IFN-beta1a inhibits the secretion of Th17-polarizing cytokines in human dendritic cells via TLR7 up-regulation.
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.
Zhang
Xin
X
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA.
Jin
Jianping
J
Tang
Yunan
Y
Speer
Danielle
D
Sujkowska
Danuta
D
Markovic-Plese
Silva
S
D000276:Adjuvants, Immunologic / Q000502:physiology; D001323:Autoantibodies / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000502:physiology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000502:physiology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D018925:Chemokines; D016207:Cytokines; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D020381:Interleukin-17; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D016899:Interferon-beta; D000068556:Interferon beta-1a