Inflammation Research

, Volume 59, Issue 10, pp 791–808 | Cite as

Important aspects of Toll-like receptors, ligands and their signaling pathways

  • Z. L. Chang


Due to the rapid increase of new information on the multiple roles of Toll-like receptors (TLRs), this paper reviews several main properties of TLRs and their ligands and signaling pathways. The investigation of pathogen infections in knockout mice suggests that specific TLRs play a key role in the activation of immune responses. Although the investigation of TLR biology is just beginning, a number of important findings are emerging. This review focuses on the following seven aspects of this emerging field: (a) a history of TLR and ligand studies; (b) the molecular basis of recognition by TLRs: TLR structures, pathogen-associated molecular pattern binding sites, TLR locations and functional responses; (c) cell types in TLR expression; (d) an overview of TLRs and their ligands: expression and ligands of cell-surface TLRs and of intracellular TLRs; (e) TLR-signaling pathways; (f) discussion: TLRs control of innate and adaptive systems; the trafficking of intracellular TLRs to endolysosomes; investigation of TLRs in regulating microRNA; investigation of crystal structure of TLRs with ligand binding; incidence of infectious diseases associated with single nucleotide polymorphisms (SNPs) in TLR genes; risk of cancer related to SNPs in TLR genes; TLR-ligand mediated anti-cancer effects; and TLR-ligand induced chronic inflammation and tumorigenesis; and (g) conclusions.


TLRs Ligands Cell signaling Inflammation 



Author thanks Dr. K. Hayden, Dr. C. Tittiger, Dr. W. Yan and Dr. R. Song (University of Nevada, Reno, NV, USA) for helpful discussion and critical review. I also thank Dr. David Segal (Immune Targeting Section, Experimental Immunology Branch, NCI, NIH, Bethesda, USA), and Dr. Bruce Beutler (Department of Genetics, Professor and Chairman at the Scripps Research Institute, CA, USA) for generously providing Figs. 1 and 2, respectively.


  1. 1.
    Chang ZL. Role of Toll-like receptors in regulatory functions of T and B cells. Chin Sci Bull. 2008;53:1121–7.CrossRefGoogle Scholar
  2. 2.
    Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1–50.PubMedCrossRefGoogle Scholar
  3. 3.
    Yang H, Wei J, Zhang H, Lin L, Zhang W, He S. Upregulation of Toll-like receptor (TLR) expression and release of cytokines from P815 mast cells by GM-CSF. BMC Cell Biol. 2009;10:37.PubMedCrossRefGoogle Scholar
  4. 4.
    Liu G, Zhang L, Zhao Y. Modulation of immune responses through direct activation of Toll-like receptors to T cells. Clin Exp Immunol. 2010 [Epub ahead of print].Google Scholar
  5. 5.
    Gururajan M, Jacob J, Pulendran B. Toll-like receptor expression and responsiveness of distinct murine splenic and mucosal B-cell subsets. PLoS One. 2007;2:e863.PubMedCrossRefGoogle Scholar
  6. 6.
    McGettrick AF, O’Neill LA. Toll-like receptors: key activators of leucocytes and regulator of haematopoiesis. Br J Haematol. 2007;139:185–93.PubMedCrossRefGoogle Scholar
  7. 7.
    Pegu A, Qin S, Fallert Junecko BA, Nisato RE, Pepper MS, Reinhart TA. Human lymphatic endothelial cells express multiple functional TLRs. J Immunol. 2008;180:3399–405.PubMedGoogle Scholar
  8. 8.
    Fitzner N, Clauberg S, Essmann F, Liebmann J, Kolb-Bachofen V. Human skin endothelial cells can express all 10 TLR genes and respond to respective ligands. Clin Vaccine Immunol. 2008;15:138–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Palladino MA, Savarese MA, Chapman JL, Dughi MK, Plaska D. Localization of Toll-like receptors on epididymal epithelial cells and spermatozoa. Am J Reprod Immunol. 2008;60:541–55.PubMedCrossRefGoogle Scholar
  10. 10.
    Miller LS, Modlin RL. Human keratinocyte Toll-like receptors promote distinct immune responses. J Invest Dermatol. 2007;127:262–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Miller LS. Toll-like receptors in skin. Adv Dermatol. 2008;24:71–87.PubMedCrossRefGoogle Scholar
  12. 12.
