Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation
Joseph Khoury, … , Andrew S. Neish, Sean P. Colgan
Joseph Khoury, … , Andrew S. Neish, Sean P. Colgan
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):703-711. https://doi.org/10.1172/JCI30049.
View: Text | PDF
Research Article Vascular biology

Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation

  • Text
  • PDF
Abstract

A major adaptive pathway for hypoxia is hypoxic preconditioning (HPC), a form of endogenous protection that renders cells tolerant to severe challenges of hypoxia. We sought to define the antiinflammatory properties of HPC. cDNA microarray analysis of lung tissue from mice subjected to hypoxia or HPC identified a cluster of NF-κB–regulated genes whose expression is attenuated by HPC. Studies using an NF-κB luciferase reporter assay confirmed a significant suppression of NF-κB activation during HPC. HPC-elicited activity was conferrable, as a soluble supernatant from HPC-treated cells, and the active fraction was purified and identified as adenosine (Ado). Guided by recent studies demonstrating bacterial inhibition of NF-κB through cullin-1 (Cul-1) deneddylation, we found a dose-dependent deneddylation of Cul-1 by Ado receptor stimulation predominantly mediated by the Ado A2B receptor subtype. Further, siRNA-mediated repression of CSN5, a subunit of the COP9 signalosome responsible for deneddylation of Cul-1, partially reversed HPC-mediated inhibition of NF-κB. Cul-1 deneddylation was evident in a murine model of HPC and lost in animals lacking extracellular Ado (Cd73–/– mice). Taken together, these results demonstrate that HPC induces extracellular accumulation of Ado and suppresses NF-κB activity through deneddylation of Cul-1. These results define a molecular regulatory pathway by which Ado provides potent antiinflammatory properties.

Authors

Joseph Khoury, Juan C. Ibla, Andrew S. Neish, Sean P. Colgan

×

Figure 1

HPC attenuates NF-κB activity via the release of a soluble factor.

Options: View larger image (or click on image) Download as PowerPoint
HPC attenuates NF-κB activity via the release of a soluble factor.
(A) H...
(A) HeLa cells transfected with pNRE were either untreated (Control) or subjected to hypoxia or an HPC protocol followed by hypoxia. Cells that had been preconditioned showed a significant (*P < 0.02, HPC versus hypoxia) attenuation of NF-κB activity, whereas cells that had not been preconditioned showed NF-κB activation. (B) Supernatants (Sup) were taken from cells undergoing HPC following each hypoxic cycle and were placed on naive cells for 3 cycles of 65 minutes (corresponding to 1 whole preconditioning cycle). Naive cells that received supernatants (white bars) were capable of attenuating NF-κB activity comparably to cells that had been preconditioned (**P < 0.05 supernatant versus control hypoxia; #P < 0.05, HPC versus hypoxia). (C) Supernatants taken during HPC were successively filtered through 100-, 30-, and 5-kDa filters and then placed onto naive cells. Filtrates displayed an enhanced inactivation of NF-κB as compared with cells that underwent HPC alone (*P < 0.05).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts