Modulation of interferon-γ-induced glial cell activation by transforming growth factor β1: A role for STAT1 and MAPK pathways

Overactivated glial cells can produce neurotoxic oxidant molecules such as nitric oxide (NO center dot) and superoxide anion (O2 center dot-). We have previously reported that transforming growth factor beta 1 (TGF beta 1) released by hippocampal cells modulates interferon-? (IFN?)-induced production of O2 center dot- and NO center dot by glial cells. However, underlying molecular mechanisms are not completely understood, thereby, the aim of this work was to study the effect of TGF beta 1 on IFN?-induced signaling pathways. We found that costimulation with TGF beta 1 decreased IFN?-induced phosphorylation of signal transducer and activator of transcription-type-1 (STAT1) and extracellular signal-regulated kinase (ERK), which correlated with a reduced O2 center dot- and NO center dot production in mixed and purified glial cultures. Moreover, IFN? caused a decrease in TGF beta 1-mediated phosphorylation of P38, whereas pre-treatment with ERK and P38 inhibitors decreased IFN?-induced phosphorylation of STAT1 on serine727 and production of radical species. These results suggested that modulation of glial activation by TGF beta 1 is mediated by deactivation of MAPKs. Notably, TGF beta 1 increased the levels of MAPK phosphatase-1 (MKP-1), whose participation in TGF beta 1-mediated modulation was confirmed by MKP-1 siRNA transfection in mixed and purified glial cultures. Our results indicate that the cross-talk between IFN? and TGF beta 1 might regulate the activation of glial cells and that TGF beta 1 modulated IFN?-induced production of neurotoxic oxidant molecules through STAT1, ERK, and P38 pathways.