Th2-predominant inflammation and blockade of IFN-γ signaling induce aneurysms in allografted aortas
Author
Shimizu, Koichi
Shichiri, Masayoshi
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https://doi.org/10.1172/JCI19855Metadata
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Shimizu, Koichi, Masayoshi Shichiri, Peter Libby, Richard T. Lee, and Richard N. Mitchell. 2004. “Th2-Predominant Inflammation and Blockade of IFN-γ Signaling Induce Aneurysms in Allografted Aortas.” J. Clin. Invest. 114 (2) (July 15): 300–308. doi:10.1172/jci19855.Abstract
Abdominal aortic aneurysms (AAAs) cause death due to complications related to expansion and rupture. The underlying mechanisms that drive AAA development remain largely unknown. We recently described evidence for a shift toward T helper type 2 (Th2) cell responses in human AAAs compared with stenotic atheromas. To evaluate putative pathways in AAA formation, we induced Th1- or Th2-predominant cytokine environments in an inflammatory aortic lesion using murine aortic transplantation into WT hosts or those lacking the receptors for the hallmark Th1 cytokine IFN-γ, respectively. Allografts in WT recipients developed intimal hyperplasia, whereas allografts in IFN-γ receptor–deficient (GRKO) hosts developed severe AAA formation associated with markedly increased levels of MMP-9 and MMP-12. Allografts in GRKO recipients treated with anti–IL-4 antibody to block the characteristic IL-4 Th2 cytokine or allografts in GRKO hosts also congenitally deficient in IL-4 did not develop AAA and likewise exhibited attenuated collagenolytic and elastolytic activities. These observations demonstrate an important dichotomy between cellular immune responses that induce IFN-γ– or IL-4–dominated cytokine environments. The findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling and have important implications for the pathophysiology of AAAs and arteriosclerosis.Other Sources
http://www.ncbi.nlm.nih.gov/pubmed/15254597Terms of Use
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