Minimal role for STAT1 in interleukin-6 signaling and actions in the murine brain

Elisenda Sanz, Markus J. Hofer, Mercedes Unzeta, Iain L. Campbell

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

Interleukin (IL)-6 is a pleiotropic cytokine whose production by astrocytes in the CNS of transgenic mice (termed GF-IL6) causes neuroinflammation and neurodegeneration. The binding of IL-6 to its receptor (IL6R) triggers gp130-mediated activation of STAT1 and STAT3 as well as SHP2 phosphatase and ERK1/2. We determined the relative contribution of STAT1 to IL-6 signaling and actions in vivo in the brain of GF-IL6 mice. GF-IL6 mice that were null for STATl (termed GF-IL6STAT1 KO) were viable, bred normally and physically indistinguishable from GF-IL6 controls. The level of phosphotyrosine (p-Y) STAT1 was increased significantly in GF-IL6 mice but not detectable in GF-IL6STAT1 KO animals. Phospho-STAT3 and phospho-ERK1/2 were increased markedly in GF-IL6 mice and were not altered by the absence of STAT1. Both the density and distribution of phospho-STAT3-positive cells (mainly astrocytes, microglia and endothelial cells) was similar in GF-IL6 and GF-IL6STAT1 KO mice. Despite a minor decrease in IL-1 and TNF mRNA, the overall inflammatory phenotype of GF-IL6 mice was not altered significantly by the absence of STAT1. IFN-regulated genes activated by STAT1 homodimers via the GAS element (e.g. CXCL9) showed a small increase in GF-IL6 but not GF-IL6STAT1 KO animals. When compared with transgenic mice with astrocyte-targeted production of the type I IFN, IFN-α, the increased levels of p-Y-STAT1 and IFN-regulated gene expression were considerably lower in GF-IL6 mice. In conclusion, although IL-6 can activate STATl this plays minimal, if any, role in IL-6 signaling and actions in the CNS. © 2007 Wiley-Liss, Inc.
Original languageEnglish
Pages (from-to)190-199
JournalGLIA
Volume56
DOIs
Publication statusPublished - 15 Jan 2008

Keywords

  • Astrocyte
  • Cytokine
  • STAT3
  • Transgenic mouse

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