糖蛋白130
肺动脉高压
生物
信号转导
缺氧(环境)
车站3
发病机制
内分泌学
内皮素1
内科学
STAT蛋白
磷酸化
受体
癌症研究
细胞生物学
免疫学
化学
医学
有机化学
氧气
作者
Tatsuro Ishibashi,T. Inagaki,Makoto Okazawa,Akiko Yamagishi,Keiko Ohta‐Ogo,Ryotaro Asano,Masaki Tomita,Yui Kotani,Xiao Ding,Tomomi Chikaishi-Kirino,Noriko Maedera,Makoto Shirai,Kinta Hatakeyama,Yoshiaki Kubota,Tadamitsu Kishimoto,Yoshikazu Nakaoka
标识
DOI:10.1073/pnas.2315123121
摘要
Pulmonary arterial hypertension (PAH) is characterized by stenosis and occlusions of small pulmonary arteries, leading to elevated pulmonary arterial pressure and right heart failure. Although accumulating evidence shows the importance of interleukin (IL)-6 in the pathogenesis of PAH, the target cells of IL-6 are poorly understood. Using mice harboring the floxed allele of gp130 , a subunit of the IL-6 receptor, we found substantial Cre recombination in all hematopoietic cell lineages from the primitive hematopoietic stem cell level in SM22α-Cre mice. We also revealed that a CD4 + cell-specific gp130 deletion ameliorated the phenotype of hypoxia-induced pulmonary hypertension in mice. Disruption of IL-6 signaling via deletion of gp130 in CD4 + T cells inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and suppressed the hypoxia-induced increase in T helper 17 cells. To further examine the role of IL-6/gp130 signaling in more severe PH models, we developed Il6 knockout (KO) rats using the CRISPR/Cas9 system and showed that IL-6 deficiency could improve the pathophysiology in hypoxia-, monocrotaline-, and Sugen5416/hypoxia (SuHx)-induced rat PH models. Phosphorylation of STAT3 in CD4 + cells was also observed around the vascular lesions in the lungs of the SuHx rat model, but not in Il6 KO rats. Blockade of IL-6 signaling had an additive effect on conventional PAH therapeutics, such as endothelin receptor antagonist (macitentan) and soluble guanylyl cyclase stimulator (BAY41-2272). These findings suggest that IL-6/gp130 signaling in CD4 + cells plays a critical role in the pathogenesis of PAH.
科研通智能强力驱动
Strongly Powered by AbleSci AI