Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity

A 'stop' signaling switch for aspirin-triggered lipoxin A4

Bruce D. Levy, Valery V. Fokin, Joanna M. Clark, Michael J O Wakelam, Nicos A. Petasis, Charles N. Serhan

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

It is of wide interest to understand how opposing extracellular signals (positive or negative) are translated into intracellular signaling events. Receptor-ligand interactions initiate the generation of bioactive lipids by human neutrophils (PMN), which serve as signals to orchestrate cellular responses important in host defense and inflammation. We recently identified a novel polyisoprenyl phosphate (PIPP) signaling pathway and found that one of its components, presqualene diphosphate (PSDP), is a potent negative intracellular signal in PMN that regulates superoxide anion generation by several stimuli, including phosphatidic acid. We determined intracellular PIPP signaling by autocoids with opposing actions on PMN: leukotriene B4 (LTB4), a potent chemoattractant, and lipoxin A4 (LXA4), a 'stop signal' for recruitment. LTB4 receptor activation initiated a rapid decrease in PSDP levels concurrent with activation of PLD and cellular responses. In sharp contrast, activation of the LXA4 receptor reversed LTB4-initiated PSDP remodeling, leading to an accumulation of PSDP and potent inhibition of both PLD and superoxide anion generation. Thus, an inverse relationship was established for PSDP levels and PLD activity with two PMN ligands that evoke opposing responses. In addition, PSDP directly inhibited both isolated human recombinant (K(i)= 6 nM) and plant (K(i) = 20 nM) PLD. Together, these findings link PIPP remodeling to intracellular regulation of PMN function and suggest a role for PIPPs as lipid repressors in signal transduction, a novel mechanism that may also explain aspirin's suppressive actions in vivo in cell signaling.

Original languageEnglish
Pages (from-to)903-911
Number of pages9
JournalFASEB Journal
Volume13
Issue number8
Publication statusPublished - 1999
Externally publishedYes

Fingerprint

Polyisoprenyl Phosphates
Phospholipase D
phospholipase D
leukotrienes
aspirin
Aspirin
Switches
phosphates
superoxide anion
receptors
Leukotriene B4
chemoattractants
Chemical activation
lipids
Superoxides
Lipoxin Receptors
signal transduction
neutrophils
Leukotriene B4 Receptors
inflammation

Keywords

  • Eicosanoids
  • Inflammation
  • Lipid mediators
  • PMN

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Levy, B. D., Fokin, V. V., Clark, J. M., Wakelam, M. J. O., Petasis, N. A., & Serhan, C. N. (1999). Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: A 'stop' signaling switch for aspirin-triggered lipoxin A4. FASEB Journal, 13(8), 903-911.

Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity : A 'stop' signaling switch for aspirin-triggered lipoxin A4. / Levy, Bruce D.; Fokin, Valery V.; Clark, Joanna M.; Wakelam, Michael J O; Petasis, Nicos A.; Serhan, Charles N.

In: FASEB Journal, Vol. 13, No. 8, 1999, p. 903-911.

Research output: Contribution to journalArticle

Levy, BD, Fokin, VV, Clark, JM, Wakelam, MJO, Petasis, NA & Serhan, CN 1999, 'Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: A 'stop' signaling switch for aspirin-triggered lipoxin A4', FASEB Journal, vol. 13, no. 8, pp. 903-911.
Levy, Bruce D. ; Fokin, Valery V. ; Clark, Joanna M. ; Wakelam, Michael J O ; Petasis, Nicos A. ; Serhan, Charles N. / Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity : A 'stop' signaling switch for aspirin-triggered lipoxin A4. In: FASEB Journal. 1999 ; Vol. 13, No. 8. pp. 903-911.
@article{6f7ab974cd0a4d7cb3b560d83002cbe4,
title = "Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: A 'stop' signaling switch for aspirin-triggered lipoxin A4",
abstract = "It is of wide interest to understand how opposing extracellular signals (positive or negative) are translated into intracellular signaling events. Receptor-ligand interactions initiate the generation of bioactive lipids by human neutrophils (PMN), which serve as signals to orchestrate cellular responses important in host defense and inflammation. We recently identified a novel polyisoprenyl phosphate (PIPP) signaling pathway and found that one of its components, presqualene diphosphate (PSDP), is a potent negative intracellular signal in PMN that regulates superoxide anion generation by several stimuli, including phosphatidic acid. We determined intracellular PIPP signaling by autocoids with opposing actions on PMN: leukotriene B4 (LTB4), a potent chemoattractant, and lipoxin A4 (LXA4), a 'stop signal' for recruitment. LTB4 receptor activation initiated a rapid decrease in PSDP levels concurrent with activation of PLD and cellular responses. In sharp contrast, activation of the LXA4 receptor reversed LTB4-initiated PSDP remodeling, leading to an accumulation of PSDP and potent inhibition of both PLD and superoxide anion generation. Thus, an inverse relationship was established for PSDP levels and PLD activity with two PMN ligands that evoke opposing responses. In addition, PSDP directly inhibited both isolated human recombinant (K(i)= 6 nM) and plant (K(i) = 20 nM) PLD. Together, these findings link PIPP remodeling to intracellular regulation of PMN function and suggest a role for PIPPs as lipid repressors in signal transduction, a novel mechanism that may also explain aspirin's suppressive actions in vivo in cell signaling.",
keywords = "Eicosanoids, Inflammation, Lipid mediators, PMN",
author = "Levy, {Bruce D.} and Fokin, {Valery V.} and Clark, {Joanna M.} and Wakelam, {Michael J O} and Petasis, {Nicos A.} and Serhan, {Charles N.}",
year = "1999",
language = "English",
volume = "13",
pages = "903--911",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "8",

