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

Authors

  • Rodrigo Herrera-Molina,

    1. Departamento de Neurología, Laboratorio de Neurosciencias, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
    2. Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, Germany
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    • Both authors contributed equally to this work.

  • Betsi Flores,

    1. Departamento de Neurología, Laboratorio de Neurosciencias, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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    • Both authors contributed equally to this work.

  • Juan A. Orellana,

    1. Departamento de Neurología, Laboratorio de Neurosciencias, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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  • Rommy von Bernhardi

    1. Departamento de Neurología, Laboratorio de Neurosciencias, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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Address correspondence and reprint requests to Rommy von Bernhardi, Laboratorio de Neurosciencias, Facultad de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago, CHILE. E-mail: rvonb@med.puc.cl

Abstract

Overactivated glial cells can produce neurotoxic oxidant molecules such as nitric oxide (NO·) and superoxide anion (O2·). We have previously reported that transforming growth factor β1 (TGFβ1) released by hippocampal cells modulates interferon-γ (IFNγ)-induced production of O2· 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 O2· 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.

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