Human Platelets Utilize Cycloxygenase-1 to Generate Dioxolane A(3), a Neutrophil-activating Eicosanoid
Volume
291
Pagination
13448 - 13464
Publisher
DOI
10.1074/jbc.M115.700609
Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Issue
ISSN
0021-9258
Metadata
Show full item recordAbstract
Eicosanoids are important mediators of fever, pain, and
inflammation that modulate cell signaling during acute and
chronic disease. We show by using lipidomics that thrombinactivated human platelets generate a new type of eicosanoid that
both stimulates and primes human neutrophil integrin (Mac-1)
expression, in response to formylmethionylleucylphenylalanine. Detailed characterization proposes a dioxolane structure,
8-hydroxy-9,11-dioxolane eicosatetraenoic acid (dioxolane A3,
DXA3). The lipid is generated in nanogram amounts by platelets
from endogenous arachidonate during physiological activation,
with inhibition by aspirin in vitro or in vivo, implicating
cyclooxygenase-1 (COX). Pharmacological and genetic studies
on human/murine platelets revealed that DXA3 formation
requires protease-activated receptors 1 and 4, cytosolic phospholipase A2 (cPLA2), Src tyrosine kinases, p38 MAPK, phospholipase C, and intracellular calcium. From data generated by
purified COX isoforms and chemical oxidation, we propose that
DXA3 is generated by release of an intermediate from the active
site followed by oxygenation at C8. In summary, a new neutrophil-activating platelet-derived lipid generated by COX-1 is
presented that can activate or prime human neutrophils, suggesting a role in innate immunity and acute inflammation.
Authors
Hinz, C; Aldrovandi, M; Uhlson, C; Marnett, LJ; Longhurst, HJ; Warner, TD; Alam, S; Slatter, DA; Lauder, SN; Allen-Redpath, KCollections
- Centre for Immunobiology [1153]
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