Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105.
Activation of Toll-like receptor (TLR) signaling by microbial signatures is critical to the induction of immune responses. Such responses demand tight regulation. RP105 is a TLR homolog thought to be mostly B cell specific, lacking a signaling domain. We report here that RP105 expression was wide, directly mirroring that of TLR4 on antigen-presenting cells. Moreover, RP105 was a specific inhibitor of TLR4 signaling in HEK 293 cells, a function conferred by its extracellular domain. Notably, RP105 and its helper molecule, MD-1, interacted directly with the TLR4 signaling complex, inhibiting its ability to bind microbial ligand. Finally, RP105 regulated TLR4 signaling in dendritic cells as well as endotoxin responses in vivo. Thus, our results identify RP105 as a physiological negative regulator of TLR4 responses.
Divanovic
Senad
S
Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Trompette
Aurelien
A
Atabani
Sowsan F
SF
Madan
Rajat
R
Golenbock
Douglas T
DT
Visintin
Alberto
A
Finberg
Robert W
RW
Tarakhovsky
Alexander
A
Vogel
Stefanie N
SN
Belkaid
Yasmine
Y
Kurt-Jones
Evelyn A
EA
Karp
Christopher L
CL
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D066298:In Vitro Techniques; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
D015703:Antigens, CD; D000954:Antigens, Surface; C092722:CD180 protein, human; D002352:Carrier Proteins; D016207:Cytokines; C495377:LY96 protein, human; C490500:Ly78 protein, mouse; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D004247:DNA