Moderate hypoxia potentiates interleukin-1β production in activated human macrophages.

Abstract

RATIONALE:

Inflammation drives atherogenesis. Animal and human studies have implicated interleukin-1β (IL-1β) in this disease. Moderate hypoxia, a condition that prevails in the atherosclerotic plaque, may conspire with inflammation and contribute to the evolution and complications of atherosclerosis through mechanisms that remain incompletely understood.

OBJECTIVE:

This study investigated the links between hypoxia and inflammation by testing the hypothesis that moderate hypoxia modulates IL-1β production in activated human macrophages.

METHODS AND RESULTS:

Our results demonstrated that hypoxia enhances pro-IL-1β protein, but not mRNA, expression in lipopolysaccharide-stimulated human macrophages. We show that hypoxia limits the selective targeting of pro-IL-1β to autophagic degradation, thus prolonging its half-life and promoting its intracellular accumulation. Furthermore, hypoxia increased the expression of NLRP3, a limiting factor in NLRP3 inflammasome function, and augmented caspase-1 activation in lipopolysaccharide-primed macrophages. Consequently, hypoxic human macrophages secreted higher amounts of mature IL-1β than did normoxic macrophages after treatment with crystalline cholesterol, an endogenous danger signal that contributes to atherogenesis. In human atherosclerotic plaques, IL-1β localizes predominantly to macrophage-rich regions that express activated caspase-1 and the hypoxia markers hypoxia-inducible factor 1α and hexokinase-2, as assessed by immunohistochemical staining of carotid endarterectomy specimens.

CONCLUSIONS:

These results indicate that hypoxia potentiates IL-1β expression in cultured human macrophages and in the context of atheromata, therefore unveiling a novel proinflammatory mechanism that may participate in atherogenesis.

• Authors: Eduardo J Folco, Galina K Sukhova, Thibaut Quillard, Peter Libby
• Journal: Circulation research (Circ Res) Vol. 115 Issue 10 Pg. 875-83 (Oct 24 2014) ISSN: 1524-4571 [Electronic] United States
• PMID: 25185259 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Interleukin-1beta

Topics

• Cell Hypoxia (physiology)
• Cells, Cultured
• Humans
• Interleukin-1beta (biosynthesis)
• Leukocytes, Mononuclear (metabolism)
• Macrophages (metabolism)