    Kurokawa I, Danby FW, Ju Q, Wang X, Xiang LF, Xia L, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol. 2009;18:821–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Ospelt C, Gay S. TLRs and chronic inflammation. Int J Biochem Cell Biol. 2010;42:495–505.PubMedCrossRefGoogle Scholar
  14. 14.
    Szajnik M, Szczepanski MJ, Czystowska M, Elishaev E, Mandapathil M, Nowak-Markwitz E, et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene. 2009;28:4353–63.PubMedCrossRefGoogle Scholar
  15. 15.
    Szczepanski MJ, Czystowska M, Szajnik M, Harasymczuk M, Boyiadzis M, Kruk-Zagajewska A, et al. Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res. 2009;69:3105–13.PubMedCrossRefGoogle Scholar
  16. 16.
    Pasare C, Medzhitov R. Toll-like receptors and acquired immunity. Semin Immunol. 2004;16:23–6.PubMedCrossRefGoogle Scholar
  17. 17.
    O’Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev. 2009;61:177–97.PubMedCrossRefGoogle Scholar
  18. 18.
    Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer. 2009;9:57–63.PubMedCrossRefGoogle Scholar
  19. 19.
    Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol. 2009;21:317–37.PubMedCrossRefGoogle Scholar
  20. 20.
    Ishii KJ, Koyama S, Nakagawa A, Coban C, Akira S. Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe. 2008;3:352–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Cristofaro P, Opal SM. Role of Toll-like receptors in infection and immunity: clinical implications. Drugs. 2006;66:15–29.PubMedCrossRefGoogle Scholar
  22. 22.
    Hoebe K, Beutler B. TLRs as bacterial sensors. In: O’Neil L, Brint E, editors. Toll-like receptors inflammation. Berlin: Birkauser Verlag; 2005. p. 1–17.Google Scholar
  23. 23.
    Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 2004;430:257–63.PubMedCrossRefGoogle Scholar
  24. 24.
    Belvin MP, Anderson KV. A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol. 1996;12:393–416.PubMedCrossRefGoogle Scholar
  25. 25.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Bassett EH, Rich T. Toll receptors and the renaissance of innate immunity. New York: Kluwer Academic/Plenum Publisher; 2005. p. 1–17.Google Scholar
  28. 28.
    Ligoxygakis P, Bulet P, Reichhart JM. Critical evaluation of the role of the Toll-like receptor 18-Wheeler in the host defense of Drosophila. EMBO Rep. 2002;3:666–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Murphy K, Travers P, Walport M. Janeway’s immuno biology. New York: Garland Science; 2008. p. 39–108.Google Scholar
  30. 30.
    Murphy K, Travers P, Walport M. Janeway’s immuno biology. New York: Garland Science; 2008. p. 143–79.Google Scholar
  31. 31.
    Fluhr R, Kaplan-Levy RN. Plant disease resistance: commonality and novelty in multicellular innate immunity. Curr Top Microbiol Immunol. 2002;270:23–46.PubMedGoogle Scholar
  32. 32.
    Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol. 2003;24:528–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, et al. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science. 2002;298:1025–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Hold GL, El-Omar EM. Genetic aspects of inflammation and cancer. Biochem J. 2008;410:225–35.PubMedCrossRefGoogle Scholar
  36. 36.
    Roelofs MF, Boelens WC, Joosten LA, Abdollahi-Roodsaz S, Geurts J, Wunderink LU, et al. Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J Immunol. 2006;176:7021–7.PubMedGoogle Scholar
  37. 37.
    Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004;4:469–78.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, et al. Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science. 2008;320:379–81.PubMedCrossRefGoogle Scholar
  39. 39.
    Matsushima N, Tanaka T, Enkhbayar P, Mikami T, Taga M, Yamada K, et al. Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors. BMC Genomics. 2007;8:124.PubMedCrossRefGoogle Scholar
  40. 40.
    Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, et al. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu Rev Immunol. 2006;24:353–89.PubMedCrossRefGoogle Scholar
  41. 41.
    Chaturvedi A, Pierce SK. How location governs Toll-like receptor signaling. Traffic. 2009;10:621–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Ishii KJ, Uematsu S, Akira S. ‘Toll’ gates for future immunotherapy. Curr Pharm Des. 2006;12:4135–42.PubMedCrossRefGoogle Scholar
  43. 43.
    O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64.PubMedCrossRefGoogle Scholar
  44. 44.
    Dellacasagrande J. Ligands, cell-based models, and readouts required for toll-like receptor action. Methods Mol Biol. 2009;517:15–32.PubMedGoogle Scholar
  45. 45.
