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Mediators of Inflammation
Volume 2010 (2010), Article ID 437246, 16 pages
http://dx.doi.org/10.1155/2010/437246
Review Article

Toll-Like Receptors: Role in Dermatological Disease

1Immunology Research Group, University of Calgary, Calgary, AB, Canada T2N 4N1
2Department of Microbiology & Infectious Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1
3Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1

Received 29 January 2010; Revised 27 April 2010; Accepted 1 July 2010

Academic Editor: Natalija Novak

Copyright © 2010 Aswin Hari et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. L. S. Miller, “Toll-like receptors in skin,” Advances in Dermatology, vol. 24, pp. 71–87, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. R. Medzhitov, “Toll-like receptors and innate immunity,” Nature Reviews Immunology, vol. 1, no. 2, pp. 135–145, 2001. View at Google Scholar · View at Scopus
  3. M. G. Netea, C. van der Graaf, J. W. M. Van der Meer, and B. J. Kullberg, “Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system,” Journal of Leukocyte Biology, vol. 75, no. 5, pp. 749–755, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Kim, M.-T. Ochoa, S. R. Krutzik et al., “Activation of Toll-like receptor 2 in acne triggers inflammatory cytokine responses,” Journal of Immunology, vol. 169, no. 3, pp. 1535–1541, 2002. View at Google Scholar · View at Scopus
  5. A. Iwasaki and R. Medzhitov, “Toll-like receptor control of the adaptive immune responses,” Nature Immunology, vol. 5, no. 10, pp. 987–995, 2004. View at Publisher · View at Google Scholar · View at Scopus
  6. K. Takeda, T. Kaisho, and S. Akira, “Toll-like receptors,” Annual Review of Immunology, vol. 21, pp. 335–376, 2003. View at Publisher · View at Google Scholar · View at Scopus
  7. R. Shimazu, S. Akashi, H. Ogata et al., “MD-2, a molecule that confers lipopolysaccharide responsiveness on toll- like receptor 4,” Journal of Experimental Medicine, vol. 189, no. 11, pp. 1777–1782, 1999. View at Publisher · View at Google Scholar · View at Scopus
  8. S. D. Wright, P. S. Tobias, R. J. Ulevitch, and R. A. Ramos, “Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages,” Journal of Experimental Medicine, vol. 170, no. 4, pp. 1231–1241, 1989. View at Google Scholar · View at Scopus
  9. T. Kaisho and S. Akira, “Toll-like receptor function and signaling,” Journal of Allergy and Clinical Immunology, vol. 117, no. 5, pp. 979–987, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. K. J. Loniewski, S. Patial, and N. Parameswaran, “Sensitivity of TLR4- and -7-induced NFκB1 p105-TPL2-ERK pathway to TNF-receptor-associated-factor-6 revealed by RNAi in mouse macrophages,” Molecular Immunology, vol. 44, no. 15, pp. 3715–3723, 2007. View at Publisher · View at Google Scholar · View at Scopus
  11. V. Petry and A. A. Gaspari, “Toll-like receptors and dermatology,” International Journal of Dermatology, vol. 48, no. 6, pp. 558–570, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Schnare, G. M. Barton, A. C. Holt, K. Takeda, S. Akira, and R. Medzhitov, “Toll-like receptors control activation of adaptive immune responses,” Nature Immunology, vol. 2, no. 10, pp. 947–950, 2001. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Kobayashi, R. Yoshiki, J. Sakabe, K. Kabashima, M. Nakamura, and Y. Tokura, “Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes,” British Journal of Dermatology, vol. 160, no. 2, pp. 297–304, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. P. I. Song, Y.-M. Park, T. Abraham et al., “Human keratinocytes express functional CD14 and toll-like receptor 4,” Journal of Investigative Dermatology, vol. 119, no. 2, pp. 424–432, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Mempel, V. Voelcker, G. Köllisch et al., “Toll-like receptor expression in human keratinocytes: nuclear factor κB controlled gene activation by Staphylococcus aureus is Toll-like receptor 2 but not Toll-like receptor 4 or platelet activating factor receptor dependent,” Journal of Investigative Dermatology, vol. 121, no. 6, pp. 1389–1396, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. B. S. Baker, J.-M. Ovigne, A. V. Powles, S. Corcoran, and L. Fry, “Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis,” British Journal of Dermatology, vol. 148, no. 4, pp. 670–679, 2003. View at Publisher · View at Google Scholar · View at Scopus
  17. L. S. Miller, O. E. Sørensen, P. T. Liu et al., “TGF-α regulates TLR expression and function on epidermal keratinocytes,” Journal of Immunology, vol. 174, no. 10, pp. 6137–6143, 2005. View at Google Scholar · View at Scopus
  18. G. Köllisch, B. N. Kalali, V. Voelcker et al., “Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes,” Immunology, vol. 114, no. 4, pp. 531–541, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. M. C. Lebre, A. M. G. van der Aar, L. Van Baarsen et al., “Human keratinocytes express functional toll-like receptor 3, 4, 5, and 9,” Journal of Investigative Dermatology, vol. 127, no. 2, pp. 331–341, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Pivarcsi, L. Bodai, B. Réthi et al., “Expression and function of Toll-like receptors 2 and 4 in human keratinocytes,” International Immunology, vol. 15, no. 6, pp. 721–730, 2003. View at Publisher · View at Google Scholar · View at Scopus
  21. J. E. McInturff, R. L. Modlin, and J. Kim, “The role of toll-like receptors in the pathogenesis and treatment of dermatological disease,” Journal of Investigative Dermatology, vol. 125, no. 1, pp. 1–8, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. Y. Lee, H. Kim, S. Kim, K. H. Kim, and J. H. Chung, “Activation of toll-like receptors 2, 3 or 5 induces matrix metalloproteinase-1 and -9 expression with the involvement of MAPKs and NF-kappaB in human epidermal keratinocytes,” Experimental Dermatology, vol. 19, no. 8, pp. 44–49, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. M. C. Lebre, J. C. Antons, P. Kalinski et al., “Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a type-1 polarized phenotype in dendritic cells: role of keratinocyte-derived tumor necrosis factor α, type I interferons, and interleukin-18,” Journal of Investigative Dermatology, vol. 120, no. 6, pp. 990–997, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. C. N. Renn, D. J. Sanchez, M. T. Ochoa et al., “TLR activation of langerhans cell-like dendritic cells triggers an antiviral immune response,” Journal of Immunology, vol. 177, no. 1, pp. 298–305, 2006. View at Google Scholar · View at Scopus
  25. N. Yu, S. Zhang, F. Zuo, K. Kang, M. Guan, and L. Xiang, “Cultured human melanocytes express functional Toll-like receptors 2-4, 7 and 9,” Journal of Dermatological Science, vol. 56, no. 2, pp. 113–120, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. M. Mempel, B. N. Kalali, M. Ollert, and J. Ring, “Toll-like receptors in dermatology,” Dermatologic Clinics, vol. 25, no. 4, pp. 531–540, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Koreck, A. Pivarcsi, A. Dobozy, and L. Kemény, “The role of innate immunity in the pathogenesis of acne,” Dermatology, vol. 206, no. 2, pp. 96–105, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. A. J. Chong, A. Shimamoto, C. R. Hampton et al., “Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart,” Journal of Thoracic and Cardiovascular Surgery, vol. 128, no. 2, pp. 170–179, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Hasannejad, R. Takahashi, M. Kimishima, K. Hayakawa, and T. Shiohara, “Selective impairment of Toll-like receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis,” Journal of Allergy and Clinical Immunology, vol. 120, no. 1, pp. 69–75, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. D.