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PMID: 10588727 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 25 ·1999-12-07 ·Pages 14459-63

Underhill DM, Ozinsky A, Smith KD, Aderem A

Abstract

The recognition of mycobacterial cell wall components causes macrophages to secrete tumor necrosis factor alpha (TNF-alpha) and other cytokines that are essential for the development of a protective inflammatory response. We show that toll-like receptors are required for the induction of TNF-alpha in macrophages by Mycobacterium tuberculosis. Expression of a dominant negative form of MyD88 (a signaling component required for toll-like receptor signaling) in a mouse macrophage cell line blocks TNF-alpha production induced by M. tuberculosis. We identify toll-like receptor-2 (TLR2) as the specific toll-like receptor required for this induction by showing that expression of an inhibitory TLR2 (TLR2-P681H) blocks TNF-alpha production induced by whole M. tuberculosis. Further, we show that TLR2-dependent signaling mediates responses to mycobacterial cell wall fractions enriched for lipoarrabinomannan, mycolylarabinogalactan-peptidoglycan complex, or M. tuberculosis total lipids. Thus, although many mycobacterial cell wall fractions are identified to be inflammatory, all require TLR2 for induction of TNF-alpha in macrophages. These data suggest that TLR2 is essential for the induction of a protective immune response to mycobacteria.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Antigens, Differentiation/physiology Cell Line Drosophila Proteins Lipopolysaccharides/metabolism Macrophages/immunology Membrane Glycoproteins/physiology Mice Mycobacterium tuberculosis/immunology Myeloid Differentiation Factor 88 NF-kappa B/metabolism Peptidoglycan/metabolism Receptors, Cell Surface/physiology Receptors, Immunologic Toll-Like Receptor 2 Toll-Like Receptors Tumor Necrosis Factor-alpha/biosynthesis
Chemicals
Adaptor Proteins, Signal Transducing Antigens, Differentiation Drosophila Proteins Lipopolysaccharides Membrane Glycoproteins Myd88 protein, mouse Myeloid Differentiation Factor 88 NF-kappa B Peptidoglycan Receptors, Cell Surface Receptors, Immunologic Toll-Like Receptor 2 Toll-Like Receptors Tumor Necrosis Factor-alpha lipoarabinomannan
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Underhill D M
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Ozinsky A
Smith K D
Aderem A
References (42)
42 references, click to expand
  1. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling.
    Science. 1997 Nov 28;278(5343):1612-5 PMID: 9374458
  2. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4)
    J Exp Med. 1999 Feb 15;189(4):615-25 PMID: 9989976
  3. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex.
    Immunity. 1997 Dec;7(6):837-47 PMID: 9430229
  4. A family of human receptors structurally related to Drosophila Toll.
    Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):588-93 PMID: 9435236
  5. Human CD14 mediates recognition and phagocytosis of apoptotic cells.
    Nature. 1998 Apr 2;392(6675):505-9 PMID: 9548256
  6. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens.
    Nature. 1999 Oct 21;401(6755):811-5 PMID: 10548109
  7. Possible existence of a novel amphipathic immunostimulator in the phenol-water extracts of Mycobacteriaceae.
    Microbiol Immunol. 1987;31(4):289-311 PMID: 2441233
  8. The role of gamma-interferon, vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis.
    Immunology. 1987 Oct;62(2):229-34 PMID: 3119471
  9. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection.
    Cell. 1989 Mar 10;56(5):731-40 PMID: 2647299
  10. Immunologic aspects of mycobacterial infections.
    Rev Infect Dis. 1989 Mar-Apr;11 Suppl 2:S455-9 PMID: 2469122
  11. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
    Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547-51 PMID: 1319065
  12. Mechanisms of stimulation of interleukin-1 beta and tumor necrosis factor-alpha by Mycobacterium tuberculosis components.
    J Clin Invest. 1993 May;91(5):2076-83 PMID: 7683696
  13. Surface expression of human CD14 in Chinese hamster ovary fibroblasts imparts macrophage-like responsiveness to bacterial endotoxin.
    J Biol Chem. 1993 Oct 15;268(29):22055-9 PMID: 7691822
  14. Lipopolysaccharide (LPS) recognition in macrophages. Participation of LPS-binding protein and CD14 in LPS-induced adaptation in rabbit peritoneal exudate macrophages.
