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IFN-β1a Inhibits the Secretion of Th17-Polarizing Cytokines in Human Dendritic Cells via TLR7 Up-Regulation¹

Xin Zhang^*, Jianping Jin, Yunan Tang^*, Danielle Speer^*, Danuta Sujkowska^* and Silva Markovic-Plese^2,*,

^* Department of Neurology, Center for Bioinformatics, and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599

IFN-β, 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-β targeting innate immune response and their effects on dendritic cell (DC)-mediated regulation of T cell differentiation. We found that IFN-β1a 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-β1a-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-β1a-induced inhibition of IL-1β and IL-23 and the induction of IL-27 secretion by DCs. Supernatant transfer experiments confirmed that IFN-β1a-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-β1a that selectively targets the autoimmune response in multiple sclerosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grant K08 NS045871 and an Independent Medical Grant by EMD Serono Inc./Pfizer (to S.M.P.). A National MS Society Center Award (to S.M.P.) provided fellowship support for X.Z.

² Address correspondence and reprint requests to Dr. Silva Markovic-Plese, 6109 Neuroscience Research Building, University of North Carolina at Chapel Hill, 103 Mason Farm Road, Chapel Hill, NC 27599. E-mail address: markovics{at}neurology.unc.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; RR, relapsing remitting; DC, dendritic cell; IRAK4, IL-1R-associated kinase 4; TRAF6, TNFR-associated factor 6; RORC, retinoic acid-related orphan nuclear hormone receptor C; CIS, clinically isolated syndrome suggestive of MS; qRT-PCR, quantitative RT-PCR; IRF, IFN regulatory factor; MRI, magnetic resonance imaging; Pen/Strep, penicillin/streptomycin; siRNA, small interfering RNA.

⁴ The online version of this article contains supplemental material.

This article has been cited by other articles:

				V. S. Ramgolam, Y. Sha, J. Jin, X. Zhang, and S. Markovic-Plese IFN-{beta} Inhibits Human Th17 Cell Differentiation J. Immunol., October 15, 2009; 183(8): 5418 - 5427. [Abstract] [Full Text] [PDF]