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IFN-beta1a inhibits the secretion of Th17-polarizing cytokines in human dendritic cells via TLR7 up-regulation.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2009 Mar 15; Vol. 182 (6), pp. 3928-36. - Publication Year :
- 2009
-
Abstract
- IFN-beta, an effective therapy against relapsing-remitting multiple sclerosis, is naturally secreted during the innate immune response against viral pathogens. The objective of this study was to characterize the immunomodulatory mechanisms of IFN-beta targeting innate immune response and their effects on dendritic cell (DC)-mediated regulation of T cell differentiation. We found that IFN-beta1a in vitro treatment of human monocyte-derived DCs induced the expression of TLR7 and the members of its downstream signaling pathway, including MyD88, IL-1R-associated kinase 4, and TNF receptor-associated factor 6, while it inhibited the expression of IL-1R. Using small interfering RNA TLR7 gene silencing, we confirmed that IFN-beta1a-induced changes in MyD88, IL-1R-associated kinase 4, and IL-1R expression were dependent on TLR7. TLR7 expression was also necessary for the IFN-beta1a-induced inhibition of IL-1beta and IL-23 and the induction of IL-27 secretion by DCs. Supernatant transfer experiments confirmed that IFN-beta1a-induced changes in DC cytokine secretion inhibit Th17 cell differentiation as evidenced by the inhibition of retinoic acid-related orphan nuclear hormone receptor C and IL-17A gene expression and IL-17A secretion. Our study has identified a novel therapeutic mechanism of IFN-beta1a that selectively targets the autoimmune response in multiple sclerosis.
- Subjects :
- Adjuvants, Immunologic physiology
Autoantibodies biosynthesis
Cell Differentiation genetics
Cell Differentiation immunology
Cell Polarity immunology
Cells, Cultured
Chemokines biosynthesis
Chemokines genetics
Cytokines genetics
Cytokines metabolism
Gene Expression Profiling
Growth Inhibitors genetics
Growth Inhibitors metabolism
Growth Inhibitors physiology
Humans
Inflammation Mediators metabolism
Interferon beta-1a
Interleukin-17 physiology
Multiple Sclerosis, Relapsing-Remitting immunology
Multiple Sclerosis, Relapsing-Remitting metabolism
Signal Transduction genetics
Signal Transduction immunology
T-Lymphocytes, Helper-Inducer metabolism
Toll-Like Receptor 7 biosynthesis
Toll-Like Receptor 7 genetics
Up-Regulation genetics
Cytokines antagonists & inhibitors
Dendritic Cells metabolism
Interferon-beta physiology
Interleukin-17 antagonists & inhibitors
T-Lymphocytes, Helper-Inducer cytology
T-Lymphocytes, Helper-Inducer immunology
Toll-Like Receptor 7 physiology
Up-Regulation immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 182
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 19265172
- Full Text :
- https://doi.org/10.4049/jimmunol.0802226