The p38 MAPK pathway mediates transcriptional activation of the plasma platelet-activating factor acetylhydrolase gene in macrophages stimulated with lipopolysaccharide.
Administration of lipopolysaccharide (LPS) to experimental animals results in the up-regulation of expression of the plasma form of platelet-activating factor acetylhydrolase (PAF AH) in tissue macrophages. To investigate the mechanism underlying induction of PAF AH by LPS we used murine RAW264.7 and human THP-1 macrophages as model systems. We found that the p38 mitogen-activated protein kinase (p38 MAPK) pathway mediates transcriptional activation of the PAF AH gene through the participation of nucleotides -68/-316 relative to the transcriptional initiation site. This promoter region spans two Sp1/Sp3 binding sites (SP-A and SP-B) and is necessary and sufficient for the observed effect. Disruption of these Sp binding sites significantly reduces promoter activity in LPS-stimulated cells. The ability of LPS to induce transcriptional activation of PAF AH is not due to enhanced Sp1/Sp3 binding to the promoter but involves enhanced transactivation function of Sp1 via p38 MAPK activation. These studies characterize the mechanism by which LPS modulates expression of PAF AH at the transcriptional level, and they have important implications for our understanding of responses that occur during the development of LPS-mediated inflammatory diseases.
Wu
Xiaoqing
X
Huntsman Cancer Institute and the Department of Oncological Sciences , University of Utah, Salt Lake City, Utah 84112, USA.
Zimmerman
Guy A
GA
Prescott
Stephen M
SM
Stafforini
Diana M
DM
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D008070:Lipopolysaccharides; D048051:p38 Mitogen-Activated Protein Kinases; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase