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A5.12 Atherosclerosis severity is independent of endogenous IL-33 signalling
  1. P Martin1,2,
  2. G Palmer1,2,
  3. E Rodriguez1,2,
  4. E Woldt1,2,
  5. I Mean1,2,
  6. D Talabot-Ayer1,2,
  7. RW James3,
  8. D Smith4,
  9. BR Kwak1,5,
  10. C Gabay1,2
  1. 1Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland
  2. 2Division of Rheumatology, University Hospital Geneva, Switzerland
  3. 3Division of Diabetes, Endocrinology and Nutrition, Department of Internal Medicine, University Hospital Geneva, Switzerland
  4. 4Inflammation Research Department, Amgen Inc. Seattle, WA, USA
  5. 5Division of Cardiology, Department of Internal Medicine, University Hospital Geneva, Switzerland

Abstract

Background and objectives Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous work demonstrated that the systemic administration of IL-33 reduces the development of atherosclerosis in the apolipoprotein E-deficient (ApoE-/-) mouse model of the disease by induction of a Th1-to-Th2 shift. However, the role of endogenous IL-33 in the atherogenesis remains elusive.

Materials and methods Atherosclerosis was induced in 10 week-old ApoE-/-, IL-33-/-ApoE-/- and ST2-/-ApoE-/- mice by feeding a high-cholesterol diet (1.25%, no cholate) for 10 weeks. Additionally, a group of ApoE-/- mice were injected with a neutralising anti-ST2 antibody or an isotype control during the period of the diet. The atherosclerotic lesion development was measured with Oil Red O in the thoracic-abdominal aorta and in the aortic sinus. The mRNA levels of several cytokines, including IL-6, IFNγ, IL-17, IL-5 and IL-10 were assessed in the aorta and in in vitro-stimulated lymph node cells.

Results We observed no differences in lipid-staining area in the aortas of IL-33-/-ApoE-/- mice (8.84 ± 0.97; mean ± SEM; n = 9–25), ST2-/-ApoE-/- mice (6.95 ± 0.78), ApoE-/- mice untreated (7.05 ± 0.78), ApoE-/- mice injected with either the neutralising anti-ST2 antibody (6.08 ± 0.79) or the isotype control (6.16 ± 0.86) after high-cholesterol diet feeding. Similar results were obtained in the aortic sinus compared to ApoE-/- controls. Total serum cholesterol and triglyceride levels were not different compared to ApoE-/- controls. IL-33 expression in aortic tissue was comparable in ApoE-/- and ST2-/-ApoE-/- mice and absent in IL-33-/-ApoE-/- mice. There was no difference in the transcript levels of inflammatory cytokines in the aorta and in in vitro-stimulated lymph node cells.

Conclusions These data indicate that in contrast to the anti-atherosclerotic effect of systemically administered recombinant IL-33, the endogenously produced cytokine and its receptor do not significantly influence the severity of atherosclerosis in ApoE-deficient mice fed with a high-cholesterol diet.

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