    Peter ME, Kubarenko AV, Weber AN, Dalpke AH. Identification of an N-terminal recognition site in TLR9 that contributes to CpG-DNA-mediated receptor activation. J Immunol. 2009;182:7690–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Uematsu S, Akira S. Toll-like receptors and Type I interferons. J Biol Chem. 2007;282:15319–23.PubMedCrossRefGoogle Scholar
  47. 47.
    Kumar H, Kawai T, Akira S. Toll-like receptors and innate immunity. Biochem Biophys Res Commun. 2009;388:621–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, et al. The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci USA. 2005;102:9577–82.PubMedCrossRefGoogle Scholar
  49. 49.
    Henderson B, Poole S, Wilson M. Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis. Microbiol Rev. 1996;60:316–41.PubMedGoogle Scholar
  50. 50.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.PubMedCrossRefGoogle Scholar
  51. 51.
    Fukata M, Chen AL, Klepper A, Krishnareddy S, Vamadevan AS, Thomas LS, et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine. Gastroenterology. 2006;131:862–77.PubMedCrossRefGoogle Scholar
  52. 52.
    Brown SL, Riehl TE, Walker MR, Geske MJ, Doherty JM, Stenson WF, et al. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J Clin Invest. 2007;117:258–69.PubMedCrossRefGoogle Scholar
  53. 53.
    Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, et al. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem. 2007;282:14975–83.PubMedCrossRefGoogle Scholar
  54. 54.
    Rakoff-Nahoum S, Medzhitov R. Role of toll-like receptors in tissue repair and tumorigenesis. Biochemistry (Mosc). 2008;73:555–61.CrossRefGoogle Scholar
  55. 55.
    Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, et al. Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002;168:4531–7.PubMedGoogle Scholar
  56. 56.
    Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001;194:863–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol. 2002;168:554–61.PubMedGoogle Scholar
  58. 58.
    Babu S, Blauvelt CP, Kumaraswami V, Nutman TB. Cutting edge: diminished T cell TLR expression and function modulates the immune response in human filarial infection. J Immunol. 2006;176:3885–9.PubMedGoogle Scholar
  59. 59.
    Danese S. Nonimmune cells in inflammatory bowel disease: from victim to villain. Trends Immunol. 2008;29:555–64.PubMedCrossRefGoogle Scholar
  60. 60.
    Parker LC, Prince LR, Sabroe I. Translational mini-review series on Toll-like receptors: networks regulated by Toll-like receptors mediate innate and adaptive immunity. Clin Exp Immunol. 2007;147:199–207.PubMedCrossRefGoogle Scholar
  61. 61.
    Carpenter S, O’Neill LA. How important are Toll-like receptors for antimicrobial responses? Cell Microbiol. 2007;9:1891–901.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Cameron JS, Alexopoulou L, Sloane JA, DiBernardo AB, Ma Y, Kosaras B, et al. Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci. 2007;27:13033–41.PubMedCrossRefGoogle Scholar
  64. 64.
    Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3 can directly trigger apoptosis in human cancer cells. J Immunol. 2006;176:4894–901.PubMedGoogle Scholar
  65. 65.
    Salaun B, Lebecque S, Matikainen S, Rimoldi D, Romero P. Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res. 2007;13:4565–74.PubMedCrossRefGoogle Scholar
  66. 66.
    van den Berk LC, Jansen BJ, Siebers-Vermeulen KG, Netea MG, Latuhihin T, Bergevoet S, et al. Toll-like receptor triggering in cord blood mesenchymal stem cells. J Cell Mol Med. 2009;13:3415–26.PubMedCrossRefGoogle Scholar
  67. 67.
    Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol. 2001;167:1882–5.PubMedGoogle Scholar
  68. 68.
    Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410:1099–103.PubMedCrossRefGoogle Scholar
  69. 69.
    Feuillet V, Medjane S, Mondor I, Demaria O, Pagni PP, Galan JE, et al. Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria. Proc Natl Acad Sci USA. 2006;103:12487–92.PubMedCrossRefGoogle Scholar
  70. 70.
    Andersen-Nissen E, Hawn TR, Smith KD, Nachman A, Lampano AE, Uematsu S, et al. Cutting edge: Tlr5−/− mice are more susceptible to Escherichia coli urinary tract infection. J Immunol. 2007;178:4717–20.PubMedGoogle Scholar
  71. 71.
    Nakao Y, Funami K, Kikkawa S, Taniguchi M, Nishiguchi M, Fukumori Y, et al. Surface-expressed TLR6 participates in the recognition of diacylated lipopeptide and peptidoglycan in human cells. J Immunol. 2005;174:1566–73.PubMedGoogle Scholar
  72. 72.
    Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E, Tancredi S, et al. Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol. 2005;174:2942–50.PubMedGoogle Scholar
  73. 73.
    Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science. 2004;303:1522–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science. 2005;308:1626–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Lauw FN, Caffrey DR, Golenbock DT. Of mice and man: TLR11 (finally) finds profilin. Trends Immunol. 2005;26:509–11.PubMedCrossRefGoogle Scholar
  76. 76.
    Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol. 2004;5:190–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Nishiya T, Kajita E, Miwa S, Defranco AL. TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. J Biol Chem. 2005;280:37107–17.PubMedCrossRefGoogle Scholar
  78. 78.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413:732–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med. 2004;10:1366–73.PubMedCrossRefGoogle Scholar
  80. 80.
    Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA. 2004;101:3516–21.PubMedCrossRefGoogle Scholar
  81. 81.
    Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008;452:591–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Beutler BA. TLRs and innate immunity. Blood. 2009;113:1399–407.PubMedCrossRefGoogle Scholar
  83. 83.
    Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol. 2002;3:499.PubMedCrossRefGoogle Scholar
  85. 85.
    Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Krug A, Luker GD, Barchet W, Leib DA, Akira S, Colonna M. Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood. 2004;103:1433–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Prakken AB, van Hoeij MJ, Kuis W, Kavelaars A, Heynen CJ, Scholtens E, et al. T-cell reactivity to human HSP60 in oligo-articular juvenile chronic arthritis is associated with a favorable prognosis and the generation of regulatory cytokines in the inflamed joint. Immunol Lett. 1997;57:139–42.PubMedCrossRefGoogle Scholar
  88. 88.
    Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem. 2002;277:15028–34.PubMedCrossRefGoogle Scholar
  89. 89.
    Huang QQ, Sobkoviak R, Jockheck-Clark AR, Shi B, Mandelin AM 2nd, Tak PP, et al. Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling. J Immunol. 2009;182:4965–73.PubMedCrossRefGoogle Scholar
  90. 90.
    Holm CK, Petersen CC, Hvid M, Petersen L, Paludan SR, Deleuran B, et al. TLR3 ligand polyinosinic:polycytidylic acid induces IL-17A and IL-21 synthesis in human Th cells. J Immunol. 2009;183:4422–31.PubMedCrossRefGoogle Scholar
  91. 91.
    Girart MV, Fuertes MB, Domaica CI, Rossi LE, Zwirner NW. Engagement of TLR3, TLR7, and NKG2D regulate IFN-gamma secretion but not NKG2D-mediated cytotoxicity by human NK cells stimulated with suboptimal doses of IL-12. J Immunol. 2007;179:3472–9.PubMedGoogle Scholar
  92. 92.
    MacRedmond R, Greene C, Taggart CC, McElvaney N, O’Neill S. Respiratory epithelial cells require Toll-like receptor 4 for induction of human beta-defensin 2 by lipopolysaccharide. Respir Res. 2005;6:116.PubMedCrossRefGoogle Scholar
  93. 93.
    Hart OM, Athie-Morales V, O’Connor GM, Gardiner CM. TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol. 2005;175:1636–42.PubMedGoogle Scholar
  94. 94.
    Sato Y, Goto Y, Narita N, Hoon DS. Cancer cells expressing toll-like receptors and the tumor microenvironment. Cancer Microenviron. 2009;2(Suppl 1):205–14.PubMedCrossRefGoogle Scholar
  95. 95.
    Szczepanski M, Stelmachowska M, Stryczynski L, Golusinski W, Samara H, Mozer-Lisewska I, et al. Assessment of expression of toll-like receptors 2, 3 and 4 in laryngeal carcinoma. Eur Arch Otorhinolaryngol. 2007;264:525–30.PubMedCrossRefGoogle Scholar
  96. 96.
    He W, Liu Q, Wang L, Chen W, Li N, Cao X. TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol. 2007;44:2850–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66:3859–68.PubMedCrossRefGoogle Scholar
  98. 98.
    Schmausser B, Andrulis M, Endrich S, Muller-Hermelink HK, Eck M. Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori. Int J Med Microbiol. 2005;295:179–85.PubMedCrossRefGoogle Scholar
  99. 99.
    Wang EL, Qian ZR, Nakasono M, Tanahashi T, Yoshimoto K, Bando Y, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer. 2010;102:908–15.PubMedCrossRefGoogle Scholar
  100. 100.
