title: Involvement of gp130-associated cytokine signaling in Müller cell activation following optic nerve lesion.
abstract: Ciliary neurotrophic factor (CNTF) and the related cytokine leukemia inhibitory factor (LIF) have been implicated in regulating astrogliosis following CNS lesions. Application of the factors activates astrocytes in vivo and in vitro, and their expression as well as their receptors is upregulated after brain injury. Here, we investigated their function by studying Müller cell activation induced by optic nerve crush in CNTF- and LIF-deficient mice, and in animals with deficiencies in cytokine signaling pathways. In the retina of CNTF(-/-) mice, basal GFAP expression was reduced, but unexpectedly, injury-induced upregulation in activated Müller cells was increased during the first 3 days after lesion as compared to wild-type animals and this corresponded with higher phosphorylation level of STAT3, an indicator of cytokine signaling. The observation that LIF expression was strongly upregulated in CNTF(-/-) mice but not in wild-type animals following optic nerve lesion provided a possible explanation. In fact, additional ablation of the LIF gene in CNTF/LIF double knockout mice almost completely abolished early lesion-induced GFAP upregulation in Müller cells and STAT3 phosphorylation. Early Müller cell activation was also eliminated in LIF(-/-) mice, despite normal CNTF levels, as well as in mutants deficient in gp130/JAK/STAT signaling and in conditional STAT3 knockout mice. Our results demonstrate that LIF signaling via the gp130/JAK/STAT3 pathway is required for the initiation of the astrogliosis-like reaction of retinal Müller cells after optic nerve injury. A potential role of CNTF was possibly masked by a compensatory increase in LIF signaling in the absence of CNTF.
authors.affiliation: Institute of Anatomy and Cell Biology, University of Freiburg, Albertstr. 23, Freiburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kirsch
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Trautmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020221:Optic Nerve Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000502:physiology; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130