title: Interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta inhibit cyclic AMP-induced Schwann cell differentiation.
abstract: Schwann cells differentiate in vivo in response to contact with axons, and cAMP simulates some of these aspects of differentiation in vitro, particularly morphologic changes and expression of certain phenotypic molecules. Unfractionated inflammatory cytokines inhibit cAMP-induced Schwann cell expression of galactolipids (Gal). We sought to identify which cytokines were responsible for this inhibition and to determine whether other phenotypic indicators of Schwann cell differentiation were also affected. Neonatal rat Schwann cells were incubated in vitro with 1 mM 8 Bromo cAMP (8 Br cAMP) with or without the addition of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), or transforming growth factor-beta (TGF-beta). Cells were then examined for morphologic changes and for expression of surface Gal and low-affinity nerve growth factor receptor (NGFRp75), employing indirect immunofluorescence. 8 Br cAMP induced Schwann cell upregulation of Gal, downregulation of NGFRp75, and the cells became enlarged and somewhat amorphous and irregular in appearance. Cells treated with IFN-gamma or TNF-alpha alone were more bipolar and more evenly distributed on coverslips than were control cells, whereas TGF-beta alone induced elongated cells often in a swirling pattern. None of the cytokines alone induced upregulation of Gal or downregulation of NGFRp75. TNF-alpha, IFN-gamma, and TGF-beta inhibited the 8 Br cAMP-induced morphologic changes, as well as the upregulation of Gal and downregulation of NGFRp75. The other cytokines had no effects on Gal or NGFRp75 expression. Thus, these three cytokines, which are present in inflammatory lesions in the peripheral nervous system, are capable of inhibiting Schwann cell differentiation.
authors.affiliation: Department of Neurology, Division of Neuroimmunology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Lisak
authors.forename: B
authors.initials: B
authors.lastname: Bealmear
authors.forename: J A
authors.initials: JA
authors.lastname: Benjamins
authors.forename: A M
authors.initials: AM
authors.lastname: Skoff
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D003711:Demyelinating Diseases / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D038983:Galactolipids; D006017:Glycolipids / Q000819:agonists / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D017933:Peripheral Nervous System / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D016207:Cytokines; D038983:Galactolipids; D006017:Glycolipids; D020800:Receptor, Nerve Growth Factor; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D015124:8-Bromo Cyclic Adenosine Monophosphate; D007371:Interferon-gamma; D000242:Cyclic AMP