Myelin basic protein (MBP) and MBP peptides are mitogens for cultured astrocytes

Abstract

After CNS demyelination, astrogliosis interferes with axonal regeneration and remyelination. We now provide evidence that myelin basic protein (MBP) can contribute to this observed astrocyte proliferation. We found that astrocytes grown in either serum-containing or serum-free medium proliferate in response to MBP. The mitogenic regions of MBP in both media were MBP(1-44), MBP(88-151) and MBP(152-167). The mitogenic effect of these individual peptides was potentiated by simultaneous treatment with microglia conditioned media (CM). MBP-induced proliferation was inhibited by suramin at concentrations known to block the fibroblast growth factor receptor (FGFR), whereas neither MBP(1-44), MBP(88-151) nor MBP(152-167) were affected. Cholera toxin B, that binds to ganglioside GM(1), inhibited the mitogenicity of MBP(1-44) and had no significant effect on the mitogenicity of MBP, MBP(88-151) or MBP(152-167). Treatment of astrocytes with MBP and MBP(152-167) caused a modest and transitory elevation of intracellular calcium, whereas treatment with MBP(1-44) resulted in a substantial and sustained increase in intracellular calcium. These results suggest that for cultured astrocytes 1) FGFR and extracellular calcium play a major role in MBP mitogenicity; 2) MBP(1-44), MBP(88-151) and MBP(152-167) are the mitogenic regions of MBP; 3) MBP(1-44) and MBP(152-167) interact with ganglioside GM(1) and FGFR, respectively; 4) Component(s) present in microglial CM potentiate the mitogenicity of MBP(1-44), MBP(88-151) and MBP(152-167). These data support the hypothesis that MBP related peptides in conjunction with microglial secreted factors may stimulate astrogliosis after demyelination in vivo.