PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids

Author:

Foulks Jason M.12,Marathe Gopal K.3,Michetti Noemi2,Stafforini Diana M.45,Zimmerman Guy A.24,McIntyre Thomas M.3,Weyrich Andrew S.24

Affiliation:

1. Department of Experimental Pathology, and

2. Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City;

3. Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic, OH; and

4. Department of Internal Medicine, and

5. Huntsman Cancer Institute, University of Utah, Salt Lake City

Abstract

AbstractPlatelet 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 αIIbβ3-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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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