Extended JAK activation and delayed STAT1 dephosphorylation contribute to the distinct signaling profile of CNS neurons exposed to interferon-gamma

J Neuroimmunol. 2012 Oct 15;251(1-2):33-8. doi: 10.1016/j.jneuroim.2012.06.006. Epub 2012 Jul 4.

Abstract

Although interferon-gamma (IFN-γ) plays a critical role in the noncytolytic elimination of many neurotropic viral infections, the signaling response to this cytokine has not been extensively characterized in primary CNS neurons. We previously demonstrated that the IFN-γ response at the signaling and gene expression levels is temporally extended in primary mouse hippocampal neurons, as compared to the transient response of primary mouse embryonic fibroblasts (MEF). We hypothesize that the protracted kinetics of STAT1 phosphorylation in IFN-γ-treated neurons are due to extended receptor activation and/or delayed STAT1 dephosphorylation in the nucleus. Here, we show that in response to IFN-γ, the Janus kinases (JAK1/JAK2) associated with the neuronal IFN-γ receptor complex remain active for an extended period as compared to MEF. Experimental inactivation of JAK1/JAK2 in neurons after IFN-γ treatment did not reverse the extended STAT1 phosphorylation phenotype. These results suggest that the extended kinetics of neuronal IFN-γ signaling are a product of distinct negative feedback mechanisms operating at both the receptor and within the nucleus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Hippocampus / metabolism*
  • Interferon-gamma / metabolism*
  • Interferon-gamma / pharmacology
  • Janus Kinase 1 / metabolism*
  • Janus Kinase 2 / metabolism*
  • Mice
  • Neurons / immunology
  • Neurons / metabolism*
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*

Substances

  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Interferon-gamma
  • Jak1 protein, mouse
  • Jak2 protein, mouse
  • Janus Kinase 1
  • Janus Kinase 2