TY - JOUR
T1 - Hif-1α regulates il-1βand il-17 in sarcoidosis
AU - Talreja, Jaya
AU - Talwar, Harvinder
AU - Bauerfeld, Christian
AU - Grossman, Lawrence I.
AU - Zhang, Kezhong
AU - Tranchida, Paul
AU - Samavati, Lobelia
N1 - Funding Information:
U.S. Department of Defense W81XWH-16-1-0516 Wayne State University Henry L Brasza endowment National Heart, Lung, and Blood Institute R01HL113508.
Funding Information:
This work was supported by grants from NIH (R01HL113508) (LS) and the American Lung Association (LS) and as well as the Department of Medicine and the Center for Molecular Medicine and Genetics, Wayne State University School of Medicine (LS). The Microscopy, Imaging and Cytometry Resources Core is supported, in part, by NIH Center grant P30 CA022453 to the Karmanos Cancer Institute at Wayne State University and the Perinatology Research Branch of the National Institutes of Child Health and Development at Wayne State University. LIG is supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program under Award W81XWH-16-1-0516 and the Henry L Brasza endowment at Wayne State University. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the US Department of Defense or the United States government.
Publisher Copyright:
© Talreja et al.
PY - 2019/4
Y1 - 2019/4
N2 - 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-a isoforms, HIF-1b, 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-1a in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1b and IL-17 since targeted down regulation of HIF-1a via short interfering RNA or a HIF-1a inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1a levels and modified cytokine production. These data suggest that increased activity of HIF-a isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis.
AB - 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-a isoforms, HIF-1b, 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-1a in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1b and IL-17 since targeted down regulation of HIF-1a via short interfering RNA or a HIF-1a inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1a levels and modified cytokine production. These data suggest that increased activity of HIF-a isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis.
UR - http://www.scopus.com/inward/record.url?scp=85065810220&partnerID=8YFLogxK
U2 - 10.7554/eLife.44519
DO - 10.7554/eLife.44519
M3 - Article
C2 - 30946009
AN - SCOPUS:85065810220
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e44519
ER -