    Molteni M, Marabella D, Orlandi C, Rossetti C. Melanoma cell lines are responsive in vitro to lipopolysaccharide and express TLR-4. Cancer Lett. 2006;235:75–83.PubMedCrossRefGoogle Scholar
  101. 101.
    Kundu SD, Lee C, Billips BK, Habermacher GM, Zhang Q, Liu V, et al. The toll-like receptor pathway: a novel mechanism of infection-induced carcinogenesis of prostate epithelial cells. Prostate. 2008;68:223–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Rhee SH, Im E, Pothoulakis C. Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology. 2008;135:518–28.PubMedCrossRefGoogle Scholar
  103. 103.
    Chang S, Kodys K, Szabo G. Impaired expression and function of toll-like receptor 7 in hepatitis C virus infection in human hepatoma cells. Hepatology. 2010;51:35–42.PubMedGoogle Scholar
  104. 104.
    Spaner DE, Masellis A. Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia. Leukemia. 2007;21:53–60.PubMedCrossRefGoogle Scholar
  105. 105.
    Smits EL, Ponsaerts P, Berneman ZN, Van Tendeloo VF. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist. 2008;13:859–75.PubMedCrossRefGoogle Scholar
  106. 106.
    Schon M, Bong AB, Drewniok C, Herz J, Geilen CC, Reifenberger J, et al. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst. 2003;95:1138–49.PubMedCrossRefGoogle Scholar
  107. 107.
    Lee JW, Choi JJ, Seo ES, Kim MJ, Kim WY, Choi CH, et al. Increased toll-like receptor 9 expression in cervical neoplasia. Mol Carcinog. 2007;46:941–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Ilvesaro JM, Merrell MA, Swain TM, Davidson J, Zayzafoon M, Harris KW, et al. Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. Prostate. 2007;67:774–81.PubMedCrossRefGoogle Scholar
  109. 109.
    Droemann D, Albrecht D, Gerdes J, Ulmer AJ, Branscheid D, Vollmer E, et al. Human lung cancer cells express functionally active Toll-like receptor 9. Respir Res. 2005;6:1.PubMedCrossRefGoogle Scholar
  110. 110.
    Zhang ZL, Song QB, Lin MQ, Ding YM, Kang XW, Yao Z. Immunomodulated signaling in macrophages: studies on activation of Raf-1, MAPK, cPLA(2) and secretion of IL-12. Sci China Ser C Life Sci. 1997;40:583–92.CrossRefGoogle Scholar
  111. 111.
    Gay NJ, Kubota K. The signal transduction pathway leading from the toll receptor to nuclear localization of dorsal transcription factor. Biochem Soc Trans. 1996;24:35–8.PubMedGoogle Scholar
  112. 112.
    Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7.PubMedCrossRefGoogle Scholar
  113. 113.
    Miyake K, Ogata H, Nagai Y, Akashi S, Kimoto M. Innate recognition of lipopolysaccharide by Toll-like receptor 4/MD-2 and RP105/MD-1. J Endotoxin Res. 2000;6:389–91.PubMedGoogle Scholar
  114. 114.
    Tanimura N, Saitoh S, Matsumoto F, Akashi-Takamura S, Miyake K. Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun. 2008;368:94–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–80.PubMedCrossRefGoogle Scholar
  116. 116.
    Jiang Z, Georgel P, Li C, Choe J, Crozat K, Rutschmann S, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc Natl Acad Sci USA. 2006;103:10961–6.PubMedCrossRefGoogle Scholar
  117. 117.
    Zhang JS, Feng WG, Li CL, Wang XY, Chang ZL. NF-kappa B regulates the LPS-induced expression of interleukin 12 p40 in murine peritoneal macrophages: roles of PKC, PKA, ERK, p38 MAPK, and proteasome. Cell Immunol. 2000;204:38–45.PubMedCrossRefGoogle Scholar
  118. 118.
    Kobayashi K, Hernandez LD, Galan JE, Janeway CA Jr, Medzhitov R, Flavell RA. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell. 2002;110:191–202.PubMedCrossRefGoogle Scholar
  119. 119.
    Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S, Zacharioudaki V, et al. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity. 2009;31:220–31.PubMedCrossRefGoogle Scholar
  120. 120.
    Hamilton T. Molecular basis of macrophage activation: from gene expression to phenotype diversity. In: Lewis BBCE, editor. The macrophage. Oxford: Oxford University Press; 2002. p. 73–102.Google Scholar
  121. 121.
