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IL-13 – IL-13 Receptor Alpha 2 –Arginase 2: A Novle Inflammatory Pathway in Pulmonary Arterial Hypertension

C Lee

W Cho

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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

BACKGROUND: Although previous literature suggests that IL-13, a T helper type 2 cell effector cytokine, might be involved in the pathogenesis of pulmonary hypertension (PH), direct proof is lacking. Further, a potential mechanism underlying IL-13-induced PH has never been explored. This study was to investigate the role of IL-13 signaling in the pathogenesis of PH.

METHODS: Lung-specific IL-13 overexpressing transgenic mice (CC10-IL-13 Transgenic mice: IL-13 Tg) were examined for hemodynamic changes and pulmonary vascular remodeling. Proliferation of human pulmonary artery smooth muscle cells (hpaSMC) in in vitro was assessed in response to IL-13. Increased expression and activity of arginase2 (Arg2) was observed in transgenic mice. Thus, Arg2 null mutant mice and specific siRNA were used for genetic ablation to explore the role of arignase2 in IL-13-induced PH.

RESULTS: We observed that IL-13 Tg mice spontaneously develop the PH phenotype by the age of 2 months. We also observed increased activity of Arg2 in IL-13 Tg lungs. Arg2 can decrease bioavailability of nitric oxide in the pulmonary vasculature by competing with NOS3 for the substrate L-arginine, which could contribute to the development of PH. When IL-13 Tg mice were crossed with Arg2 null mutant mice, the medial remodeling of pulmonary arteries and RV systolic pressure were significantly decreased, and the production of NO was increased in the lungs of IL-13 Tg mice. Also, we observed that treatment with recombinant IL-13 proliferated hPASMC in an Arg2-dependent manner. Furthermore, this IL-13-induced proliferation of hPASMC by Arg2 was markedly decreased with ablation of IL-13 Rα2 gene in hPASMC.

CONCLUSIONS: We provide, for the first time, direct evidence of a role for IL-13 in the pathogenesis of PH. This study also highlights that an IL-13 - IL-13Rα2 - Arg2 pathway could be a potential therapeutic target in PAH.