    J Clin Invest. 1993 Oct;92(4):2053-9 PMID: 7691891
  15. The spätzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo.
    Cell. 1994 Feb 25;76(4):677-88 PMID: 8124709
  16. CD14 is a pattern recognition receptor.
    Immunity. 1994 Sep;1(6):509-16 PMID: 7534618
  17. Lipoarabinomannans derived from different strains of Mycobacterium tuberculosis differentially stimulate the activation of NF-kappa B and KBF1 in murine macrophages.
    Infect Immun. 1995 May;63(5):1960-8 PMID: 7729908
  18. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.
    Immunity. 1995 Jun;2(6):561-72 PMID: 7540941
  19. The importance of a lipopolysaccharide-initiated, cytokine-mediated host defense mechanism in mice against extraintestinally invasive Escherichia coli.
    J Clin Invest. 1995 Aug;96(2):676-86 PMID: 7635960
  20. Mycobacterial lipoarabinomannan recognition requires a receptor that shares components of the endotoxin signaling system.
    J Immunol. 1996 Sep 15;157(6):2549-54 PMID: 8805656
  21. Lipopolysaccharide binding protein and soluble CD14 catalyze exchange of phospholipids.
    J Clin Invest. 1997 Jan 15;99(2):315-24 PMID: 9006000
  22. Cloning and characterization of two Toll/Interleukin-1 receptor-like genes TIL3 and TIL4: evidence for a multi-gene receptor family in humans.
    Blood. 1998 Jun 1;91(11):4020-7 PMID: 9596645
  23. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.
    Immunity. 1998 Jul;9(1):143-50 PMID: 9697844
  24. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways.
    Mol Cell. 1998 Aug;2(2):253-8 PMID: 9734363
  25. Phosphatidylinositides bind to plasma membrane CD14 and can prevent monocyte activation by bacterial lipopolysaccharide.
    J Biol Chem. 1998 Sep 18;273(38):24309-13 PMID: 9733716
  26. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling.
    Nature. 1998 Sep 17;395(6699):284-8 PMID: 9751057
  27. Soluble CD14(1-152) confers responsiveness to both lipoarabinomannan and lipopolysaccharide in a novel HL-60 cell bioassay.
    J Immunol. 1998 Oct 15;161(8):4244-51 PMID: 9780199
  28. MacMARCKS is not essential for phagocytosis in macrophages.
    J Biol Chem. 1998 Dec 11;273(50):33619-23 PMID: 9837946
  29. Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide.
    J Exp Med. 1998 Dec 7;188(11):2091-7 PMID: 9841923
  30. Recognition of gram-negative bacteria and endotoxin by the innate immune system.
    Curr Opin Immunol. 1999 Feb;11(1):19-22 PMID: 10047547
  31. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction.
    J Biol Chem. 1999 Apr 16;274(16):10689-92 PMID: 10196138
  32. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product.
    J Immunol. 1999 Apr 1;162(7):3749-52 PMID: 10201887
  33. Pulmonary tuberculosis.
    Curr Opin Pulm Med. 1999 May;5(3):143-50 PMID: 10228738
  34. TLR6: A novel member of an expanding toll-like receptor family.
    Gene. 1999 Apr 29;231(1-2):59-65 PMID: 10231569
  35. Cutting edge: cells that carry A null allele for toll-like receptor 2 are capable of responding to endotoxin.
    J Immunol. 1999 Jun 15;162(12):6971-5 PMID: 10358136
  36. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2.
    J Biol Chem. 1999 Jun 18;274(25):17406-9 PMID: 10364168
  37. Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2.
    J Immunol. 1999 Jul 1;163(1):1-5 PMID: 10384090
  38. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors.
    Science. 1999 Jul 30;285(5428):732-6 PMID: 10426995
  39. Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2.
    J Immunol. 1999 Sep 1;163(5):2382-6 PMID: 10452971
  40. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
    Science. 1998 Dec 11;282(5396):2085-8 PMID: 9851930
  41. Preparation of cell-wall fractions from mycobacteria.
    Methods Mol Biol. 1998;101:91-107 PMID: 9921472
  42. Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms.
    Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14614-9 PMID: 9405661
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.25.14459
Published
1999-12-07
Pages
14459-63
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC24458
Subset
IM
Grants
NIAID NIH HHS · R01 AI032972 · United States
NIAID NIH HHS · AI25032 · United States
NIAID NIH HHS · AI32972 · United States
NIAID NIH HHS · R01 AI025032 · United States
NIAID NIH HHS · R37 AI025032 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.25.14459 PMC Full Text View journal details
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