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

Abstract

IFN-␤, 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-␤ targeting innate immune response and their effects on dendritic cell (DC)-mediated regulation of T cell differentiation. We found that IFN-␤1a 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-␤1a-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␤1a-induced inhibition of IL-1␤ and IL-23 and the induction of IL-27 secretion by DCs. Supernatant transfer experiments confirmed that IFN-␤1a-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-␤1a that selectively targets the autoimmune response in multiple sclerosis. The Journal of Immunology, 2009, 182: 3928 -3936. M ultiple sclerosis (MS)3 is a chronic inflammatory CNS disease initiated by sensitization of the immune system to CNS myelin Ags (1). IFN-␤1a has been used for many years as a first-line therapy for releasing relapsing (RR) MS. Although its efficacy in suppressing disease activity is well documented in large randomized placebo-controlled clinical trials (2), its in vivo operative mechanisms of action are not completely elucidated. IFN-␤1a's reported mechanisms of action include inhibition of MHC class II expression on monocytes and microglia, suppression of T cell proliferation, regulation of IL-12/IL-10 cytokine transcription, and inhibition of inflammatory cell migration into the CNS via interference with VLA-4-mediated cell adhesion and matrix metalloproteinase 9 activity (3). However, IFN-␤'s effects are complex and cellular responses to IFN-␤ involve Ͼ500 genes (4), suggesting that some of the relevant mechanisms of action may still not be identified. Although IFN-␤ is secreted during the antiviral innate immune response, the physiological role of endogenous type I IFNs in the regulation of the adaptive immune response is poorly understood. We propose that the administration of high-dose recombinant IFN-␤1a, which provides a strong therapeutic effect, may enhance the naturally operative IFN-␤-mediated control of the autoimmune response. We studied the effects of IFN-␤ in the context of recent advances in our understanding of the role of the innate immune response (5) and Th17 cells (6) in the development of the autoimmune response.The discovery of the Th17 cell lineage marked a new era in the studies of the autoimmune res...

B Cells as a Therapeutic Target for IFN-β in Relapsing–Remitting Multiple Sclerosis

“…We demonstrated that IFN-b-1b in vitro treatment inhibit B cells' IL-1b and IL-23 and induces IL-12 and IL-27 secretion, similar to our previous report on the IFN-b-1b modification of cytokine secretion in DCs (8). It has been previously demonstrated by our laboratory and others (8,33) that IFN-b induces SOCS3 expression in DCs, which inhibited IL-1b (34,35) and IL-23 secretion (34,36). In an attempt to elucidate the molecular mechanism of IFN-b-induced cytokine changes in B cells, we demonstrated that IFN-b-1b induces STAT3 phosphorylation, a transcription factor for SOCS3 (37).…”

IFN-β Inhibits Human Th17 Cell Differentiation

“…1A). Recent studies from our laboratory have also detected that IFN-␤-1a inhibits the secretion of IL-1␤ and IL-23 by monocyte-derived DCs from RR MS patients (18). To further characterize the mechanisms involved in the IFN-␤-1a-induced changes in DC cytokine gene expression, we demonstrated that IFN-␤-1a induces STAT1 and STAT3 phosphorylation in DCs derived from MS patients (Fig.…”

Conventional Dendritic Cells Mount a Type I IFN Response againstCandidaspp. Requiring Novel Phagosomal TLR7-Mediated IFN-β Signaling

“…In humans and mice, IFNs-I inhibit DCmediated Th17 cell differentiation (59)(60)(61)(62). Furthermore, by stimulating IL-10 expression and downregulating IL-12 production, IFNs-I appear to modulate Th1/Th2 polarization favoring reduced inflammation and host tissue damage, indicating a protective role (63).…”