title: Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain.
abstract: IL-6 is implicated in the pathogenesis of various neuroinflammatory and neurodegenerative disorders of the CNS. IL-6 signals via binding to either the membrane bound IL-6Rα (classic signaling) or soluble (s)IL-6Ra (trans-signaling) that then form a complex with gp130 to activate the JAK/STAT signaling pathway. The importance of classic versus trans-signaling in mediating IL-6 actions in the living CNS is relatively unknown and was the focus of this investigation. Bigenic mice (termed GFAP-IL6/sgp130 mice) were generated with CNS-restricted, astrocyte-targeted production of IL-6 and coproduction of the specific inhibitor of IL-6 trans-signaling, human sgp130-Fc. Transgene-encoded IL-6 mRNA levels were similar in the brain of GFAP-IL6 and GFAP-IL6/sgp130 mice. However, GFAP-IL6/sgp130 mice had decreased pY(705)-STAT3 in the brain due to a reduction in the total number of pY(705)-STAT3-positive cells and a marked loss of pY(705)-STAT3 in specific cell types. Blockade of trans-signaling in the brain of the GFAP-IL6 mice significantly attenuated Serpina3n but not SOCS3 gene expression, whereas vascular changes including angiogenesis and blood-brain barrier leakage as well as gliosis were also reduced significantly. Hippocampal neurogenesis which was impaired in GFAP-IL6 mice was rescued in young GFAP-IL6 mice with cerebral sgp130 production. Finally, degenerative changes in the cerebellum characteristic of GFAP-IL6 mice were absent in GFAP-IL6/sgp130 mice. The findings indicate that in the CNS: (1) sgp130 is able to block IL-6 trans-signaling, (2) trans-signaling is important for IL-6 cellular communication with selective cellular and molecular targets, and (3) blocking of trans-signaling alleviates many of the detrimental effects of IL-6.
authors: School of Molecular Bioscience, The University of Sydney, New South Wales 2006, Australia, Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona 08193, Spain, Department of Biochemistry, University of Kiel, D-24098 Kiel, Germany, and Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, 40225 Düsseldorf, Germany.
authors: Iain L
authors: IL
authors: Campbell
authors: Maria
authors: M
authors: Erta
authors: Sue Ling
authors: SL
authors: Lim
authors: Ricardo
authors: R
authors: Frausto
authors: Ulrike
authors: U
authors: May
authors: Stefan
authors: S
authors: Rose-John
authors: Jürgen
authors: J
authors: Scheller
authors: Juan
authors: J
authors: Hidalgo
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D050822:Cytokine Receptor gp130
keywords: interleukin-6; neuropathology; signal transduction; trans-signaling; transgenic mouse