Minimal role for STAT1 in interleukin-6 signaling and actions in the murine brain.
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 STAT1 (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-alpha, 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 STAT1 this plays minimal, if any, role in IL-6 signaling and actions in the CNS.
Sanz
Elisenda
E
Department of Biochemistry and Molecular Biology, The Autonomous University of Barcelona, Barcelona, Spain.
Hofer
Markus J
MJ
Unzeta
Mercedes
M
Campbell
Iain L
IL
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000502:physiology; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D015850:Interleukin-6; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D049452:Green Fluorescent Proteins