Evolution of the TIR, Tolls and TLRs: Functional Inferences from Computational Biology

  • B. Beutler
  • M. Rehli

Abstract

The mammalian toll-like receptors (TLRs) are products of an evolutionary process that began prior to the separation of plants and animals. The most conserved protein motif within the TLRs is the TIR, which denotes Toll, the Interleukin-l receptor, and plant disease Resistance genes. To trace the ancestry of the TLRs, it is desirable to draw upon the sequences of TIR domains from TLRs of diverse vertebrate species, including species with known dates of divergence (i.e., representatives of Mammalia and Aves) in order to establish a relationship between time and genetic divergence. It appears that a gene ancestral to modern TLRs 1 and 6 duplicated approximately 130 million years ago, only shortly before the speciation event that led to humans and mice. Though it is not represented in mice, TLR10 split from the TLR[l/6] precursor about 300 million years ago. The origins of other TLRs are more ancient, dating to the origins of vertebrate life, and some present-day vertebrate species appear to have many more TLRs than others. Moreover, the patterns of TLR expression are quite variable at the level of tissues, even among closely related species. A given TLR in species that are related by descent from a common ancestor may acquire different duties within each descendant line, so that some microbial inducers are avidly recognized in one species but not in others; likewise the intensity and the anatomic location of an innate immune response may vary considerably. In this review, we discuss the computational methods used to analyze divergence of the TIR, and the conclusions that may be safely drawn.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-KB by Toll-like receptor 3. Nature 413: 732 - 738PubMedCrossRefGoogle Scholar
  2. Bazzoni F, Beutler B (1996) The tumor necrosis factor ligand and receptor families. N Engl J Med 334: 1717 - 1725PubMedCrossRefGoogle Scholar
  3. Bowie A, Kiss-Toth E, Symons JA, Smith GL, Dower SK, O’Neill LA (2000) A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll- like receptor signaling. Proc Natl Acad Sci USA 97: 10162 - 10167PubMedCrossRefGoogle Scholar
  4. Chaudhary PM, Ferguson C, Nguyen V, Nguyen O, Massa HF, Eby M, Jasmin A, Trask BJ, Hood L, Nelson PS (1998) Cloning and characterization of two Toll/Interleukin-1 receptor-like genes TIL3 and TIL4: evidence for a multi-gene receptor family in humans. Blood 91: 4020 - 4027PubMedGoogle Scholar
  5. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O’Neill LA (2001) Mai (MyD88- adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413: 78 - 83PubMedCrossRefGoogle Scholar
  6. Fukui A, Inoue N, Matsumoto M, Nomura M, Yamada K, Matsuda Y, Toyoshima K, Seya T (2001) Molecular cloning and functional characterization of chicken toll-like receptors: a single chicken toll covers multiple molecular patterns. J Biol Chem 276: 47143 - 47149PubMedCrossRefGoogle Scholar
  7. Gery I, Gershon RK, Waksman BH (1972) Potentiation of the T-lymphocyte response to mitogens. I. The responding cell. J Exp Med 136: 128 - 142PubMedCrossRefGoogle Scholar
  8. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408: 740 - 745PubMedCrossRefGoogle Scholar
  9. Horng T, Barton GM, Medzhitov R (2001) TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2: 835 - 841PubMedCrossRefGoogle Scholar
  10. Inamori K, Koori K, Mishima C, Muta T, Kawabata S (2000) A horseshoe crab receptor structurally related to Drosophila Toll. J Endotoxin Res 6: 397 - 399PubMedGoogle Scholar
  11. Iwami KI, Matsuguchi T, Masuda A, Kikuchi T, Musikacharoen T, Yoshikai Y (2000) Cutting edge: naturally occurring soluble form of mouse Toll-like receptor 4 inhibits lipopolysaccharide signaling. J Immunol 165: 6682 - 6686PubMedGoogle Scholar
  12. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194: 863 - 869PubMedCrossRefGoogle Scholar
