PPAR activation has dichotomous control on the expression levels of cytosolic and secretory phospholipase A2 in astrocytes; inhibition in naive, untreated cells and enhancement in LPS-stimulated cells

P>Despite the importance of cytosolic phospholipase A(2) type IVA (cPLA(2)) and secretory PLA(2) (sPLA(2)) in physiological and pathological responses of astrocytes in inflammatory conditions, the regulation of the expression of these genes is still unclear. Both genes have peroxisome proliferator-activated receptors (PPAR) binding sites in their promoters. The role of synthetic PPAR agonists in the regulation of gene expression in naive and lipopolysaccharide (LPS)-stimulated rat astrocytes in culture was investigated. Exposure to LPS resulted in a time-dependent, fourfold transient increase of sPLA(2) expression, with maximum at 4 h; cPLA(2) expression was notably increased after 16-h LPS stimulation. Using selective PPAR alpha, PPAR beta/delta, and PPAR gamma agonists, we found that expression of both cPLA(2) and sPLA(2) is under PPAR control, but with different isotypes sensitivity. In naive astrocytes, all three PPAR agonists significantly suppressed the expression of sPLA(2), while only PPAR alpha and PPAR gamma activation suppressed cPLA(2) expression. Astonishingly, simultaneous addition of LPS with PPAR agonists evoked the opposite effect. All three PPAR agonists induced potentiation of cPLA(2) expression level. Potentiation of sPLA(2) expression was induced only by simultaneous addition of LPS with PPAR gamma agonist. By knockdown of PPAR alpha, PPAR beta/delta, and PPAR gamma, we confirmed the involvement of PPAR-dependent pathways. The important novelty of our findings is that both sPLA(2) and cPLA(2) are under dichotomous control of PPARs: suppression in naive control cells, but induction in LPS-stimulated astrocytes.