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Inhibition of TLR-4/MD-2 signaling by RP105/MD-1

Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Aurelien Trompette

Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Sowsan F. Atabani

Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Rajat Madan

Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Douglas T. Golenbock

Division of Infectious Diseases & Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Alberto Visintin

Division of Infectious Diseases & Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Robert W. Finberg

Division of Infectious Diseases & Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Alexander Tarakhovsky

Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, New York, USA

Stefanie N. Vogel

Departments of Microbiology & Immunology and Medicine, University of Maryland-Baltimore, Baltimore, Maryland, USA

Yasmine Belkaid

Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Evelyn A. Kurt-Jones

Division of Infectious Diseases & Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Christopher L. Karp

Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA, chris.karp{at}chmcc.org

Activation of Toll-like receptor (TLR) signaling by microbial and host molecular signatures is critical to the induction of immune responses. Such signaling is, perforce, kept under tight control. We recently discovered a novel endogenous inhibitor of TLR-4 — RP105. Initially identified as a B-cell-specific molecule with a role in B-cell proliferation in response to RP105 mAb and LPS, RP105 is a TLR-4 homologue. Further, like TLR-4 whose surface expression and signaling depends upon co-expression of the secreted protein MD-2, surface expression of RP105 is dependent upon co-expression of the MD2 homologue, MD-1. Unlike the TLRs, however, RP105 lacks a signaling domain, having the apparent structure of a TLR inhibitor. Further, RP105 is not B-cell-specific; its expression directly mirrors that of TLR-4 on dendritic cells and macrophages. These considerations suggested a role for RP105 as a physiological inhibitor of TLR-4 signaling. Indeed, we have recently found that: (i) RP105 is a specific inhibitor of TLR-4 signaling in HEK293 cells; (ii) RP105/MD-1 interacts directly with TLR-4/MD-2, inhibiting the ability of this signaling complex to bind LPS; (iii) RP105 regulates TLR-4 signaling in dendritic cells and macrophages; and (iv) RP105 regulates in vivo responses to LPS.

Key Words: Macrophage • dendritic cells • immune regulation

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