Differential effects of IFN-ß on IL-12, IL-23, and IL-10 expression in TLR-stimulated dendritic cells.
J Leukoc Biol
; 98(5): 689-702, 2015 Nov.
Article
em En
| MEDLINE
| ID: mdl-26059829
ABSTRACT
MS is an autoimmune disease characterized by immune cell infiltration in the CNS, leading to cumulative disability. IFN-ß, used clinically in RR-MS reduces lesion formation and rates of relapse. Although the molecular mechanisms are not entirely elucidated, myeloid cells appear to be a major target for the therapeutic effects of IFN-ß. DCs have a critical role in experimental models of MS through their effect on encephalitogenic Th1/Th17 cell differentiation and expansion. Here we focused on the effects of IFN-ß on DC expression of cytokines involved in the control of Th1/Th17 differentiation and expansion. Administration of IFN-ß to mice immunized with MOG35-55 inhibited IL-12 and IL-23 expression in splenic DC and reduced in vivo differentiation of Th1/Th17 cells. IFN-ß affected cytokine expression in TLR-stimulated DC in a similar manner in vitro, inhibiting IL-12 and IL-23 and stimulating IL-10 at both mRNA and protein levels, by signaling through IFNAR. We investigated the role of the signaling molecules STAT1/STAT2, IRF-1 and IRF-7, and of the PI3KâGSK3 pathway. IFN-ß inhibition of the IL-12 subunits p40 and p35 was mediated through STAT1/STAT2, whereas inhibition of IL-23 was STAT1 dependent, and the stimulatory effect on IL-10 expression was mediated through STAT2. IFN-ß induces IRF-7 and, to a lesser degree, IRF-1. However, neither IRF mediated the effects of IFN-ß on IL-12, IL-23, or IL-10. We found that the PI3K pathway mediated IL-12 inhibition but did not interfere with the inhibition of IL-23 or stimulation of IL-10.
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Base de dados:
MEDLINE
Assunto principal:
Células Dendríticas
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Transdução de Sinais
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Interleucina-10
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Interferon beta
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Receptores Toll-Like
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Subunidade p35 da Interleucina-12
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Subunidade p40 da Interleucina-12
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Interleucina-23
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article