Soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro differentiation of purified rat oligodendroglial lineage cells.
We investigated the effects of a chimeric protein (IL6RIL6 chimera) containing interleukin-6 (IL-6) fused to its soluble receptor (sIL-6R) on the proliferation and/or differentiation of rat oligodendrocyte progenitor cells (OPCs) and on oligodendrocyte survival. Exposure of OPCs to IL6RIL6 chimera for 48 h induced a dose-dependent decrease of bromodeoxyuridine (BrdU) incorporation. IL6RIL6 chimera treatment for 48 h also strongly increased the reduction of the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) by mitochondrial enzymes and enhanced oligodendrocyte staining with a mitochondrial fluorescent dye. A strong, dose-dependent increase in the number and length of processes immunostained for early (galactocerebroside) or late (myelin basic protein) oligodendrocyte differentiation markers was revealed after OPC treatment with IL6RIL6 chimera for 2-7 days, respectively. Moreover, treatment with IL6RIL6 chimera improved oligodendrocyte survival. The chimera-induced increase of oligodendrocyte arborization was mimicked, although with lower efficacy, by ciliary neurotrophic factor (CNTF) but not by IL-6 and was reduced in the presence of a gp130 soluble peptide which is able to inhibit the gp130-mediated signals of the IL-6/sIL-6R complex. Oligodendrocyte treatment with IL6RIL6 chimera for 30 min induced both signal transducer and the activator of transcription-1 (STAT-1) and STAT-3 phosphorylation and nuclear translocation. We conclude that, by interacting with membrane gp130 and possibly by activating Janus kinase/STAT pathways, IL6RIL6 chimera induces OPCs to differentiate into mature oligodendrocytes, promotes their survival, and could deserve investigation as a therapeutic strategy for enhancing remyelination.
Valerio
Alessandra
A
Division of Pharmacology, Department of Biomedical Sciences & Biotechnologies, University of Brescia, 25123 Brescia, Italy. valerio@med.unibs.it
Ferrario
Marina
M
Dreano
Michel
M
Garotta
Gianni
G
Spano
Pierfranco
P
Pizzi
Marina
M
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000187:drug effects* / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006133:Growth Substances / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D018121:Receptors, Cytokine / Q000276:immunology / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D013234:Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism
D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D006133:Growth Substances; D015850:Interleukin-6; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D015534:Trans-Activators; C456339:cytokine receptor, GLM-R