HIF-1? regulates IL-1? and IL-17 in sarcoidosis.

ABSTRACT: 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-? isoforms, HIF-1?, 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-1? in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1? and IL-17 since targeted down regulation of HIF-1? via short interfering RNA or a HIF-1? inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1? levels and modified cytokine production. These data suggest that increased activity of HIF-? isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis.

SUBMITTER: Talreja J 

PROVIDER: S-EPMC6506207 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature