PMID- 16495221
OWN - NLM
STAT- MEDLINE
DCOM- 20060605
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 281
IP  - 15
DP  - 2006 Apr 14
TI  - Effect of arachidonic acid reacylation on leukotriene biosynthesis in human 
      neutrophils stimulated with granulocyte-macrophage colony-stimulating factor and 
      formyl-methionyl-leucyl-phenylalanine.
PG  - 10134-42
AB  - Priming of human neutrophils with granulocyte-macrophage colony-stimulating 
      factor (GM-CSF) followed by treatment with formyl-methionyl-leucyl-phenylalanine 
      (fMLP) stimulates cells in a physiologically relevant manner with modest 
      5-lipoxygenase activation and formation of leukotrienes. However, pretreatment of 
      neutrophils with thimerosal, an organomercury thiosalicylic acid derivative, led 
      to a dramatic increase (>50-fold) in the production of leukotriene B(4) and 
      5-hydroxyeicosatetraenoic acid, significantly higher than that observed after 
      stimulation with calcium ionophore A23187. Little or no effect was observed with 
      thimerosal alone or in combination with either GM-CSF or fMLP. Elevation of 
      [Ca(2+)](i) induced by thimerosal in neutrophils stimulated with GM-CSF/fMLP was 
      similar but more sustained compared with samples where thimerosal was absent. 
      However, [Ca(2+)](i) was significantly lower compared with calcium 
      ionophore-treated cells, suggesting that a sustained calcium rise was necessary 
      but not sufficient to explain the effects of this compound on the 
      GM-CSF/fMLP-stimulated neutrophil. Thimerosal was found to directly inhibit 
      neutrophil lysophospholipid:acyl-CoA acyltransferase activity at the doses that 
      stimulate leukotriene production, and analysis of lysates from neutrophil 
      preparations stimulated in the presence of thimerosal showed a marked increase in 
      free arachidonic acid, supporting the inhibition of the reincorporation of this 
      fatty acid into the membrane phospholipids as a mechanism of action for this 
      compound. The dramatic increase in production of leukotrienes by neutrophils when 
      a physiological stimulus such as GM-CSF/fMLP is employed in the presence of 
      thimerosal suggests a critical regulatory role of arachidonate reacylation that 
      limits leukotriene biosynthesis in concert with 5-lipoxygenase and cytosolic 
      phospholipase A(2)alpha activation.
FAU - Zarini, Simona
AU  - Zarini S
AD  - Department of Pharmacology, University of Colorado at Denver and Health Sciences 
      Center, 12801 E. 17th Avenue, Aurora, CO 80045, USA.
FAU - Gijon, Miguel A
AU  - Gijon MA
FAU - Folco, Giancarlo
AU  - Folco G
FAU - Murphy, Robert C
AU  - Murphy RC
LA  - eng
GR  - HL 25785/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060222
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Ionophores)
RN  - 0 (Leukotrienes)
RN  - 2225PI3MOV (Thimerosal)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - 37H9VM9WZL (Calcimycin)
RN  - 467RNW8T91 (5-hydroxy-6,8,11,14-eicosatetraenoic acid)
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - EC 1.13.11.34 (Arachidonate 5-Lipoxygenase)
RN  - EC 3.1.1.32 (Phospholipases A)
RN  - EC 3.1.1.4 (Group IV Phospholipases A2)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Arachidonate 5-Lipoxygenase/metabolism
MH  - Arachidonic Acid/*metabolism
MH  - Calcimycin/pharmacology
MH  - Calcium/metabolism/pharmacology
MH  - Cytosol/enzymology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - Gas Chromatography-Mass Spectrometry
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/*metabolism
MH  - Group IV Phospholipases A2
MH  - Humans
MH  - Hydroxyeicosatetraenoic Acids/metabolism
MH  - Ionophores/metabolism
MH  - Leukotrienes/*metabolism
MH  - Mass Spectrometry
MH  - N-Formylmethionine Leucyl-Phenylalanine/*pharmacology
MH  - Neutrophils/*metabolism
MH  - Phospholipases A/metabolism
MH  - Thimerosal/pharmacology
MH  - Time Factors
EDAT- 2006/02/24 09:00
MHDA- 2006/06/06 09:00
CRDT- 2006/02/24 09:00
PHST- 2006/02/24 09:00 [pubmed]
PHST- 2006/06/06 09:00 [medline]
PHST- 2006/02/24 09:00 [entrez]
AID - S0021-9258(19)56363-3 [pii]
AID - 10.1074/jbc.M510783200 [doi]
PST - ppublish
SO  - J Biol Chem. 2006 Apr 14;281(15):10134-42. doi: 10.1074/jbc.M510783200. Epub 2006 
      Feb 22.