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

ABSTRACT: Inflammation drives atherogenesis. Animal and human studies have implicated interleukin-1? (IL-1?) 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.This study investigated the links between hypoxia and inflammation by testing the hypothesis that moderate hypoxia modulates IL-1? production in activated human macrophages.Our results demonstrated that hypoxia enhances pro-IL-1? protein, but not mRNA, expression in lipopolysaccharide-stimulated human macrophages. We show that hypoxia limits the selective targeting of pro-IL-1? 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-1? than did normoxic macrophages after treatment with crystalline cholesterol, an endogenous danger signal that contributes to atherogenesis. In human atherosclerotic plaques, IL-1? localizes predominantly to macrophage-rich regions that express activated caspase-1 and the hypoxia markers hypoxia-inducible factor 1? and hexokinase-2, as assessed by immunohistochemical staining of carotid endarterectomy specimens.These results indicate that hypoxia potentiates IL-1? expression in cultured human macrophages and in the context of atheromata, therefore unveiling a novel proinflammatory mechanism that may participate in atherogenesis.

SUBMITTER: Folco EJ

PROVIDER: S-EPMC4209192 | biostudies-other | 2014 Oct

REPOSITORIES: biostudies-other

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

Folco Eduardo J EJ Sukhova Galina K GK Quillard Thibaut T Libby Peter P

Circulation research 20140902 10

<h4>Rationale</h4>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.<h4>Objective</h4>This study investigated the links between hypoxia and inflammation by testing the hypothesis that moderate hypoxia mod ...[more]

PMID: 25185259

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Project description:The mechanisms that underlie valvular inflammation in streptococcus-induced infective endocarditis (IE) remain unclear. We previously demonstrated that streptococcal glucosyltransferases (GTFs) can activate human heart valvular interstitial cells (VIC) to secrete interleukin-6 (IL-6), a cytokine involved in T helper 17 (Th17) cell differentiation. Here, we tested the hypothesis that activated VIC can enhance neutrophil infiltration through sustained IL-17 production, leading to valvular damage. To monitor cytokine and chemokine production, leukocyte recruitment, and the induction or expansion of CD4(+) CD45RA(-) CD25(-) CCR6(+) Th17 cells, primary human VIC were cultured in vitro and activated by GTFs. Serum cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA), and neutrophils and Th17 cells were detected by immunohistochemistry in infected valves from patients with IE. The expression of IL-21, IL-23, IL-17, and retinoic acid receptor-related orphan receptor C (Rorc) was upregulated in GTF-activated VIC, which may enhance the proliferation of memory Th17 cells in an IL-6-dependent manner. Many chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), were upregulated in GTF-activated VIC, which might recruit neutrophils and CD4(+) T cells. Moreover, CXCL1 production in VIC was induced in a dose-dependent manner by IL-17 to enhance neutrophil chemotaxis. CXCL1-expressing VIC and infiltrating neutrophils could be detected in infected valves, and serum concentrations of IL-17, IL-21, and IL-23 were increased in patients with IE compared to healthy donors. Furthermore, elevated serum IL-21 levels have been significantly associated with severe valvular damage, including rupture of chordae tendineae, in IE patients. Our findings suggest that VIC are activated by bacterial modulins to recruit neutrophils and that such activities might be further enhanced by the production of Th17-associated cytokines. Together, these factors can amplify the release of neutrophilic contents in situ, which might lead to severe valvular damage.

Dataset Information

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

Publications

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

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