The Journal of Experimental Medicine
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Published online December 1, 2008
doi:10.1084/jem.20080462
The Journal of Experimental Medicine, Vol. 205, No. 13, 2995-3006
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Lee et al.
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ARTICLE

 TLR7-dependent and Fc{gamma}R-independent production of type I interferon in experimental mouse lupus

Pui Y. Lee1, Yutaro Kumagai3, Yi Li1, Osamu Takeuchi3, Hideo Yoshida1,4, Jason Weinstein1, Erinn S. Kellner1, Dina Nacionales1, Tolga Barker1, Kindra Kelly-Scumpia1, Nico van Rooijen5, Himanshu Kumar3, Taro Kawai3, Minoru Satoh1,2, Shizuo Akira3, and Westley H. Reeves1,2

1 Division of Rheumatology and Clinical Immunology and Center for Autoimmune Disease and 2 Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610
3 Laboratory of Host Defense, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
4 Division of Rheumatology and Infectious Diseases, Department of Internal Medicine, Fujita Health University, Toyoake, Aichi-Ken 470-1192, Japan
5 Department of Molecular Cell Biology, Free University Medical Center, 1007MB Amsterdam, Netherlands

CORRESPONDENCE Pui Y. Lee: puilee05{at}ufl.edu

Increased type I interferon (IFN-I) production and IFN-stimulated gene (ISG) expression are linked to the pathogenesis of systemic lupus erythematosus (SLE). Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibody-mediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D.C., K.M. Kelly-Scumpia, P.Y. Lee, J.S. Weinstein, R. Lyons, E. Sobel, M. Satoh, and W.H. Reeves. 2007. Arthritis Rheum. 56:3770–3783). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Toll-like receptor (TLR) 7– and myeloid differentiation factor 88 (MyD88)–dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplified by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fc{gamma} receptors (Fc{gamma}Rs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by Fc{gamma}Rs.

Abbreviations used: ago2, argonaute 2; ANA, antinuclear antibody; clo-lip, clodronate-containing liposomes; ds, double stranded; IC, immune complex; IFN-I, type I IFN; IPS-1, IFN-b promoter stimulator 1; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; MCP, monocyte chemoattractant protein; Mda5, melanoma differentiation-associated gene 5; MFI, mean fluorescence intensity; Mx1, myxoma response protein 1; MyD88, myeloid differentiation factor 88; PDC, plasmacytoid DC; PEC, peritoneal exudate cell; RIG-I, retinoic acid–inducible gene I; RT-PCR, real-time quantitative PCR; SLE, systemic lupus erythematosus; snRNP, small nuclear ribonucleoprotein; ss, single stranded; TBK-1, TANK-binding kinase 1; TLR, Toll-like receptor; TMPD, 2,6,10,14-tetramethylpentadecane; TRIF, Toll/IL-1 receptor domain–containing adaptor inducing IFN-b; Yaa, Y-linked autoimmune accelerating.

© 2008 Lee et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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