Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy and pulmonary artery smooth muscle cell (paSMC) proliferation in pulmonary arteries. Interleukin (IL)-13 is a potent regulator of tissue fibrosis and remodeling, and its effects are dependent on the cell-type specific expression of the IL-13 receptor isotypes IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2. This study analyzed the expression of the IL-13 receptors in IPAH in vivo and paSMC ex vivo, and the effects of IL-13 stimulation on paSMC proliferation and apoptosis. Using quantitative RT-PCR and immunohistochemistry, we detected an increased expression of IL-13Ralpha2, but not IL-4Ralpha, or IL-13Ralpha1, in lungs of IPAH patients compared with controls (transplant donors). Similar results were obtained in lungs of mice subjected to chronic hypoxia-induced pulmonary hypertension or rats exposed to monocrotaline. Immunohistochemistry and laser-captured microdissection analysis further demonstrated a strong localization of IL-13Ralpha2 to paSMC. Functional analysis using freshly isolated paSMC revealed that IL-13 induced a dose-dependent growth inhibition, without inducing apoptotic effects. This anti-proliferative effect of IL-13 was due to G0/G1 cell cycle arrest and phosphorylation of STAT3 and STAT6 in paSMC. Finally, ectopic overexpression of IL-13Ralpha2 in primary paSMC attenuated the anti-proliferative effect exerted by IL-13, and diminished IL-13-induced STAT3 and 6 phosphorylation. Our studies thus demonstrate that IL-13 is a potent anti-proliferative regulator of paSMC. Up-regulation of the decoy receptor IL-13Ralpha2 on paSMC in IPAH leads to a loss of this anti-proliferative effect and therefore enhanced paSMC proliferation during the pathogenesis of the disease.Furthermore, microarray analysis revealed that IL-13 induced a massive downregulation of the pro-proliferative endothelin-1 in paSMC, a finding that was also confirmed on protein level. Thus, the described anti-proliferative effect of IL-13 on paSMC might be mediated by a downregulation of endothelin-1.
