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Hypoxia Induces Macrophage tnfa Expression via Cyclooxygenase and Prostaglandin E2 in vivo.

ABSTRACT: Macrophage phenotypes are poorly characterized in disease systems in vivo. Appropriate macrophage activation requires complex coordination of local microenvironmental cues and cytokine signaling. If the molecular mechanisms underpinning macrophage activation were better understood, macrophages could be pharmacologically tuned during disease situations. Here, using zebrafish tnfa:GFP transgenic lines as in vivo readouts, we show that physiological hypoxia and stabilization of Hif-1? promotes macrophage tnfa expression. We demonstrate a new mechanism of Hif-1?-induced macrophage tnfa expression via a cyclooxygenase/prostaglandin E2 axis. These findings uncover a macrophage HIF/COX/TNF axis that links microenvironmental cues to macrophage phenotype, with important implications during inflammation, infection, and cancer, where hypoxia is a common microenvironmental feature and where cyclooxygenase and TNF are major mechanistic players.

SUBMITTER: Lewis A

PROVIDER: S-EPMC6776637 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Hypoxia Induces Macrophage tnfa Expression via Cyclooxygenase and Prostaglandin E2 in vivo.

Lewis Amy A Elks Philip M PM

Frontiers in immunology 20190927

Macrophage phenotypes are poorly characterized in disease systems in vivo. Appropriate macrophage activation requires complex coordination of local microenvironmental cues and cytokine signaling. If the molecular mechanisms underpinning macrophage activation were better understood, macrophages could be pharmacologically tuned during disease situations. Here, using zebrafish tnfa:GFP transgenic lines as in vivo readouts, we show that physiological hypoxia and stabilization of ...[more]

PMID: 31611882

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Project description:Prostaglandin E2 (PGE2 ) plays a critical role in intestinal mucosal tolerance and barrier integrity. Cyclooxygenase-2 (COX-2)-dependent PGE2 production involves mobilisation of arachidonic acid. Lactobacillus rhamnosus GG (LbGG) is one of the most widely used probiotics reported to colonise the colonic mucosa. LbGG contributes to the protection of the small intestine against radiation injury through the repositioning of mucosal COX-2 expressing cells. However, it is unknown if LbGG modulates PGE2 production in the colonic mucosa under homeostasis and the major cellular elements involved in these processes. Colonic epithelial and CD90+ mesenchymal stromal cells, also known as (myo) fibroblasts (CMFs), are abundant innate immune cells in normal colonic mucosa able to produce PGE2 . Herein, we tested the hypothesis that under colonic mucosal homeostasis, LbGG modulates the eicosanoid pathway resulting in increased PGE2 production in both epithelial and stromal cells. Among the five tested human colonic epithelial cell lines, only exposure of Caco-2 to LbGG for 24 hr led to the mobilisation of arachidonic acid with concomitant increase in the components within the leukotriene and COX-2-dependent PGE2 pathways. By contrast, CMFs isolated from the normal human colonic mucosa responded to LbGG with increased expression of COX-2 and PGE2 in the prostaglandin pathway, but not 5-LO in the leukotriene pathway. Oral gavage of C57BL/6 mice for 5 days with LbGG (5 × 108 Colony-Forming Unit (CFU)/dose) increased COX-2 expression in the colonic mucosa. The majority of cells upregulating COX-2 protein expression were located in the colonic lamina propria and colocalised with ?-SMA+ cells corresponding to the CMF phenotype. This process was myeloid differentiation factor-88-dependent, because silencing of myeloid differentiation factor-88 expression in CMFs abrogated LbGG-induced upregulation of COX-2 in culture and in vivo. Taken together, our data suggest that LbGG increases release of COX-2-mediated PGE2 , contributing to the maintenance of mucosal homeostasis in the colon and CMFs are among the major contributors to this process.

Dataset Information

Hypoxia Induces Macrophage tnfa Expression via Cyclooxygenase and Prostaglandin E2 in vivo.

Publications

Hypoxia Induces Macrophage <i>tnfa</i> Expression via Cyclooxygenase and Prostaglandin E2 <i>in vivo</i>.

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