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 STAT1 (termed GF‐IL6^STAT1 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‐IL6^STAT1 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‐IL6^STAT1 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‐IL6^STAT1 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 STAT1 this plays minimal, if any, role in IL‐6 signaling and actions in the CNS. © 2007 Wiley‐Liss, Inc.