    Murphy K, Travers P, Walport M. Janeway’s immuno biology. New York: Garland Science; 2008. p. 111–42.Google Scholar
  122. 122.
    Murphy K, Travers P, Walport M. Janeway’s immuno biology. New York: Garland Science; 2008. p. 1–38.Google Scholar
  123. 123.
    O’Brien AD, Rosenstreich DL, Scher I, Campbell GH, MacDermott RP, Formal SB. Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene. J Immunol. 1980;124:20–4.PubMedGoogle Scholar
  124. 124.
    Hagberg L, Hull R, Hull S, McGhee JR, Michalek SM, Svanborg Eden C. Difference in susceptibility to gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice. Infect Immun. 1984;46:839–44.PubMedGoogle Scholar
  125. 125.
    Takeuchi O, Hoshino K, Akira S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol. 2000;165:5392–6.PubMedGoogle Scholar
  126. 126.
    Conley ME. Immunodeficiency: UNC-93B gets a toll call. Trends Immunol. 2007;28:99–101.PubMedCrossRefGoogle Scholar
  127. 127.
    Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA, et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature. 2008;456:658–62.PubMedCrossRefGoogle Scholar
  128. 128.
    Brinkmann MM, Spooner E, Hoebe K, Beutler B, Ploegh HL, Kim YM. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol. 2007;177:265–75.PubMedCrossRefGoogle Scholar
  129. 129.
    Akashi-Takamura S, Miyake K. TLR accessory molecules. Curr Opin Immunol. 2008;20:420–5.PubMedCrossRefGoogle Scholar
  130. 130.
    Tam W, Ben-Yehuda D, Hayward WS. bic, a novel gene activated by proviral insertions in avian leukosis virus-induced lymphomas, is likely to function through its noncoding RNA. Mol Cell Biol. 1997;17:1490–502.PubMedGoogle Scholar
  131. 131.
    Tam W. Identification and characterization of human BIC, a gene on chromosome 21 that encodes a noncoding RNA. Gene. 2001;274:157–67.PubMedCrossRefGoogle Scholar
  132. 132.
    Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA. 2005;102:3627–32.PubMedCrossRefGoogle Scholar
  133. 133.
    Tam W, Dahlberg JE. miR-155/BIC as an oncogenic microRNA. Genes Chromosom Cancer. 2006;45:211–2.PubMedCrossRefGoogle Scholar
  134. 134.
    Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316:608–11.PubMedCrossRefGoogle Scholar
  135. 135.
    O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA. 2007;104:1604–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.PubMedCrossRefGoogle Scholar
  137. 137.
    Faller M, Guo F. MicroRNA biogenesis: there’s more than one way to skin a cat. Biochim Biophys Acta. 2008;1779:663–7.PubMedGoogle Scholar
  138. 138.
    Alexiou P, Vergoulis T, Gleditzsch M, Prekas G, Dalamagas T, Megraw M, et al. miRGen 2.0: a database of microRNA genomic information and regulation. Nucleic Acids Res. 2009;38D:137–41.Google Scholar
  139. 139.
    Sonkoly E, Pivarcsi A. Advances in microRNAs: implications for immunity and inflammatory diseases. J Cell Mol Med. 2009;13:24–38.PubMedCrossRefGoogle Scholar
  140. 140.
    Sewer A, Paul N, Landgraf P, Aravin A, Pfeffer S, Brownstein MJ, et al. Identification of clustered microRNAs using an ab initio prediction method. BMC Bioinform. 2005;6:267.CrossRefGoogle Scholar
  141. 141.
    Ro S, Song R, Park C, Zheng H, Sanders KM, Yan W. Cloning and expression profiling of small RNAs expressed in the mouse ovary. RNA. 2007;13:2366–80.PubMedCrossRefGoogle Scholar
  142. 142.
    Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36:D154–8.PubMedCrossRefGoogle Scholar
  143. 143.
    Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931–4.PubMedCrossRefGoogle Scholar
  144. 144.
    Lu LF, Liston A. MicroRNA in the immune system, microRNA as an immune system. Immunology. 2009;127:291–8.PubMedCrossRefGoogle Scholar
  145. 145.
    Taganov KD, Boldin MP, Baltimore D. MicroRNAs and immunity: tiny players in a big field. Immunity. 2007;26:133–7.PubMedCrossRefGoogle Scholar
  146. 146.
    Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD. MicroRNAs: new regulators of immune cell development and function. Nat Immunol. 2008;9:839–45.PubMedCrossRefGoogle Scholar
  147. 147.
