Exp Mol Med.  2010 Sep;42(9):662-673. 10.3858/emm.2010.42.9.066.

Phosphatidylinositol 4-phosphate 5-kinase alpha is induced in ganglioside-stimulated brain astrocytes and contributes to inflammatory responses

• Lee SY
• Kim B
• Yoon S
• Kim YJ
• Liu T
• Woo JH
• Chwae YJ
• Joe EH
• Jou I

• KMID: 983958
• DOI: http://doi.org/10.3858/emm.2010.42.9.066

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 (PIP5Kalpha) 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 PIP5Kalpha 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 PIP5Kalpha 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 PIP5Kalpha knockdown strongly reduced ganglioside-induced transcription of proinflammatory cytokines IL-1beta and TNFalpha. PIP5Kalpha knockdown also suppressed ganglioside-induced phosphorylation and nuclear translocation of NF-kappaB and the degradation of IkappaB-alpha, indicating that PIP5Kalpha knockdown interfered with the ganglioside-activated NF-kappaB signaling. Together, these results suggest that PIP5Kalpha is a novel inflammatory mediator that undergoes upregulation and contributes to immune responses by facilitating NF-kappaB activation in ganglioside-stimulated astrocytes.

Keyword

astrocytes; brain; gangliosides; inflammation; NF-kappaB; 1-phosphatidylinositol-4-phosphate 5-kinase

MeSH Terms

Animals
Astrocytes/*metabolism
Cells, Cultured
Gangliosides/*metabolism
Gene Knockdown Techniques
Inflammation/*metabolism
Interleukin-1/metabolism
NF-kappa B/metabolism
Phosphotransferases (Alcohol Group Acceptor)/*metabolism
RNA, Messenger/*genetics/metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction
Tumor Necrosis Factor-alpha/metabolism
Up-Regulation