title: Proapoptotic and antiapoptotic actions of Stat1 versus Stat3 underlie neuroprotective and immunoregulatory functions of IL-11.
abstract: Current therapies for multiple sclerosis target inflammation but do not directly address oligodendrocyte protection or myelin repair. The gp130 family cytokines ciliary neurotrophic factor, leukemia inhibitory factor, and IL-11 have been identified as oligodendrocyte growth factors, and IL-11 is also strongly immunoregulatory, but their underlying mechanisms of action are incompletely characterized. In this study, we demonstrate that these effects of IL-11 are mediated via differential regulation of apoptosis in oligodendrocytes versus Ag-presenting dendritic cells (DCs), and are dependent on lineage-specific activity of the transcription factors Stat1 versus Stat3. Focal demyelinating lesions induced in cerebral cortices of IL-11Rα(-/-) mice using stereotactic microinjection of lysolecithin were larger than in controls, and remyelination was delayed. In IL-11Rα(-/-) mice, lesions displayed extensive oligodendrocyte loss and axonal transection, and increased infiltration by inflammatory cells including CD11c(+) DCs, CD3(+) lymphocytes, and CD11b(+) phagocytes. In oligodendrocyte progenitor cell (OPC) cultures, IL-11 restricted caspase 9 activation and apoptosis, and it increased myelination in OPC-neuron cocultures. Importantly, siRNA inhibition of Stat1 enhanced the antiapoptotic effects of IL-11 on OPCs, but IL-11 induced apoptosis in the presence of Stat3 silencing. In contrast, IL-11 augmented caspase activation and apoptosis in cultures of CD11c(+) DCs, but not in CD11b(+) or CD3(+) cells. Inhibition of Stat3 exacerbated the proapoptotic effects of IL-11 on DCs, whereas they were ablated in Stat1(-/-) cultures. Collectively, these findings reveal novel mechanisms underlying the actions of a neuroprotective and immunoregulatory member of the gp130 cytokine family, suggesting avenues to enhance oligodendrocyte viability and restrict CNS inflammation in multiple sclerosis.
authors.affiliation: Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Jingya
authors.initials: J
authors.lastname: Zhang
authors.forename: Yueting
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dipankar J
authors.initials: DJ
authors.lastname: Dutta
authors.forename: Azeb T
authors.initials: AT
authors.lastname: Argaw
authors.forename: Virginie
authors.initials: V
authors.lastname: Bonnamain
authors.forename: Jeremy
authors.initials: J
authors.lastname: Seto
authors.forename: David A
authors.initials: DA
authors.lastname: Braun
authors.forename: Andleeb
authors.initials: A
authors.lastname: Zameer
authors.forename: Fernand
authors.initials: F
authors.lastname: Hayot
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Lòpez
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.forename: Gareth R
authors.initials: GR
authors.lastname: John
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003711:Demyelinating Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D018390:Gene Targeting / Q000379:methods; D017370:Interleukin-11 / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D017370:Interleukin-11; D018696:Neuroprotective Agents; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse