Effects of hypoxia on monocyte inflammatory mediator production. Dissociation between changes in cyclooxygenase-2 expression and eicosanoid synthesis

Maryanne Demasi, Leslie G. Cleland, Rebecca J. Cook-Johnson, Gillian Caughey, Michael J. James

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Blood-derived monocytes are found at sites of inflammation as well as in solid tumors and atherosclerotic arteries. They are an abundant source of inflammatory eicosanoids such as prostaglandin E2 (PGE2) and thromboxane A2, which are formed via arachidonic acid (AA) metabolism by cyclooxygenase-1/2 (COX-1/2). In vitro studies of inflammatory mediator production are conducted invariably in room air, which does not reflect the oxygen tensions found in monocyte-containing lesions, which are frequently hypoxic. In this work we examined the effects of hypoxia at levels reported in these lesions, on monocyte COX-2 expression, the related events that lead to eicosanoid synthesis, and relationships with tumor necrosis factor (TNF)-α synthesis. In fresh human monocytes exposed to hypoxia (1% O 2) there was an increase in COX-2 protein compared with cells in normoxia, and this was attributable to increased transcription and mRNA stability. However, the synthesis of PGE2 and thromboxane A 2 was reduced in hypoxia and did not reflect the increased level of COX-2. Monocytes prelabeled with [3H]AA followed by lipopolysaccharide stimulation in the presence of hypoxia showed a reduced release of AA compared with cells in normoxia. In addition, hypoxia resulted in decreased phosphorylation of the p44/42 mitogen-activated protein kinase and of cytosolic phospholipase A2. Hypoxia also increased TNF-α synthesis, which appeared to play a role in COX-2 expression, and the observed increase TNF-α synthesis appeared to result from reduced PGE2 synthesis. Overall, the results suggest the existence of an autocrine loop of regulation between monocyte eicosanoid and TNF-α production, which is dysregulated in hypoxia and establishes hypoxia as being an important environmental determinant of inflammatory mediator production.

Number of pages10
JournalJournal of Biological Chemistry
Issue number40
Publication statusPublished - 3 Oct 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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