Abstract
In brain tissue, astrocytes play defensive roles in central nervous system integrity by mediating immune responses against pathological conditions. Type I phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5K alpha) that is responsible for production of phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2) regulates many important cell functions at the cell surface. Here, we have examined whether PIP5K alpha is associated with astrocyte inflammatory responses. Gangliosides are releasable from damaged cell membranes of neurons and capable of inducing inflammatory responses. We found that treatment of primary cultured astrocytes with gangliosides significantly enhanced PIP5K alpha mRNA and protein expression levels. PI(4,5)P2 imaging using a fluorescent tubby (R332H) expression as a PI(4,5)P2-specific probe showed that ganglioside treatment increased PI(4,5)P2 level. Interestingly, microRNA-based PIP5K alpha knockdown strongly reduced ganglioside-induced transcription of proinflammatory cytokines IL-1 beta and TNFalpha. PIP5K alpha knockdown also suppressed ganglioside-induced phosphorylation and nuclear translocation of NF-kappaB and the degradation of I kappaB-alpha, indicating that PIP5K alpha knockdown interfered with the ganglioside-activated NF-kappaB signaling. Together, these results suggest that PIP5K alpha is a novel inflammatory mediator that undergoes upregulation and contributes to immune responses by facilitating NF-kappaB activation in ganglioside-stimulated astrocytes.
Highlights
Astrocytes are the most abundant glial cells in the brain and play crucial roles as immune effector cells against brain insult (Farina et al, 2007)
Our findings revealed that gangliosides enhanced phosphatidylinositol 4-phosphate 5-kinase α (PIP5Kα) expression, which led to an increase in PI(4,5)P2, and that gene knockdown of PIP5Kα attenuated the ganglioside-induced activation of NF-κB signaling and inflammatory responses in rat primary cultured astrocytes
We examined whether ganglioside treatment altered PIP5Kα expression levels
Summary
Astrocytes are the most abundant glial cells in the brain and play crucial roles as immune effector cells against brain insult (Farina et al, 2007). Reactive astrocytes produce inflammatory mediators, including proinflammatory cytokines such as IL-1β and TNFα, reactive oxygen species, and nitric oxide (Pawate et al, 2004; Jou et al, 2006; Farina et al, 2007). Under pathological conditions such as neurodegenerative disorders, astrocyte immune function exerts a neuroprotective role, but is recognized to cause the progression of neuronal damage (Teismann and Schulz, 2004; Schwab and McGeer, 2008). PIP5K and PI(4,5)P2 are critical regulators of a variety of cellular processes involving membrane signaling and trafficking, and actin dynamics (Takenawa and Itoh, 2001; Doughman et al, 2003; Di Paolo and De Camilli, 2006)
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