    Bazzoni F, Rossato M, Fabbri M, Gaudiosi D, Mirolo M, Mori L, et al. Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc Natl Acad Sci USA. 2009;106:5282–7.PubMedCrossRefGoogle Scholar
  148. 148.
    Sheedy FJ, O’Neill LA. Adding fuel to fire: microRNAs as a new class of mediators of inflammation. Ann Rheum Dis. 2008;67(Suppl 3):iii50–5.PubMedCrossRefGoogle Scholar
  149. 149.
    Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, et al. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity. 2009;30:80–91.PubMedCrossRefGoogle Scholar
  150. 150.
    Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell. 2007;130:1071–82.PubMedCrossRefGoogle Scholar
  151. 151.
    Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell. 2007;130:906–17.PubMedCrossRefGoogle Scholar
  152. 152.
    Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature. 2009;458:1191–5.PubMedCrossRefGoogle Scholar
  153. 153.
    Vasl J, Prohinar P, Gioannini TL, Weiss JP, Jerala R. Functional activity of MD-2 polymorphic variant is significantly different in soluble and TLR4-bound forms: decreased endotoxin binding by G56R MD-2 and its rescue by TLR4 ectodomain. J Immunol. 2008;180:6107–15.PubMedGoogle Scholar
  154. 154.
    Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25:187–91.PubMedCrossRefGoogle Scholar
  155. 155.
    Turvey SE, Hawn TR. Towards subtlety: understanding the role of Toll-like receptor signaling in susceptibility to human infections. Clin Immunol. 2006;120:1–9.PubMedCrossRefGoogle Scholar
  156. 156.
    Awomoyi AA, Rallabhandi P, Pollin TI, Lorenz E, Sztein MB, Boukhvalova MS, et al. Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J Immunol. 2007;179:3171–7.PubMedGoogle Scholar
  157. 157.
    Gu W, Shan YA, Zhou J, Jiang DP, Zhang L, Du DY, et al. Functional significance of gene polymorphisms in the promoter of myeloid differentiation-2. Ann Surg. 2007;246:151–8.PubMedCrossRefGoogle Scholar
  158. 158.
    Hawn TR, Dunstan SJ, Thwaites GE, Simmons CP, Thuong NT, Lan NT, et al. A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. J Infect Dis. 2006;194:1127–34.PubMedCrossRefGoogle Scholar
  159. 159.
    Carvalho A, Cunha C, Carotti A, Aloisi T, Guarrera O, Di Ianni M, et al. Polymorphisms in Toll-like receptor genes and susceptibility to infections in allogeneic stem cell transplantation. Exp Hematol. 2009;37:1022–9.PubMedCrossRefGoogle Scholar
  160. 160.
    Higgins SC, Lavelle EC, McCann C, Keogh B, McNeela E, Byrne P, et al. Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology. J Immunol. 2003;171:3119–27.PubMedGoogle Scholar
  161. 161.
    El-Omar EM, Ng MT, Hold GL. Polymorphisms in Toll-like receptor genes and risk of cancer. Oncogene. 2008;27:244–52.PubMedCrossRefGoogle Scholar
  162. 162.
    Zheng SL, Augustsson-Balter K, Chang B, Hedelin M, Li L, Adami HO, et al. Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res. 2004;64:2918–22.PubMedCrossRefGoogle Scholar
  163. 163.
    Sun J, Wiklund F, Zheng SL, Chang B, Balter K, Li L, et al. Sequence variants in Toll-like receptor gene cluster (TLR6–TLR1–TLR10) and prostate cancer risk. J Natl Cancer Inst. 2005;97:525–32.PubMedCrossRefGoogle Scholar
  164. 164.
    Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991;262:3–11.PubMedGoogle Scholar
  165. 165.
    Okamoto M, Oshikawa T, Tano T, Ahmed SU, Kan S, Sasai A, et al. Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis and Toll-like receptor 4 signaling. J Immunother. 2006;29:78–86.PubMedCrossRefGoogle Scholar
  166. 166.
    Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene. 2008;27:218–24.PubMedCrossRefGoogle Scholar
  167. 167.
    Shi Y, White D, He L, Miller RL, Spaner DE. Toll-like receptor-7 tolerizes malignant B cells and enhances killing by cytotoxic agents. Cancer Res. 2007;67:1823–31.PubMedCrossRefGoogle Scholar
  168. 168.
    Spaner DE, Shi Y, White D, Shaha S, He L, Masellis A, et al. A phase I/II trial of TLR-7 agonist immunotherapy in chronic lymphocytic leukemia. Leukemia. 2010;24:222–6.Google Scholar
  169. 169.
