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

Abstract

J. Neurochem. (2010) 115, 399–410. Abstract Despite the importance of cytosolic phospholipase A2 type IVA (cPLA2) and secretory PLA2 (sPLA2) 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 naïve and lipopolysaccharide (LPS)‐stimulated rat astrocytes in culture was investigated. Exposure to LPS resulted in a time‐dependent, fourfold transient increase of sPLA2 expression, with maximum at 4 h; cPLA2 expression was notably increased after 16‐h LPS stimulation. Using selective PPARα, PPARβ/δ, and PPARγ agonists, we found that expression of both cPLA2 and sPLA2 is under PPAR control, but with different isotypes sensitivity. In naïve astrocytes, all three PPAR agonists significantly suppressed the expression of sPLA2, while only PPARα and PPARγ activation suppressed cPLA2 expression. Astonishingly, simultaneous addition of LPS with PPAR agonists evoked the opposite effect. All three PPAR agonists induced potentiation of cPLA2 expression level. Potentiation of sPLA2 expression was induced only by simultaneous addition of LPS with PPARγ agonist. By knockdown of PPARα, PPARβ/δ, and PPARγ, we confirmed the involvement of PPAR‐dependent pathways. The important novelty of our findings is that both sPLA2 and cPLA2 are under dichotomous control of PPARs: suppression in naïve control cells, but induction in LPS‐stimulated astrocytes.

Conjugated linoleic acid-enriched butter improved memory and up-regulated phospholipase A2 encoding-genes in rat brain tissue

“…Agonists of PPARa and PPARc have been reported to possess anti-inflammatory activity in astrocytes (Xu and Drew 2007;Bernardo and Minghetti 2008), and there is evidence that PPARc is activated by CLA in animal models and clinical studies (Reynolds and Roche 2010). Interestingly, a recent in vitro study (Sergeeva et al 2010) showed that the expression of cPLA 2 and sPLA 2 was inhibited by PPARa and PPARc agonists in naïve astrocytes, but was increased by PPARc activation in lipopolysaccharide (LPS)-stimulated astrocytes. Thus, if the anti-inflammatory properties of CLA reported in several studies are mediated by the activation of PPARc, the resulting effects on the activity and gene expression of PLA 2 groups in brain tissue seem to depend on the inflammatory status of the tissue.…”

Neuroprotective Mechanisms of PPARδ: Modulation of Oxidative Stress and Inflammatory Processes

“…The antioxidant and anti-inflammatory actions of PPAR δ agonists have been observed in a variety of cell types, including astrocytes and microglia [32–35]. In particular, PPAR δ can activate transcription of antioxidant genes, including catalase and superoxide dismutase (SOD) [36–38].…”

“…As the authors noted, LPS stimulates NF- κ B and activator protein-1 (AP-1), which PPARs have been shown to transrepress. It is possible that in this model LPS-induced activation of NF- κ B and AP-1 is acting to transrepress PPAR δ [35]. Furthermore, LPS-induced Cox-2 expression in rat primary astrocytes may be modulated, in part, by PPAR δ .…”

Berberine ameliorates the LPS-induced imbalance of osteogenic and adipogenic differentiation in rat bone marrow-derived mesenchymal stem cells

“…Cortical bone formation in the knock-out mice is also increased. In fact, Pparγ is a protein with complex mechanism, which could inhibit certain gene expression levels in untreated cells and enhance these in LPS-stimulated cells (42). Thus, it was suggested that the inhibition of Pparγ gene expression by LPS in undifferentiated BMSCs may reflect a potential osteogenic role.…”