}

TY - JOUR

T1 - Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity

T2 - A 'stop' signaling switch for aspirin-triggered lipoxin A4

AU - Levy, Bruce D.

AU - Fokin, Valery V.

AU - Clark, Joanna M.

AU - Wakelam, Michael J O

AU - Petasis, Nicos A.

AU - Serhan, Charles N.

PY - 1999

Y1 - 1999

N2 - It is of wide interest to understand how opposing extracellular signals (positive or negative) are translated into intracellular signaling events. Receptor-ligand interactions initiate the generation of bioactive lipids by human neutrophils (PMN), which serve as signals to orchestrate cellular responses important in host defense and inflammation. We recently identified a novel polyisoprenyl phosphate (PIPP) signaling pathway and found that one of its components, presqualene diphosphate (PSDP), is a potent negative intracellular signal in PMN that regulates superoxide anion generation by several stimuli, including phosphatidic acid. We determined intracellular PIPP signaling by autocoids with opposing actions on PMN: leukotriene B4 (LTB4), a potent chemoattractant, and lipoxin A4 (LXA4), a 'stop signal' for recruitment. LTB4 receptor activation initiated a rapid decrease in PSDP levels concurrent with activation of PLD and cellular responses. In sharp contrast, activation of the LXA4 receptor reversed LTB4-initiated PSDP remodeling, leading to an accumulation of PSDP and potent inhibition of both PLD and superoxide anion generation. Thus, an inverse relationship was established for PSDP levels and PLD activity with two PMN ligands that evoke opposing responses. In addition, PSDP directly inhibited both isolated human recombinant (K(i)= 6 nM) and plant (K(i) = 20 nM) PLD. Together, these findings link PIPP remodeling to intracellular regulation of PMN function and suggest a role for PIPPs as lipid repressors in signal transduction, a novel mechanism that may also explain aspirin's suppressive actions in vivo in cell signaling.

AB - It is of wide interest to understand how opposing extracellular signals (positive or negative) are translated into intracellular signaling events. Receptor-ligand interactions initiate the generation of bioactive lipids by human neutrophils (PMN), which serve as signals to orchestrate cellular responses important in host defense and inflammation. We recently identified a novel polyisoprenyl phosphate (PIPP) signaling pathway and found that one of its components, presqualene diphosphate (PSDP), is a potent negative intracellular signal in PMN that regulates superoxide anion generation by several stimuli, including phosphatidic acid. We determined intracellular PIPP signaling by autocoids with opposing actions on PMN: leukotriene B4 (LTB4), a potent chemoattractant, and lipoxin A4 (LXA4), a 'stop signal' for recruitment. LTB4 receptor activation initiated a rapid decrease in PSDP levels concurrent with activation of PLD and cellular responses. In sharp contrast, activation of the LXA4 receptor reversed LTB4-initiated PSDP remodeling, leading to an accumulation of PSDP and potent inhibition of both PLD and superoxide anion generation. Thus, an inverse relationship was established for PSDP levels and PLD activity with two PMN ligands that evoke opposing responses. In addition, PSDP directly inhibited both isolated human recombinant (K(i)= 6 nM) and plant (K(i) = 20 nM) PLD. Together, these findings link PIPP remodeling to intracellular regulation of PMN function and suggest a role for PIPPs as lipid repressors in signal transduction, a novel mechanism that may also explain aspirin's suppressive actions in vivo in cell signaling.

KW - Eicosanoids

KW - Inflammation

KW - Lipid mediators

KW - PMN

UR - http://www.scopus.com/inward/record.url?scp=0032952048&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032952048&partnerID=8YFLogxK

M3 - Article

VL - 13

SP - 903

EP - 911

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 8

ER -