Abstract
Specific control of group IVA cytosolic phospholipase A2 (cPLA2α or PLA2G4A) expression modulates arachidonic acid production, thus tightly regulating the downstream effects of pro- and anti-inflammatory eicosanoids. The significance of this pathway in human disease is apparent in a range of pathologies from inflammation to tumorigenesis. While much of the regulation of cPLA2α has focused on posttranslational phosphorylation of the protein, studies on transcriptional regulation of this gene have focused only on proximal promoter regions. We have identified a DNase I hypersensitive site encompassing a 5' distal enhancer element containing a highly conserved consensus AP-1 site involved in transcriptional activation of cPLA2α by interleukin (IL)-1β. Chromatin immunoprecipitation (ChIP), knockdown, knockout, and overexpression analyses have shown that c-Jun acts both in a negative and positive regulatory role. Transcriptional activation of cPLA2α occurs through the phosphorylation of c-Jun in conjunction with increased association of C/EBPβ with the distal novel enhancer. The association of C/EBPβ with the transcriptional activation complex does not require an obvious DNA binding site. These data provide new and important contributions to the understanding of cPLA2α regulation at the transcriptional level, with implications for eicosanoid metabolism, cellular signaling, and disease pathogenesis.
Highlights
Specific control of group IVA cytosolic phospholipase A2 expression modulates arachidonic acid production, tightly regulating the downstream effects of pro- and anti-inflammatory eicosanoids
It has been previously shown that induction of cPLA2␣ gene expression by the proinflammatory cytokines IL-1, tumor necrosis factor (TNF)-␣ and IFN-␥ requires de novo transcription [16, 44]
As shown by northern blot analysis and corresponding densitometry (Fig. 1B), trichostatin A (TSA) was able to induce cPLA2␣ in a time-dependent manner, indicating that cPLA2␣ gene induction may be linked to changes in histone acetylation and potential alterations in chromatin structure
Summary
Specific control of group IVA cytosolic phospholipase A2 (cPLA2␣ or PLA2G4A) expression modulates arachidonic acid production, tightly regulating the downstream effects of pro- and anti-inflammatory eicosanoids. The significance of this pathway in human disease is apparent in a range of pathologies from inflammation to tumorigenesis. Transcriptional activation of cPLA2␣ occurs through the phosphorylation of c-Jun in conjunction with increased association of C/EBP with the distal novel enhancer. The association of C/EBP with the transcriptional activation complex does not require an obvious DNA binding site These data provide new and important contributions to the understanding of cPLA2␣ regulation at the transcriptional level, with implications for eicosanoid metabolism, cellular signaling, and disease pathogenesis.— Bickford, J.
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