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Production by Mouse Conventional Dendritic Cells and Human Monocytes after IFN-β Priming1
* Renal Section and
Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Japan; and
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118
Exacerbation of disease in systemic lupus erythematosus (SLE) is associated with bacterial infection. In conventional dendritic cells (cDCs), the TLR4 ligand bacterial LPS induces IFN-β gene expression but does not induce IFN-
. We hypothesized that when cDCs are primed by cytokines, as may frequently be the case in SLE, LPS would then induce the production of IFN-, a cytokine believed to be important in lupus pathogenesis. In this study we show that mouse cDCs and human monocytes produce abundant IFN- following TLR4 engagement whether the cells have been pretreated either with IFN-β or with a supernatant from DCs activated by RNA-containing immune complexes from lupus patients. This TLR4-induced IFN- induction is mediated by both an initial TRIF-dependent pathway and a subsequent MyD88-dependent pathway, in contrast to TLR3-induced IFN- production, which is entirely TRIF-dependent. There is also a distinct requirement for IFN regulatory factors (IRFs), with LPS-induced IFN- induction being entirely IRF7- and partially IRF5-dependent, in contrast to LPS -induced IFN-β gene induction which is known to be IRF3-dependent but largely IRF7-independent. This data demonstrates a novel pathway for IFN- production by cDCs and provides one possible explanation for how bacterial infection might precipitate disease flares in SLE.
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 work was supported by National Institutes of Health Grant PO1 AR050256 (to I.R.R.). C.R. was supported by grants from Société Française de Rhumatologie, Centre Hospitalier de Bordeaux, and Réseau Rhumatologie.
2 C.R. and K.Y. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ian R. Rifkin, Renal Section, Department of Medicine, Boston University School of Medicine, Evans Biomedical Research Center, Fifth Floor, 650 Albany Street, Boston, MA 02118. E-mail address: irifkin{at}bu.edu
4 Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic cell; cDC, conventional DC; FL, fms-like tyrosine kinase 3 ligand; IRF, interferon regulatory factor; ODN, oligodeoxynucleotide; Pam3Cys, (S)-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys4-OH, 3HCl; pDC, plasmacytoid DC; poly(I:C), polyinosinic:polycytidylic acid; RNP, ribonucleoprotein; TRIF, Toll/IL-1 receptor domain-containing adaptor protein-inducing IFN-β; WT, wild type.
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