Polyisoprenyl phosphates: natural antiinflammatory lipid signals |
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Authors: | Levy B D Serhan C N |
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Institution: | (1) Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115 (USA), Fax + 1 617 278 6957, e-mail: CNSerhan@zeus.BWH.harvard.edu, US |
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Abstract: | Lipoxins (LX) and aspirin-triggered 15-epimer LX are leukocyte-derived eicosanoids generated during host defense that serve
as down-regulatory signals. The specific intracellular events that govern cellular responses to inhibitory extracellular signals
are of wide interest in order to understand pivotal intracellular events in diseases characterized by enhanced inflammatory
responses, such as asthma, rheumatoid arthritis and atherosclerosis. We recently uncovered a novel role for polyisoprenyl
phosphates, in particular presqualene diphosphate (PSDP), as natural down-regulatory signals in human neutrophils that directly
inhibit phospholipase D and superoxide anion generation. Activation of LXA4 receptors (ALXR) reverses proinflammatory receptor-initiated decrements in PSDP and inhibits cellular responses. These findings
represent evidence for a novel paradigm for lipid-protein interactions in the control of cellular responses, namely receptor-initiated
degradation of repressor lipids that is subject to regulation by aspirin treatment via the actions of aspirin-triggered 15-epimer
LX at the ALXR, and identify new templates for antiinflammatory drugs by design. |
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Keywords: | , Eicosanoids, lipid mediators, signal transduction, aspirin, inflammation, leukocytes, |
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