflammatory cytokines in ApoE+/−-IL-6−/− mice compared to ApoE+/−-IL-6+/− mice, irrespective of diet or inoculation.

Conclusion

The genetic deficiency of IL-6 was found to enhance the formation of diet- and/or pathogen-associated atherosclerotic plaques and suggests that IL-6 may play an atheroprotective role.

Keywords: Atherosclerosis, Cytokine, Infection, Inflammation, Porphyromonas gingivalis

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PII: S0021-9150(07)00128-1

doi:10.1016/j.atherosclerosis.2007.02.023

Refers to corrigendum:

  • Corrigendum to “Atheroprotective role of interleukin-6 in diet- and/or pathogen-associated atherosclerosis using in ApoE heterozygote murine model” [Atherosclerosis 197 (2008) 504–514] , 09 July 2008

    Monika Madan, Biswadev Bishayi, Michael Hoge, Salomon Amar
    Atherosclerosis October 2008 (Vol. 200, Issue 2, Pages 448-450)

Atherosclerosis
Volume 197, Issue 2 , Pages 504-514, April 2008

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