Glial cells release
neurotrophic factors that maintain neurons functionally. Previously, we have shown that the scabronines isolated from Sarcodon scabrosus enhanced the secretion of
neurotrophic factors from 1321N1 human
astrocytoma cells. In the present study, we examined the mechanism of newly synthesized
scabronine G-methylester (ME)-induced secretion of
neurotrophic factors from 1321N1 cells. The dramatic neuronal differentiation of rat
pheochromocytoma cells (PC-12) was observed by
scabronine G-ME-
conditioned medium of 1321N1 cells.
Scabronine G-ME increased the secretion of
nerve growth factor (
NGF) and
interleukin-6 (IL-6) from 1321N1 cells with the enhancement of their
mRNA expressions.
Scabronine G-ME concentration-dependently inhibited the
carbachol-induced
inositol phosphate accumulation in 1321N1 cells, which was reversed by
GF109203X, an inhibitor of
protein kinase C (PKC)
isoforms. Furthermore,
GF109203X inhibited the
scabronine G-ME-induced
mRNA expressions of both
NGF and
IL-6 and the differentiation of PC-12 cells, showing that
scabronine G-ME activated PKC. Although
scabronine G-ME enhanced activities of neither conventional nor novel types of
PKCs, it translocated PKC-zeta to membranes in intact cells and cell-free condition. Furthermore, recombinant PKC-zeta activity was also increased by
scabronine G-ME, suggesting the involvement of PKC-zeta in the effect of
scabronine G-ME. Concerning the downstream effectors of the PKC-zeta,
scabronine G-ME translocated
nuclear factor-kappaB to nucleus, and enhanced its transcriptional activity. In addition,
scabronine G-ME caused the degradation of inhibitor of
nuclear factor-kappaB concentration-dependently, which was inhibited by
GF109203X. These results suggest that
scabronine G-ME potentially enhances the secretion of
neurotrophic factors from 1321N1 cells mediated via the activation of PKC-zeta.