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- Title
Inhibition of TLR-4/MD-2 signaling by RP105/MD-1.
- Authors
Divanovic, Senad; Trompette, Aurelien; Atabani, Sowsan F; Madan, Rajat; Golenbock, Douglas T; Visintin, Alberto; Finberg, Robert W; Tarakhovsky, Alexander; Vogel, Stefanie N; Belkaid, Yasmine; Kurt-Jones, Evelyn A; Karp, Christopher L
- Abstract
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.
- Publication
Journal of endotoxin research, 2005, Vol 11, Issue 6, p363
- ISSN
0968-0519
- Publication type
Journal Article
- DOI
10.1179/096805105X67300