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Interferon (IFN) beta ‐1a induces IL‐27 and IL‐12, and down‐regulates IL‐23 and IL‐1beta in dendritic cells (DCs), establishing inhibitory conditions for Th‐17 cell differentiation: Implications for treatment of multiple sclerosis (MS)
Author(s) -
Ramgolam Vinod,
Speer Danielle,
MarkovicPlese Silva
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1074.8
Subject(s) - socs3 , stat1 , cytokine , stat3 , microbiology and biotechnology , stat6 , gene silencing , beta (programming language) , signal transduction , transcription factor , biology , stat4 , chemistry , interleukin 4 , immunology , stat , gene , biochemistry , computer science , programming language
Background: Th‐17 cells have been implicated in the pathogenesis of MS. DC‐derived cytokines IL‐6, IL‐1 beta and IL‐23 promote, whereas IL‐27 and IL‐12 suppress Th‐17 cells differentiation. Objective: To investigate the effect of IFN beta‐1a, a standard therapy for MS, on DC‐derived cytokines and signaling events that regulate Th‐17 cells differentiation. Materials/Method: Monocyte‐derived mature DCs from 13 donors were cultured in the absence or presence of IFN beta‐1a (1000 IU/ml) and analyzed for cytokine gene expression by quantitative RT‐PCR and for signal transduction by Western blots. Results: IFN beta‐1a increased the expression of IL‐27 (191.5‐fold, p=0.002), IL‐12p35 (6.7‐fold, p=0.008) and decreased IL‐23 (−3.7 fold, p=0.002), and IL‐1 beta (−2.7‐fold, p=0.004) in DCs derived from 10 healthy donors. The results were confirmed in 3 MS patients. IFN beta‐1a induced phosphorylation of STAT‐1, a transcription factor for IL‐27. The role of STAT1 as a transcription factor for IL‐27 was confirmed in the experiments where STAT‐1 gene silencing reduced IL‐27 transcription by 30% in IFN beta‐1a‐treated DCs. IFN beta‐1a induced the expression of SOCS3, which may mediate inhibition of IL‐23 and IL‐1b expression. Conclusion: IFN beta‐1 induces IL‐27 expression via STAT‐1 activation and inhibits IL‐23 and IL‐1beta, possibly through the induction of SOCS3, promoting the suppression of Th‐17 cell differentiation in MS. The study was supported by EMD Serono.