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J. Biol. Chem., Vol. 279, Issue 34, 36158-36165, August 20, 2004

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The p38 MAPK Pathway Mediates Transcriptional Activation of the Plasma Platelet-activating Factor Acetylhydrolase Gene in Macrophages Stimulated with Lipopolysaccharide^*

Xiaoqing Wu, Guy A. Zimmerman¶, Stephen M. Prescott¶, and Diana M. Stafforini¶||

From the Huntsman Cancer Institute and the Departments of Oncological Sciences and ^¶Internal Medicine, University of Utah, Salt Lake City, Utah 84112

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.

Received for publication, March 4, 2004 , and in revised form, June 22, 2004.

^* This work was supported in part by National Institutes of Health Grant HL35828 (to D. M. S.) and Special Center of Research in Acute Respiratory Distress Syndrome Grant HL50153. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Huntsman Cancer Institute, 2000 Circle of Hope, Suite 5362, University of Utah, Salt Lake City, UT 84112-5550. Tel.: 801-585-3402; Fax: 801-585-6345; E-mail: diana.stafforini{at}hci.utah.edu.

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