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Pigment epithelium‐derived factor induces pro‐inflammatory genes in neonatal astrocytes through activation of NF‐κB and CREB

Pigment epithelium‐derived factor (PEDF) is a potent and broadly acting neurotrophic factor that protects neurons in various types of cultured neurons against glutamate excitotoxicity and induced‐apoptosis. Some of the effects of PEDF reflect specific changes in gene expression, mediated via activation of the transcription factor NF‐κB in neurons. To investigate whether PEDF also modulates gene expression in astrocytes, we employed the use of RT‐PCR to analyze the gene expression of certain pro‐inflammatory genes and found that genes such as IL‐1β, IL‐6, TNF‐α, MIP1α, and MIP3α were induced in PEDF‐treated cultured neonatal astrocytes, but not in adult astrocytes. Electrophoresis mobility shift assay (EMSA) revealed that a time‐ and dose‐dependent increase of NF‐κB‐ and AP‐1‐DNA binding activity was observed in PEDF‐treated neonatal astrocytes. Furthermore, rapid phosphorylation of CREB protein had occurred in PEDF‐treated neonatal astrocytes. Upregulation of pro‐inflammatory and AP‐1‐related genes by PEDF was blocked by overexpression of dominant negative CREB or a mutated form of IκBα. These results suggest that the induction of pro‐inflammatory genes is mediated via activation of NF‐κB, AP‐1, and CREB in neonatal astrocytes. Taken together, these results demonstrate that PEDF is a multipotent factor, capable of affecting not only neurons, but also neonatal astrocytes, and suggests that it may act as a neuroimmune modulator in the developmental brain. © 2005 Wiley‐Liss, Inc.