title: S-nitrosoglutathione induces ciliary neurotrophic factor expression in astrocytes, which has implications to protect the central nervous system under pathological conditions.
abstract: Accumulating evidence suggests that reactive astrogliosis has beneficial and detrimental outcomes in various CNS disorders, but the mechanism behind this dichotomy is unclear. Recent advances in this direction suggested that NO signaling is critical to regulate the outcomes of reactive astrogliosis in vivo. Using biochemical and genetic approaches, we here investigated the effect of S-nitrosoglutathione (GSNO; a physiological NO donor) in astrocytes in vitro settings. GSNO enhanced the expressions of glial fibrillary acidic protein and neurotrophic factors including ciliary neurotrophic factor (CNTF) in astrocytes in a dose-dependent manner. The enhanced CNTF expression in GSNO-treated astrocytes was ascribed to NO-mediated sGC/cGMP/PKG signaling. It was associated with p38 MAPK-dependent increased peroxisome proliferator-activated receptor-γ transactivation. In addition, the chromatin accessibility of peroxisome proliferator-activated receptor-γ accompanied with ATF2 and CREB (cAMP-response element-binding protein) was enhanced across the CNTF gene promoter in GSNO treated astrocytes. Interestingly, secreted CNTF was responsible for increased expression of glial fibrillary acidic protein in GSNO-treated astrocytes in an autocrine manner via a JAK2- and STAT3-dependent mechanism. In addition, CNTF secreted by GSNO-treated astrocytes enhanced the differentiation of immature oligodendrocytes in vitro. These effects of GSNO were consistent with an endogenously produced NO in astrocytes stimulated with proinflammatory cytokines in vitro. We conclude that NO signaling induces CNTF expression in astrocytes that favors the beneficial outcomes of reactive astrogliosis in vivo. Our data suggest that the endogenously produced NO or its exogenous source has potential to modulate the outcomes of reactive astrogliosis to protect CNS under pathological conditions.
authors.affiliation: Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Paintlia
authors.forename: Ajaib S
authors.initials: AS
authors.lastname: Paintlia
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D020934:Ciliary Neurotrophic Factor / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D020030:Nitric Oxide Donors; D047495:PPAR gamma; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D048051:p38 Mitogen-Activated Protein Kinases