Home LiteratureArticle Details
PMID: 15852007 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105.

Nature immunology ·Vol. 6 ·No. 6 ·2005-06-00 ·Pages 571-8

Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL

Abstract

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.

MeSH Terms
Animals Antigens, CD/chemistry,genetics,metabolism Antigens, Surface/genetics,metabolism Base Sequence Carrier Proteins/genetics,metabolism Cell Line Cytokines/biosynthesis DNA/genetics Dendritic Cells/immunology Gene Expression Humans Immunity, Innate In Vitro Techniques Lymphocyte Antigen 96 Membrane Glycoproteins/genetics,metabolism Mice Mice, Inbred C57BL Mice, Knockout Protein Structure, Tertiary Receptors, Cell Surface/genetics,metabolism Receptors, Immunologic/genetics,metabolism Recombinant Proteins/genetics,metabolism Signal Transduction Toll-Like Receptor 4 Toll-Like Receptors Transfection
Chemicals
Antigens, CD Antigens, Surface CD180 protein, human Carrier Proteins Cytokines LY96 protein, human Ly78 protein, mouse Lymphocyte Antigen 96 Membrane Glycoproteins Receptors, Cell Surface Receptors, Immunologic Recombinant Proteins TLR4 protein, human Tlr4 protein, mouse Toll-Like Receptor 4 Toll-Like Receptors DNA
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Divanovic Senad
Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
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
References (50)
50 references, click to expand
  1. Endotoxin tolerance-current concepts in historical perspective.
    J Endotoxin Res. 2002;8(2):83-98 PMID: 12028748
  2. Of mice and men: species variations of Toll-like receptor expression.
    Trends Immunol. 2002 Aug;23(8):375-8 PMID: 12133792
  3. IRAK-M is a negative regulator of Toll-like receptor signaling.
    Cell. 2002 Jul 26;110(2):191-202 PMID: 12150927
  4. Role of toll-like receptor 2 (TLR2) in neutrophil activation: GM-CSF enhances TLR2 expression and TLR2-mediated interleukin 8 responses in neutrophils.
    Blood. 2002 Sep 1;100(5):1860-8 PMID: 12176910
  5. The pathogenesis of rheumatoid arthritis: pivotal cytokines involved in bone degradation and inflammation.
    J Rheumatol Suppl. 2002 Sep;65:3-9 PMID: 12236620
  6. Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction.
    J Biol Chem. 2002 Dec 6;277(49):47834-43 PMID: 12324469
  7. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.
    Nature. 2002 Dec 5;420(6915):502-7 PMID: 12466842
  8. Inflammatory bowel disease: new insights into pathogenesis and treatment.
    J Intern Med. 2002 Dec;252(6):475-96 PMID: 12472908
  9. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4.
    J Exp Med. 2003 Jan 20;197(2):263-8 PMID: 12538665
  10. Innate immune sensing and its roots: the story of endotoxin.
    Nat Rev Immunol. 2003 Feb;3(2):169-76 PMID: 12563300
  11. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens.
    J Exp Med. 2001 Sep 17;194(6):863-9 PMID: 11561001
  12. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12.
    Eur J Immunol. 2001 Oct;31(10):3026-37 PMID: 11592079
  13. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells.
    Eur J Immunol. 2001 Nov;31(11):3388-93 PMID: 11745357
  14. Natural measles causes prolonged suppression of interleukin-12 production.
    J Infect Dis. 2001 Jul 1;184(1):1-9 PMID: 11398102
  15. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus.
    Nat Immunol. 2000 Nov;1(5):398-401 PMID: 11062499
  16. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2.
    J Immunol. 2000 Jul 15;165(2):618-22 PMID: 10878331
  17. Toll-like receptors.
    Annu Rev Immunol. 2003;21:335-76 PMID: 12524386
  18. Common interaction surfaces of the toll-like receptor 4 cytoplasmic domain stimulate multiple nuclear targets.
    Mol Cell Biol. 2003 Apr;23(7):2543-55 PMID: 12640135
  19. CD19 regulates innate immunity by the toll-like receptor RP105 signaling in B lymphocytes.
    Blood. 2003 Aug 15;102(4):1374-80 PMID: 12714520
  20. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling.
    Nat Immunol. 2003 Sep;4(9):920-7 PMID: 12925853
  21. Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction.
    J Biol Chem. 2003 Nov 28;278(48):48313-20 PMID: 12960171
  22. TLRs: differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression.
    Mol Interv. 2003 Dec;3(8):466-77 PMID: 14993454
  23. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance.