-Y. Oh, R. R. Schumann, L. Hamann, K. Neumann, M. Worm, and G. Heine, “Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis,” Allergy, vol. 64, no. 11, pp. 1608–1615, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. N. Novak, C.-F. Yu, C. Bussmann et al., “Putative association of a TLR9 promoter polymorphism with atopic eczema,” Allergy, vol. 62, no. 7, pp. 766–772, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Jin, L. Kumar, C. Mathias et al., “Toll-like receptor 2 is important for the TH1 response to cutaneous sensitization,” Journal of Allergy and Clinical Immunology, vol. 123, no. 4, pp. 875–882, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. J. K. Geisse, P. Rich, A. Pandya et al., “Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study,” Journal of the American Academy of Dermatology, vol. 47, no. 3, pp. 390–398, 2002. View at Publisher · View at Google Scholar · View at Scopus
  34. E. Stockfleth, U. Trefzer, C. Garcia-Bartels, T. Wegner, T. Schmook, and W. Sterry, “The use of Toll-like receptor-7 agonist in the treatment of basal cell carcinoma: an overview,” British Journal of Dermatology, Supplement, vol. 149, no. 66, pp. 53–56, 2003. View at Google Scholar · View at Scopus
  35. R. Dummer, M. Urosevic, W. Kempf, K. Hoek, J. Hafner, and G. Burg, “Imiquimod in basal cell carcinoma: how does it work?” British Journal of Dermatology, Supplement, vol. 149, no. 66, supplement, pp. 57–58, 2003. View at Google Scholar · View at Scopus
  36. G. Stary, C. Bangert, M. Tauber, R. Strohal, T. Kopp, and G. Stingl, “Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells,” Journal of Experimental Medicine, vol. 204, no. 6, pp. 1441–1451, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. L. C. Zaba, J. G. Krueger, and M. A. Lowes, “Resident and "inflammatory" dendritic cells in human skin,” Journal of Investigative Dermatology, vol. 129, no. 2, pp. 302–308, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. M. A. Hofmann, C. Kors, H. Audring, P. Walden, W. Sterry, and U. Trefzer, “Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma,” Journal of Immunotherapy, vol. 31, no. 5, pp. 520–527, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. Y. Horie, A. Meguro, M. Ota et al., “Association of TLR4 polymorphisms with Behçet's disease in a Korean population,” Rheumatology, vol. 48, no. 6, pp. 638–642, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Yavuz, Y. Elbir, A. Tulunay, E. Eksioglu-Demiralp, and H. Direskeneli, “Differential expression of toll-like receptor 6 on granulocytes and monocytes implicates the role of microorganisms in Behcet's disease etiopathogenesis,” Rheumatology International, vol. 28, no. 5, pp. 401–406, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. J. C. Salazar, C. D. Pope, T. J. Sellati et al., “Coevolution of markers of innate and adaptive immunity in skin and peripheral blood of patients with erythema migrans,” Journal of Immunology, vol. 171, no. 5, pp. 2660–2670, 2003. View at Google Scholar · View at Scopus
  42. Y. Bulut, E. Faure, L. Thomas, O. Equils, and M. Arditi, “Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein a lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling,” Journal of Immunology, vol. 167, no. 2, pp. 987–994, 2001. View at Google Scholar · View at Scopus
  43. H. Tada, E. Nemoto, H. Shimauchi et al., “Saccharomyces cerevisiae- and Candida albicans-derived mannan induced production of tumor necrosis factor alpha by human monocytes in a CD14- and Toll-like receptor 4-dependent manner,” Microbiology and Immunology, vol. 46, no. 7, pp. 503–512, 2002. View at Google Scholar · View at Scopus
  44. T. Jouault, S. Ibata-Ombetta, O. Takeuchi et al., “Candida albicans phospholipomannan is sensed through toll-like receptors,” Journal of Infectious Diseases, vol. 188, no. 1, pp. 165–172, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. M. G. Netea, N. A. R. Gow, C. A. Munro et al., “Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors,” Journal of Clinical Investigation, vol. 116, no. 6, pp. 1642–1650, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. K. R. Cooke, A. Gerbitz, J. M. Crawford et al., “LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation,” Journal of Clinical Investigation, vol. 107, no. 12, pp. 1581–1589, 2001. View at Google Scholar · View at Scopus
  47. P.-Y. Bochud, A. S. Magaret, D. M. Koelle, A. Aderem, and A. Wald, “Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus type 2 infection,” Journal of Infectious Diseases, vol. 196, no. 4, pp. 505–509, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. S.-Y. Zhang, E. Jouanguy, S. Ugolini et al., “TLR3 deficiency in patients with herpes simplex encephalitis,” Science, vol. 317, no. 5844, pp. 1522–1527, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. A. Sato, M. M. Linehan, and A. Iwasaki, “Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 46, pp. 17343–17348, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. S. S. W. Kang, L. S. Kauls, and A. A. Gaspari, “Toll-like receptors: applications to dermatologic disease,” Journal of the American Academy of Dermatology, vol. 54, no. 6, pp. 951–983, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. S. R. Krutzik, M. T. Ochoa, P. A. Sieling et al., “Activation and regulation of Toll-like receptors 2 and 1 in human leprosy,” Nature Medicine, vol. 9, no. 5, pp. 525–532, 2003. View at Publisher · View at Google Scholar · View at Scopus
  52. R. B. Oliveira, M. T. Ochoa, P. A. Sieling et al., “Expression of toll-like receptor 2 on human schwann cells: a mechanism of nerve damage in leprosy,” Infection and Immunity, vol. 71, no. 3, pp. 1427–1433, 2003. View at Publisher · View at Google Scholar · View at Scopus
  53. S. Meller, M. Gilliet, and B. Homey, “Chemokines in the pathogenesis of lichenoid tissue reactions,” Journal of Investigative Dermatology, vol. 129, no. 2, pp. 315–319, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Li, J. Chen, Z. Tan, H. Liu, and Z. Liu, “Expression of TLR9 and its mRNA in the lesions of lichen planus,” Journal of Huazhong University of Science and Technology, vol. 27, no. 2, pp. 203–205, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. P. Pisitkun, J. A. Deane, M. J. Difilippantonio, T. Tarasenko, A. B. Satterthwaite, and S. Bolland, “Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication,” Science, vol. 312, no. 5780, pp. 1669–1672, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. E. L. Greidinger, Y. Zang, K. Jaimes et al., “A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen,” Arthritis and Rheumatism, vol. 54, no. 2, pp. 661–669, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. T. K. Means and A. D. Luster, “Toll-like receptor activation in the pathogenesis of systemic lupus erythematosus,” Annals of the New York Academy of Sciences, vol. 1062, pp. 242–251, 2005. View at Publisher · View at Google Scholar · View at Scopus
  58. J. Wenzel, D. Tormo, and T. Tüting, “Toll-like receptor-agonists in the treatment of skin cancer: history, current developments and future prospects,” Handbook of Experimental Pharmacology, no. 183, pp. 201–220, 2008. View at Google Scholar · View at Scopus
  59. V. Voelcker, C. Gebhardt, M. Averbeck et al., “Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4,” Experimental Dermatology, vol. 17, no. 2, pp. 100–107, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. L. Fang, A. S. Lonsdorf, and S. T. Hwang, “Immunotherapy for advanced melanoma,” Journal of Investigative Dermatology, vol. 128, no. 11, pp. 2596–2605, 2008. View at Publisher · View at Google Scholar · View at Scopus
  61. M. Gilliet and R. Lande, “Antimicrobial peptides and self-DNA in autoimmune skin inflammation,” Current Opinion in Immunology, vol. 20, no. 4, pp. 401–407, 2008. View at Publisher · View at Google Scholar · View at Scopus
  62. B. S. Baker, J.-M. Ovigne, A. V. Powles, S. Corcoran, and L. Fry, “Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis,” British Journal of Dermatology, vol. 148, no. 4, pp. 670–679, 2003. View at Publisher · View at Google Scholar · View at Scopus
  63. É. Begon, L. Michel, B. Flageul et al., “Expression, subcellular localization and cytokinic modulation of Toll-like receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin,” European Journal of Dermatology, vol. 17, no. 6, pp. 497–506, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Pabst, G. Baumgarten, A. Stremmel et al., “Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis,” Clinical and Experimental Immunology, vol. 143, no. 3, pp. 420–426, 2006. View at Publisher · View at Google Scholar · View at Scopus
  65. M. Veltkamp, P. A. H. M. Wijnen, C. H. M. Van Moorsel et al., “Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis,” Clinical and Experimental Immunology, vol. 149, no. 3, pp. 453–462, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. M. Wikén, J. Grunewald, A. Eklund, and J. Wahlström, “Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis,” Journal of Clinical Immunology, vol. 29, no. 1, pp. 78–89, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. A. Yoshizaki, Y. Iwata, K. Komura et al., “CD19 regulates skin and lung fibrosis via toll-like receptor signaling in a model of bleomycin-induced scleroderma,” American Journal of Pathology, vol. 172, no. 6, pp. 1650–1663, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. K. Peris, T. Micantonio, M. C. Fargnoli, G. P. Lozzi, and S. Chimenti, “Imiquimod 5% cream in the treatment of Bowen's disease and invasive squamous cell carcinoma,” Journal of the American Academy of Dermatology, vol. 55, no. 2, pp. 324–327, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. G. K. Patel, R. Goodwin, M. Chawla et al., “Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen's disease): a randomized, double-blind, placebo-controlled trial,” Journal of the American Academy of Dermatology, vol. 54, no. 6, pp. 1025–1032, 2006. View at Publisher · View at Google Scholar · View at Scopus
  70. S. J. Huang, D. Hijnen, G. F. Murphy et al., “Imiquimod enhances ifn-γ production and effector function of T cells infiltrating human squamous cell carcinomas of the skin,” Journal of Investigative Dermatology, vol. 129, no. 11, pp. 2676–2685, 2009. View at Publisher · View at Google Scholar · View at Scopus
  71. Y. Lai and R. L. Gallo, “Toll-like receptors in skin infections and inflammatory diseases,” Infectious Disorders—drug Targets, vol. 8, no. 3, pp. 144–155, 2008. View at Google Scholar · View at Scopus
  72. N. W. J. Schröder, S. Morath, C. Alexander et al., “Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved,” The Journal of Biological Chemistry, vol. 278, no. 18, pp. 15587–15594, 2003. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Ueta, C. Sotozono, T. Inatomi et al., “Toll-like receptor 3 gene polymorphisms in Japanese patients with Stevens-Johnson syndrome,” British Journal of Ophthalmology, vol. 91, no. 7, pp. 962–965, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. S. B. Mizel, A. N. Honko, M. A. Moors, P. S. Smith, and A. P. West, “Induction of macrophage nitric oxide production by gram-negative flagellin involves signaling via heteromeric Toll-like receptor 5/Toll-like receptor 4 complexes,” Journal of Immunology, vol. 170, no. 12, pp. 6217–6223, 2003. View at Google Scholar · View at Scopus
