HIF-1α regulates IL-1β and IL-17 in sarcoidosis

eLife

Kezhong Zhang¹  Lawrence I Grossman¹  Jaya Talreja²  Lobelia Samavati²  Harvinder Talwar²  Paul Tranchida³  Christian Bauerfeld⁴ 

[1] Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, United States;Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, United States;Department of Pathology, Wayne State University School of Medicine and Detroit Medical Center, Detroit, United States;Department of Pediatrics, Division of Critical Care, Wayne State University School of Medicine and Detroit Medical Center, Detroit, United States;

关键词: sarcoidosis;    HIF-1α;    monocytes;    alveolar macrophages;    IL-1β;    IL-17;   

DOI  :  10.7554/eLife.44519

来源: DOAJ

【 摘 要 】

Sarcoidosis is a complex systemic granulomatous disease of unknown etiology characterized by the presence of activated macrophages and Th1/Th17 effector cells. Data mining of our RNA-Seq analysis of CD14+monocytes showed enrichment for metabolic and hypoxia inducible factor (HIF) pathways in sarcoidosis. Further investigation revealed that sarcoidosis macrophages and monocytes exhibit higher protein levels for HIF-α isoforms, HIF-1β, and their transcriptional co-activator p300 as well as glucose transporter 1 (Glut1). In situ hybridization of sarcoidosis granulomatous lung tissues showed abundance of HIF-1α in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1β and IL-17 since targeted down regulation of HIF-1α via short interfering RNA or a HIF-1α inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1α levels and modified cytokine production. These data suggest that increased activity of HIF-α isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis.

【 授权许可】

Unknown