  13. Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R, Giese T, Engelmann H, Endres S, Krieg AM, Hartmann G (2001) 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 31: 3026 - 3037PubMedCrossRefGoogle Scholar
  14. Kumar S, Hedges SB (1998) A molecular timescale for vertebrate evolution. Nature 392: 917 - 920PubMedCrossRefGoogle Scholar
  15. Lachman L, Hacker MP, Handschumacher RE (1977) Partial purification of human lymphocyte activating factor (LAF) by ultrafiltration and electrophoretic techniques. J Immunol 119: 2019 - 2023PubMedGoogle Scholar
  16. Li W-H (1997) Rates and patterns of nucleotide substitution. In: Molecular Evolution. Sunderland, MA,Sinauer Associates, Inc., pp 177 - 214Google Scholar
  17. Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK, Dinarello CA (1986) Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol 124: 179 - 185PubMedGoogle Scholar
  18. Matsuguchi T, Musikacharoen T, Ogawa T, Yoshikai Y (2000) Gene expressions of toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol 165: 5767 - 5772PubMedGoogle Scholar
  19. Matsuguchi T, Takagi K, Musikacharoen T, Yoshikai Y (2000) Gene expressions of lipopolysaccharide receptors, Toll-like receptors 2 and 4, are differently regulated in mouse T lymphocytes. Blood 95: 1378 - 1385PubMedGoogle Scholar
  20. Medzhitov R, Preston-Hurlburt P, Janeway CA, Jr. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity [see comments]. Nature 388: 394 - 397PubMedCrossRefGoogle Scholar
  21. Musikacharoen T, Matsuguchi T, Kikuchi T, Yoshikai Y (2001) NF-K B and STAT5 play important roles in the regulation of mouse Toll-like receptor 2 gene expression. J Immunol 166: 4516 - 4524PubMedGoogle Scholar
  22. Muzio M, Bosisio D, Polentarutti N, D’amico G, Stoppacciaro A, Mancinelli R, van’t Veer C, Penton- Rol G, Ruco LP, Allavena P, Mantovani A (2000) Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 164: 5998 - 6004PubMedGoogle Scholar
  23. Poltorak A, He X, Smirnova I, Liu M-Y, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg MA, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085 - 2088PubMedCrossRefGoogle Scholar
  24. Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, Gros P, Malo D, Lipopolysaccharide, Inflammation, Positional c, Salmonella, Mice (1999) Endotoxin-tolerant mice have mutations in toll¬like receptor 4 (Tlr4). J Exp Med 189: 615 - 625PubMedCrossRefGoogle Scholar
  25. Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, Gros P, Malo D (1999) Endotoxin-tolerant mice have mutations in toll-like receptor 4 (Tlr4). J Exp Med 189: 1519 - 1520CrossRefGoogle Scholar
  26. Rehli M, Poltorak A, Schwarzfischer L, Krause SW, Andreesen R, Beutler B (2000) PU.l and interferon consensus sequence binding protein (ICSBP) regulate the myeloid expression of the human Toll-like receptor 4 gene. J Biol Chem 275: 9773 - 9781PubMedCrossRefGoogle Scholar
  27. Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (1998) A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 95: 588 - 593PubMedCrossRefGoogle Scholar
  28. Visintin A, Mazzoni A, Spitzer JH, Wyllie DH, Dower SK, Segal DM (2001) Regulation of Toll-like Receptors in human monocytes and dendritic cells. J Immunol 166: 249 - 255PubMedGoogle Scholar
  29. Wang T, Lafuse WP, Zwilling BS (2000) Regulation of toll-like receptor 2 expression by macrophages following Mycobacterium avium infection. J Immunol 165: 6308 - 6313PubMedGoogle Scholar
  30. Wang T, Lafuse WP, Zwilling BS (2001) NF-KB and Spl elements are necessary for maximal transcription of Toll-like receptor 2 induced by Mycobacterium avium. J Immunol 167: 6924 - 6932PubMedGoogle Scholar
  31. Yang R-B, Mark MR, Gray A, Huang A, Xie MH, Zhang M, Goddard A, Wood WI, Gurney AL, Godowski PJ (1998) Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Nature 395: 284 – 288PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • B. Beutler
    • 1
  • M. Rehli
    • 2
  1. 1.Department of ImmunologyThe Scripps Research InstituteLa JollaUSA
  2. 2.Abt. für Hämatologie und Internistische OnkologieKlinikum der Universitat RegensburgRegensburgGermany

Personalised recommendations