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PEDF Stimulates Synthesis of Chemokines in Neural Cells

J. Taylor Herbert
A. Takanohashi
T. Yabe
J.P. Schwartz

PEDF differentially protects immature (days in vitro [DIV]2) but not mature (DIV6) cerebellar granule cells (CGCs) against low K+/serum-free-induced apoptosis, while PEDF-treated mature CGCs (DIV8) are protected against glutamate-induced neurotoxicity. Some of the effects of PEDF reflect specific changes in gene expression, mediated via activation of the transcription factor NF-kB. Identification of altered gene expression associated with the neuroprotective effects of PEDF, using mciroarray analysis, has provided novel markers for neurotrophic effects. Interestingly, PEDF induces expression of genes for several chemokines and cytokines, including MIP-1a (macrophage inhibitory protein), MIP-2, MIP-3a, interleukin-1b, granulocyte colony-stimulating factor (G-CSF), lipopolysaccharide-induced chemokine (LIX), and plasminogen activator inhibitor-1 (PAI-1) in both immature and mature CGCs. We show that PEDF treatment induces synthesis of MIP-1a, MIP-2, and MIP-3a proteins and that blocking antibodies to all three chemokines enhance the neuroprotective effect of PEDF against apoptosis. In contrast, blocking antibodies against LIX and PAI-1 had no effect; the cells did not synthesize G-CSF, either in the presence or absence of PEDF. Because the cultures contain about 1 percent each microglia and astocytes, we have also looked at the ability of PEDF to alter synthesis of the MIPs in these cells. PEDF turned on synthesis of MIP-1a and MIP-2 in both microglia and astrocytes. These results suggest that PEDF can be both neuroprotective and neurotoxic, the latter by its stimulation of chemokine expression in neurons, astrocytes, and microglia. Therefore, use of this factor in vivo must be undertaken with some care.