Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation.
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-kappaB-regulated genes whose expression is attenuated by HPC. Studies using an NF-kappaB luciferase reporter assay confirmed a significant suppression of NF-kappaB 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-kappaB 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-kappaB. 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-kappaB activity through deneddylation of Cul-1. These results define a molecular regulatory pathway by which Ado provides potent antiinflammatory properties.
Khoury
Joseph
J
Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Ibla
Juan C
JC
Neish
Andrew S
AS
Colgan
Sean P
SP
D000222:Adaptation, Physiological; D000241:Adenosine / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology
D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex; D000241:Adenosine