DJ-1 mutation decreases astroglial release of inflammatory mediators

Abstract Mutations in DJ-1, reactive gliosis and concomitant inflammatory processes are implicated in the pathogenesis and progression of Parkinson’s disease (PD). To study the physiological consequences of DJ-1 mutation in the context of neuroinflammatory insult, primary cortical astrocytes were isolated from DJ-1 knockout mice. Astrocytes were exposed to 1 μg/mL lipopolysaccharide (LPS) for 24 h following 2 h pre-exposure to inhibitors of MEK (U0126), JNK (JNK inhibitor II) or p38 (SB203580). Real-time PCR was used to assess the LPS-induced expression of pro-inflammatory mediators cyclooxygenase 2 (COX2), inducible nitric oxide synthetase (NOS2), and tumor necrosis factor α (TNFα). LPS-induced expression of COX2 decreased similarly in DJ-1 +/+ and DJ-1 −/− astrocytes in response to inhibition of p38, but was unaffected by inhibition of MEK or JNK. No significant alterations in NOS2 expression were observed in any inhibitor-treated cells. The inhibitors did not affect expression of TNFα; however, DJ-1 −/− astrocytes had consistently lower expression compared to DJ-1 +/+ counterparts. Secretion of TNFα and prostaglandin E2 (PGE2) into the culture medium was significantly decreased in DJ-1 −/− astrocytes, and inhibition of p38 decreased this secretion in both genotypes. In conclusion, DJ-1 −/− astrocytes may provide decreased neuroprotection to surrounding neurons due to alterations in pro-inflammatory mediator expression.