Differential effects of IFN‐β on IL‐12, IL‐23, and IL‐10 expression in TLR‐stimulated dendritic cells
In vivo and in vitro inhibition of IL‐12, IL‐23, and IL‐10 stimulation by IFNβ. MS is an autoimmune disease characterized by immune cell infiltration in the CNS, leading to cumulative disability. IFN‐β, used clinically in RR‐MS reduces lesion formation and rates of relapse. Although the molecular me...
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Published in | Journal of leukocyte biology Vol. 98; no. 5; pp. 689 - 702 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Leukocyte Biology
01.11.2015
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Subjects | |
Online Access | Get full text |
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Summary: | In vivo and in vitro inhibition of IL‐12, IL‐23, and IL‐10 stimulation by IFNβ.
MS is an autoimmune disease characterized by immune cell infiltration in the CNS, leading to cumulative disability. IFN‐β, 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‐β. 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‐β on DC expression of cytokines involved in the control of Th1/Th17 differentiation and expansion. Administration of IFN‐β 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‐β 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 PI3K→GSK3 pathway. IFN‐β 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‐β induces IRF‐7 and, to a lesser degree, IRF‐1. However, neither IRF mediated the effects of IFN‐β 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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Bibliography: | These authors contributed equally to this work. Current affiliation: Laboratory of Immunogenetics, U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0741-5400 1938-3673 |
DOI: | 10.1189/jlb.3HI0914-453R |