  75. A. Bowie and L. A. J. O'Neill, “The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products,” Journal of Leukocyte Biology, vol. 67, no. 4, pp. 508–514, 2000. View at Google Scholar · View at Scopus
  76. M. T. Harte, I. R. Haga, G. Maloney et al., “The poxvirus protein A52R targets toll-like receptor signaling complexes to suppress host defense,” Journal of Experimental Medicine, vol. 197, no. 3, pp. 343–351, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. K. K. Ja, J. K. Hyun, M.-Y. Kim et al., “Expression of toll-like receptors in verruca and molluscum contagiosum,” Journal of Korean Medical Science, vol. 23, no. 2, pp. 307–314, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. T. A. Syed, S. M. Hadi, Z. A. Qureshi, S. M. Ali, and M. S. Kwah, “Treatment of external genital warts in men with imiquimod 2% in cream. A placebo-controlled, double-blind study,” Journal of Infection, vol. 41, no. 2, pp. 148–151, 2000. View at Publisher · View at Google Scholar · View at Scopus
  79. K. R. Beutner, S. L. Spruance, A. J. Hougham, T. L. Fox, M. L. Owens, and JR. Douglas J.M., “Treatment of genital warts with an immune-response modifier (imiquimod),” Journal of the American Academy of Dermatology, vol. 38, no. 2, pp. 230–239, 1998. View at Publisher · View at Google Scholar · View at Scopus
  80. B. Berman, “Imiquimod: a new immune response modifier for the treatment of external genital warts and other diseases in dermatology,” International Journal of Dermatology, vol. 41, supplement 1, pp. 7–11, 2002. View at Google Scholar · View at Scopus
  81. A. Sing, D. Rost, N. Tvardovskaia et al., “Yersinia V-antigen exploits toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression,” Journal of Experimental Medicine, vol. 196, no. 8, pp. 1017–1024, 2002. View at Publisher · View at Google Scholar · View at Scopus
  82. K. Ruckdeschel, O. Mannel, K. Richter et al., “Yersinia outer protein P of Yersinia enterocolitica simultaneously blocks the nuclear factor-κB pathway and exploits lipopolysaccharide signaling to trigger apoptosis in macrophages,” Journal of Immunology, vol. 166, no. 3, pp. 1823–1831, 2001. View at Google Scholar · View at Scopus
  83. L. A. J. O'Neill, C. E. Bryant, and S. L. Doyle, “Therapeutic targeting of toll-like receptors for infectious and inflammatory diseases and cancer,” Pharmacological Reviews, vol. 61, no. 2, pp. 177–197, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. L. Macedo, G. Pinhal-Enfield, V. Alshits, G. Elson, B. N. Cronstein, and S. J. Leibovich, “Wound healing is impaired in MyD88-deficient mice: a role for MyD88 in the regulation of wound healing by adenosine A2A receptors,” American Journal of Pathology, vol. 171, no. 6, pp. 1774–1788, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. Y. Lai, A. Di Nardo, T. Nakatsuji et al., “Commensal bacteria regulate toll-like receptor 3-dependent inflammation after skin injury,” Nature Medicine, vol. 15, no. 12, pp. 1377–1382, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. T. S. Kupper and R. C. Fuhlbrigge, “Immune surveillance in the skin: mechanisms and clinical consequences,” Nature Reviews Immunology, vol. 4, no. 3, pp. 211–222, 2004. View at Google Scholar · View at Scopus
  87. A. De Benedetto, R. Agnihothri, L. Y. McGirt, L. G. Bankova, and L. A. Beck, “Atopic dermatitis: a disease caused by innate immune defects?” The Journal of investigative dermatology, vol. 129, no. 1, pp. 14–30, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. S.-H. Cho, I. Strickland, M. Boguniewicz, and D. Y. M. Leung, “Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin,” Journal of Allergy and Clinical Immunology, vol. 108, no. 2, pp. 269–274, 2001. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Nishijima, S. Namura, S. Kawai, H. Hosokawa, and Y. Asada, “Staphylococcus aureus on hand surface and nasal carriage in patients ith atopic dermatitis,” Journal of the American Academy of Dermatology, vol. 32, no. 4, pp. 677–679, 1995. View at Publisher · View at Google Scholar · View at Scopus