    Nat Immunol. 2004 Apr;5(4):373-9 PMID: 15004556
  24. Negative regulation of toll-like receptor-mediated signaling by Tollip.
    J Biol Chem. 2002 Mar 1;277(9):7059-65 PMID: 11751856
  25. Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide.
    Blood. 2002 Mar 1;99(5):1699-705 PMID: 11861286
  26. Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors.
    Nat Immunol. 2004 May;5(5):495-502 PMID: 15107846
  27. The toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells.
    J Exp Med. 2000 Jul 3;192(1):23-9 PMID: 10880523
  28. Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages.
    J Immunol. 2000 Apr 1;164(7):3471-5 PMID: 10725698
  29. Innate immune recognition: mechanisms and pathways.
    Immunol Rev. 2000 Feb;173:89-97 PMID: 10719670
  30. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.
    Nat Immunol. 2004 Aug;5(8):800-8 PMID: 15220916
  31. Chemical, physical, biological properties of a lipopolysaccharide from Escherichia coli K-235.
    Biochemistry. 1967 Aug;6(8):2363-72 PMID: 4867999
  32. A comprehensive set of sequence analysis programs for the VAX.
    Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387-95 PMID: 6546423
  33. Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal-ventral polarity in the Drosophila embryo.
    Genes Dev. 1991 May;5(5):797-807 PMID: 1827421
  34. Guidelines for the welfare of animals in rodent protection tests. A report from the Rodent Protection Test Working Party.
    Lab Anim. 1994 Jan;28(1):13-8 PMID: 8158963
  35. Murine B cell proliferation and protection from apoptosis with an antibody against a 105-kD molecule: unresponsiveness of X-linked immunodeficient B cells.
    J Exp Med. 1994 Oct 1;180(4):1217-24 PMID: 7523567
  36. RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucine-rich repeat protein family.
    J Immunol. 1995 Apr 1;154(7):3333-40 PMID: 7897216
  37. Ventralization of the Drosophila embryo by deletion of extracellular leucine-rich repeats in the Toll protein.
    Mol Biol Cell. 1995 May;6(5):587-96 PMID: 7663024
  38. Mechanism of suppression of cell-mediated immunity by measles virus.
    Science. 1996 Jul 12;273(5272):228-31 PMID: 8662504
  39. Molecular cloning of a human RP105 homologue and chromosomal localization of the mouse and human RP105 genes (Ly64 and LY64).
    Genomics. 1996 Dec 15;38(3):299-304 PMID: 8975706
  40. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.
    Nature. 1997 Jul 24;388(6640):394-7 PMID: 9237759
  41. Molecular cloning of human RP105.
    Eur J Immunol. 1997 Jul;27(7):1824-7 PMID: 9247598
  42. The molecular mechanism of B cell activation by toll-like receptor protein RP-105.
    J Exp Med. 1998 Jul 6;188(1):93-101 PMID: 9653087
  43. Mouse MD-1, a molecule that is physically associated with RP105 and positively regulates its expression.
    J Immunol. 1998 Aug 1;161(3):1348-53 PMID: 9686597
  44. RP105 is associated with MD-1 and transmits an activation signal in human B cells.
    Blood. 1998 Oct 15;92(8):2815-22 PMID: 9763566
  45. Multiple sequence alignment with Clustal X.
    Trends Biochem Sci. 1998 Oct;23(10):403-5 PMID: 9810230
  46. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
    Science. 1998 Dec 11;282(5396):2085-8 PMID: 9851930
  47. Anti-human RP105 sera induces lymphocyte proliferation.
    J Leukoc Biol. 1999 Jan;65(1):43-9 PMID: 9886245
  48. Cutting edge: functional characterization of the effect of the C3H/HeJ defect in mice that lack an Lpsn gene: in vivo evidence for a dominant negative mutation.
    J Immunol. 1999 May 15;162(10):5666-70 PMID: 10229796
  49. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4.
    J Exp Med. 1999 Jun 7;189(11):1777-82 PMID: 10359581
  50. The functional and structural properties of MD-2 required for lipopolysaccharide binding are absent in MD-1.
    J Immunol. 2005 Jan 1;174(1):340-4 PMID: 15611257
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2908
DOI
10.1038/ni1198
Published
2005-06-00
Epub
2005-00-24
Pages
571-8
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2144914
Subset
IM
Grants
NIAID NIH HHS · R21 AI063183 · United States
NIAID NIH HHS · R21 AI063183-01 · United States
NIAID NIH HHS · T32 AI055406 · United States
NIAID NIH HHS · T32 AI 055406 · United States
External Links
PubMed source DOI: 10.1038/ni1198 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2