Submitted November 13, 2008
Accepted April 6, 2009
PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids
Jason M. Foulks, Gopal K. Marathe, Noemi Michetti, Diana M. Stafforini, Guy A. Zimmerman, Thomas M. McIntyre, and Andrew S. Weyrich*
Department of Experimental Pathology, University of Utah, Salt Lake City, UT, United States
Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, United States
Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT, United States
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
* Corresponding author; email: andy.weyrich{at}hmbg.utah.edu.
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 towards 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 
IIb
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.