    Leonard JP, Link BK, Emmanouilides C, Gregory SA, Weisdorf D, Andrey J, et al. Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non Hodgkin’s lymphoma. Clin Cancer Res. 2007;13:6168–74.PubMedCrossRefGoogle Scholar
  170. 170.
    Wysocka M, Benoit BM, Newton S, Azzoni L, Montaner LJ, Rook AH. Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15. Blood. 2004;104:4142–9.PubMedCrossRefGoogle Scholar
  171. 171.
    Murad YM, Clay TM. CpG oligodeoxynucleotides as TLR9 agonists: therapeutic applications in cancer. BioDrugs. 2009;23:361–75.PubMedCrossRefGoogle Scholar
  172. 172.
    Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050–9.PubMedCrossRefGoogle Scholar
  173. 173.
    Krishnamachari Y, Salem AK. Innovative strategies for co-delivering antigens and CpG oligonucleotides. Adv Drug Deliv Rev. 2009;61:205–17.PubMedCrossRefGoogle Scholar
  174. 174.
    Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 2009;6:e10.PubMedCrossRefGoogle Scholar
  175. 175.
    Hagemann T, Balkwill F, Lawrence T. Inflammation and cancer: a double-edged sword. Cancer Cell. 2007;12:300–1.PubMedCrossRefGoogle Scholar
  176. 176.
    Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27:5904–12.PubMedCrossRefGoogle Scholar
  177. 177.
    Hallam S, Escorcio-Correia M, Soper R, Schultheiss A, Hagemann T. Activated macrophages in the tumour microenvironment-dancing to the tune of TLR and NF-kappaB. J Pathol. 2009;219:143–52.PubMedCrossRefGoogle Scholar
  178. 178.
    Chen R, Alvero AB, Silasi DA, Steffensen KD, Mor G. Cancers take their Toll—the function and regulation of Toll-like receptors in cancer cells. Oncogene. 2008;27:225–33.PubMedCrossRefGoogle Scholar
  179. 179.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.PubMedCrossRefGoogle Scholar
  180. 180.
    Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH, et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 2005;65:5009–14.PubMedCrossRefGoogle Scholar
  181. 181.
    Balkwill F, Coussens LM. Cancer: an inflammatory link. Nature. 2004;431:405–6.PubMedCrossRefGoogle Scholar
  182. 182.
    Chen R, Alvero AB, Silasi DA, Mor G. Inflammation, cancer and chemoresistance: taking advantage of the toll-like receptor signaling pathway. Am J Reprod Immunol. 2007;57:93–107.PubMedCrossRefGoogle Scholar
  183. 183.
    Wang EL, Qian ZR, Nakasono M, Tanahashi T, Yoshimoto K, Bando Y, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer. 2010;102:908–15.Google Scholar
  184. 184.
    Balkwill F, Mantovani A. Cancer and inflammation: implications for pharmacology and therapeutics. Clin Pharmacol Ther. 2010;87:401–6.PubMedCrossRefGoogle Scholar
  185. 185.
    Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, et al. “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med. 2008;205:1261–8.PubMedCrossRefGoogle Scholar
  186. 186.
    Hagemann T, Biswas SK, Lawrence T, Sica A, Lewis CE. Regulation of macrophage function in tumors: the multifaceted role of NF-kappaB. Blood. 2009;113:3139–46.PubMedCrossRefGoogle Scholar
  187. 187.
    Jagetia GC, Aggarwal BB. “Spicing up” of the immune system by curcumin. J Clin Immunol. 2007;27:19–35.PubMedCrossRefGoogle Scholar
  188. 188.
    Kamat AM, Tharakan ST, Sung B, Aggarwal BB. Curcumin potentiates the antitumor effects of Bacillus Calmette-Guerin against bladder cancer through the downregulation of NF-{kappa}B and upregulation of TRAIL receptors. Cancer Res. 2009;69:8958–66.PubMedCrossRefGoogle Scholar
  189. 189.
    Herberman RB, Whiteside TL. Summary of the international cancer microenvironment from meeting in Pittsburgh, Pennsylvania on October 3–6, 1999. Cancer Res. 2000;60:1465–9.PubMedGoogle Scholar
  190. 190.
    Whiteside TL. Immune responses to malignancies. J Allergy Clin Immunol. 2010;125:S272–83.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  1. 1.Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological ScienceChinese Academy of SciencesShanghaiChina

Personalised recommendations