IL-13 receptor α2-arginase 2 pathway mediates IL-13-induced pulmonary hypertension

Cho W, Lee C, Kang M, Huang Y, Giordano FJ, Lee PJ, Trow TK, Homer RJ, Sessa WC, Elias JA, Lee CG. IL-13 receptor alpha(2)-arginase 2 pathway mediates IL-13-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 304: L112-L124, 2013. First published November 2, 2012; doi:10.1152/ajplung.00101.2012.-Although previous literature suggests that interleukin (IL)-13, a T-helper type 2 cell effector cytokine, might be involved in the pathogenesis of pulmonary hypertension (PH), direct proof is lacking. Furthermore, a potential mechanism underlying IL-13-induced PH has never been explored. This study's goal was to investigate the role and mechanism of IL-13 in the pathogenesis of PH. Lung-specific IL-13-overexpressing transgenic (Tg) mice were examined for hemodynamic changes and pulmonary vascular remodeling. IL-13 Tg mice spontaneously developed PH phenotype by the age of 2 mo with increased expression and activity of arginase 2 (Arg2). The role of Arg2 in the development of IL-13-stimulated PH was further investigated using Arg2 and IL-13 receptor alpha 2 (R alpha 2) null mutant mice and the small-interfering RNA (siRNA)-silencing approach in vivo and in vitro, respectively. IL-13-stimulated medial thickening of pulmonary arteries and right ventricle systolic pressure were significantly decreased in the IL-13 Tg mice with Arg2 null mutation. On the other hand, the production of nitric oxide was further increased in the lungs of these mice. In our in vitro evaluations, the recombinant IL-13 treatment significantly enhanced the proliferation of human pulmonary artery smooth muscle cells in an Arg2-dependent manner. The IL-13-stimulated cellular proliferation and the expression of Arg2 in hpaSMC were markedly decreased with IL-13R alpha 2 siRNA silencing. Our studies demonstrate that IL-13 contributes to the development of PH via an IL-13R alpha 2-Arg2-dependent pathway. The intervention of this pathway could be a potential therapeutic target in pulmonary arterial hypertension.