PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids.
Platelet activating factor (PAF) and PAF-like lipids induce inflammatory responses in target cells. These lipid mediators are inactivated by PAF-acetylhydrolase (PAF-AH). The PAF signaling system affects the growth of hematopoietic CD34(+) cells, but roles for PAF-AH in this process are unknown. Here, we investigated PAF-AH function during megakaryopoiesis and found that human CD34(+) cells accumulate this enzymatic activity as they differentiate toward megakaryocytes, consistent with the expression of mRNA and protein for the plasma PAF-AH isoform. Inhibition of endogenous PAF-AH activity in differentiated megakaryocytes increased formation of lipid mediators that signaled the PAF receptor (PAFR) in fully differentiated human cells such as neutrophils, as well as megakaryocytes themselves. PAF-AH also controlled megakaryocyte alpha(IIb)beta(3)-dependent adhesion, cell spreading, and mobility that relied on signaling through the PAFR. Together these data suggest that megakaryocytes generate PAF-AH to modulate the accumulation of intracellular phospholipid mediators that may detrimentally affect megakaryocyte development and function.
Foulks
Jason M
JM
Department of Experimental Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Marathe
Gopal K
GK
Michetti
Noemi
N
Stafforini
Diana M
DM
Zimmerman
Guy A
GA
McIntyre
Thomas M
TM
Weyrich
Andrew S
AS
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling; D002448:Cell Adhesion; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004790:Enzyme Induction; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D019089:Stem Cell Factor / Q000494:pharmacology; D034061:Thrombopoiesis / Q000187:drug effects / Q000502:physiology*; D013926:Thrombopoietin / Q000494:pharmacology
C508596:IL3 protein, human; D007377:Interleukin-3; D010743:Phospholipids; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D019089:Stem Cell Factor; C039351:platelet activating factor receptor; D013926:Thrombopoietin; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase