title: Modulation of interferon-γ-induced glial cell activation by transforming growth factor β1: a role for STAT1 and MAPK pathways.
abstract: Overactivated glial cells can produce neurotoxic oxidant molecules such as nitric oxide (NO·) and superoxide anion (O(2)·(-)). We have previously reported that transforming growth factor β1 (TGFβ1) released by hippocampal cells modulates interferon-γ (IFNγ)-induced production of O(2)·(-) and NO· by glial cells. However, underlying molecular mechanisms are not completely understood, thereby, the aim of this work was to study the effect of TGFβ1 on IFNγ-induced signaling pathways. We found that costimulation with TGFβ1 decreased IFNγ-induced phosphorylation of signal transducer and activator of transcription-type-1 (STAT1) and extracellular signal-regulated kinase (ERK), which correlated with a reduced O(2)·(-) and NO· production in mixed and purified glial cultures. Moreover, IFNγ caused a decrease in TGFβ1-mediated phosphorylation of P38, whereas pre-treatment with ERK and P38 inhibitors decreased IFNγ-induced phosphorylation of STAT1 on serine727 and production of radical species. These results suggested that modulation of glial activation by TGFβ1 is mediated by deactivation of MAPKs. Notably, TGFβ1 increased the levels of MAPK phosphatase-1 (MKP-1), whose participation in TGFβ1-mediated modulation was confirmed by MKP-1 siRNA transfection in mixed and purified glial cultures. Our results indicate that the cross-talk between IFNγ and TGFβ1 might regulate the activation of glial cells and that TGFβ1 modulated IFNγ-induced production of neurotoxic oxidant molecules through STAT1, ERK, and P38 pathways.
authors: Departamento de Neurología, Laboratorio de Neurosciencias, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Rodrigo
authors: R
authors: Herrera-Molina
authors: Betsi
authors: B
authors: Flores
authors: Juan A
authors: JA
authors: Orellana
authors: Rommy
authors: R
authors: von Bernhardi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005562:Formazans; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D037102:Lectins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects*; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D053675:Versicans
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D005562:Formazans; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D037102:Lectins; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D009573:Nitrites; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D053773:Transforming Growth Factor beta1; C508324:Vcan protein, rat; D053675:Versicans; D007371:Interferon-gamma