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Interleukin 19: Critical Role in the Growth and Rupture of Aortic Aneurysms in Apolipoprotein E Deficient Mice

Venkat Kalapatapu, Angela Burke, Kyla Shelton, Nancy Rusch, Michael Edwards, John Eidt.
University of Arkansas for Medical Sciences, Little Rock, Ark.

OBJECTIVES: The role of cytokines in the formation of aortic aneurysms has been considered a key step and is being increasingly studied. Interleukins produced by infiltrating T-cells and macrophages produce different effects on the aorta. Interleukins 19 and 20 are proinflammatory interleukins, part of the IL-10 family, and have been implicated in various T-cell mediated diseases. We studied the effects of these interleukins in the development of aortic aneurysms in an established animal model and in in vitro studies with T-helper cells.

METHODS: In vivo and in vitro studies were conducted. Forty (n=40) apolipoprotein E deficient mice were studied. Group I (n=4) mice received no angiotensin II (Ang II). Group II (n=6) mice received Ang II only .Group III (n=12) mice received Ang II with interleukin-19 antibody. Group IV (n=12) mice received Ang II with interleukin-20 antibody. Group V (n=6) mice received AngII with antibody to the shared receptor, interleukin-20R. Ang II was infused via osmotic minipumps for 4 weeks. Antibodies to IL-19, IL-20 and IL-20R were given weekly. All surviving mice were harvested at 28 days of infusion. End-points included mortality from aortic rupture, aortic diameter, histology, aortic tissue analysis for interleukins, matrix metalloproteinase (MMP)-2, MMP-9, immunohistochemistry staining for IL-19, IL-20 and IL-20R. In-vitro studies investigated the effects of the interleukins on T-helper cells.

RESULTS: Mortality rates were Group I-0%, Group II-25%, Group III-0%, Group IV-20% and Group V-0%. Mean aortic diameter was Group I-1.72 mm, Group II-2.15 mm, Group III-1.69 mm, Group IV-1.93 mm and Group V-1.75 mm. Histological analysis revealed decreased medial dissection in the IL-19 group. Aortic MMP-2 and MMP-9 levels were significantly reduced in Group III mice (anti-IL-19 antibody). IL-19 in cell culture significantly increased production of IL-4, IL-6 and MMP-2 by T-helper cells.

CONCLUSIONS: Preliminary studies on apolipoprotein E deficient mice show that IL-19 may play a crucial role in growth and rupture of aortic aneurysms. Antibodies to IL-19 effectively reduced aortic tissue levels of MMP-2, MMP-9 and consequently aneurysm size and the rate of rupture. We are currently studying the mechanisms of interleukin-19 mediated effects in the development of aortic aneurysms.

AUTHOR DISCLOSURES: V. Kalapatapu, None; A. Burke, None; K. Shelton, None; N. Rusch, None; M. Edwards, None; J. Eidt, None.