Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway.
Reactive gliosis is characterized by enhanced glial fibrillary acidic protein (GFAP) expression, cellular hypertrophy, and astrocyte proliferation. The cellular and molecular mechanisms underlying this process are still largely undefined. We investigated the role of endothelin-1 (ET-1) in reactive gliosis in corpus callosum after lysolecithin (LPC)-induced focal demyelination and in cultured astrocytes. We show that ET-1 levels are upregulated in demyelinated lesions within 5 d after LPC injection, together with enhanced astrocyte proliferation, GFAP expression, and JNK phosphorylation. Infusion of the pan-ET-receptor (ET-R) antagonist Bosentan or the selective ET(B)-R antagonist BQ788 into the corpus callosum prevented postlesion astrocyte proliferation and JNK phosphorylation. In cultured astrocytes, ET-1-induced activation of ET(B)-Rs promotes a reactive phenotype by enhancing both GFAP expression and astrocyte proliferation. In the same cells, ET-1 activates both JNK and p38MAPK pathways, and induces c-Jun expression at the mRNA and protein levels. By using selective pharmacological inhibitors, we also provide evidence that ET-1 induces astrocyte proliferation and GFAP expression through activation of ERK- and JNK-dependent pathways, consistent with the previous observation of ET-1-induced activation of ERK (Schinelli et al., 2001). Finally, we show by gain and loss of function that increased c-Jun expression enhances the proliferative response of astrocytes to ET-1, whereas c-jun siRNA prevents ET-1-induced cell proliferation. Our results indicate that the effects of ET-1 on astrocyte proliferation depend on c-Jun induction and activation through ERK- and JNK-dependent pathways, and suggest that ET-R-associated pathways might represent important targets to control reactive gliosis.
Gadea
Ana
A
Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
Schinelli
Sergio
S
Gallo
Vittorio
V
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000502:physiology*; D005911:Gliosis / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D012333:RNA, Messenger; D048031:JNK Mitogen-Activated Protein Kinases