title: Astrocyte-specific activation of TNFR2 promotes oligodendrocyte maturation by secretion of leukemia inhibitory factor.
abstract: Tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2 have pleiotropic effects in neurodegenerative disorders. For example, while TNFR1 mediates neurodegenerative effects in multiple sclerosis, TNFR2 is protective and contributes to remyelination. The exact mode of TNFR2 action, however, is poorly understood. Here, we show that TNFR2-mediated activation of the PI3K-PKB/Akt pathway in primary astrocytes increased the expression of neuroprotective genes, including that encoding the neurotrophic cytokine leukemia inhibitory factor (LIF). To investigate whether intercellular signaling between TNFR2-stimulated astrocytes and oligodendrocytes plays a role in oligodendrocyte maturation, we established an astrocyte-oligodendrocyte coculture model, composed of primary astrocytes from huTNFR2-transgenic (tgE1335) mice and oligodendrocyte progenitor cells (OPCs) from wild-type mice, capable of differentiating into mature myelinating oligodendrocytes. In this model, selective stimulation of human TNFR2 on astrocytes, promoted differentiation of cocultured OPCs to myelin basic protein-positive mature oligodendrocytes. Addition of LIF neutralizing antibodies inhibited oligodendrocyte differentiation, indicating a crucial role of TNFR2-induced astrocyte derived LIF for oligodendrocyte maturation.
authors: Institute of Cell Biology and Immunology, University Stuttgart, Stuttgart, Germany.
authors: Roman
authors: R
authors: Fischer
authors: Harald
authors: H
authors: Wajant
authors: Roland
authors: R
authors: Kontermann
authors: Klaus
authors: K
authors: Pfizenmaier
authors: Olaf
authors: O
authors: Maier
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases
keywords: TNFR2; astrocytes; myelination; oligodendrocytes