A distal enhancer controls cytokine-dependent human cPLA2α gene expression

Specific control of group IVA cytosolic phospholipase A(2) (cPLA(2)alpha 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 cPLA(2)alpha 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 cPLA(2)alpha by interleukin (IL)-1 beta. 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 cPLA(2)alpha occurs through the phosphorylation of c-Jun in conjunction with increased association of C/EBP beta with the distal novel enhancer. The association of C/EBP beta with the transcriptional activation complex does not require an obvious DNA binding site. These data provide new and important contributions to the understanding of cPLA(2)alpha regulation at the transcriptional level, with implications for eicosanoid metabolism, cellular signaling, and disease pathogenesis.