  90. L. Y. McGirt and L. A. Beck, “Innate immune defects in atopic dermatitis,” Journal of Allergy and Clinical Immunology, vol. 118, no. 1, pp. 202–208, 2006. View at Publisher · View at Google Scholar · View at Scopus
  91. P. Ahmad-Nejad, S. Mrabet-Dahbi, K. Breuer et al., “The Toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype,” Journal of Allergy and Clinical Immunology, vol. 113, no. 3, pp. 565–567, 2004. View at Publisher · View at Google Scholar · View at Scopus
  92. M. Niebuhr, J. Langnickel, C. Draing, H. Renz, A. Kapp, and T. Werfel, “Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism,” Allergy, vol. 63, no. 6, pp. 728–734, 2008. View at Publisher · View at Google Scholar · View at Scopus
  93. S. Weidinger, N. Novak, N. Klopp et al., “Lack of association between Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and atopic eczema,” Journal of Allergy and Clinical Immunology, vol. 118, no. 1, pp. 277–279, 2006. View at Publisher · View at Google Scholar · View at Scopus
  94. N. Novak, “New insights into the mechanism and management of allergic diseases: atopic dermatitis,” Allergy, vol. 64, no. 2, pp. 265–275, 2009. View at Publisher · View at Google Scholar · View at Scopus
  95. S. Hoffjan, S. Stemmler, Q. Parwez et al., “Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease,” BMC Medical Genetics, vol. 6, article 34, 2005. View at Publisher · View at Google Scholar · View at Scopus
  96. D. Terhorst, B. N. Kalali, S. Weidinger et al., “Monocyte-derived dendritic cells from highly atopic individuals are not impaired in their pro-inflammatory response to toll-like receptor ligands,” Clinical and Experimental Allergy, vol. 37, no. 3, pp. 381–390, 2007. View at Publisher · View at Google Scholar · View at Scopus
  97. G. B. Toews, P. R. Bergstresser, and J. W. Streilein, “Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB,” Journal of Immunology, vol. 124, no. 1, pp. 445–453, 1980. View at Google Scholar · View at Scopus
  98. W. Ptak, K. Bryniarski, M. Ptak et al., “Toll-like receptor ligands reverse suppression of contact hypersensitivity reactions induced by epicutaneous immunization with protein antigen,” International Archives of Allergy and Immunology, vol. 139, no. 3, pp. 188–200, 2006. View at Publisher · View at Google Scholar · View at Scopus
  99. S. F. Martin, J. C. Dudda, E. Bachtanian et al., “Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity,” Journal of Experimental Medicine, vol. 205, no. 9, pp. 2151–2162, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. P. Y. Ong, T. Ohtake, C. Brandt et al., “Endogenous antimicrobial peptides and skin infections in atopic dermatitis,” The New England Journal of Medicine, vol. 347, no. 15, pp. 1151–1160, 2002. View at Publisher · View at Google Scholar · View at Scopus
  101. M. D. Howell, B. E. Kim, P. Gao et al., “Cytokine modulation of atopic dermatitis filaggrin skin expression,” Journal of Allergy and Clinical Immunology, vol. 120, no. 1, pp. 150–155, 2007. View at Publisher · View at Google Scholar · View at Scopus
  102. C. A. Akdis, M. Akdis, T. Bieber et al., “Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report,” Journal of Allergy and Clinical Immunology, vol. 118, no. 1, pp. 152–169, 2006. View at Publisher · View at Google Scholar · View at Scopus
  103. T. Ruzicka, T. Bieber, E. Schöpf et al., “A short-term trial of tacrolimus ointment for atopic dermatitis,” The New England Journal of Medicine, vol. 337, no. 12, pp. 816–821, 1997. View at Publisher · View at Google Scholar · View at Scopus
  104. A. S. Büchau, J. Schauber, T. Hultsch, A. Stuetz, and R. L. Gallo, “Pimecrolimus enhances TLR2/6-induced expression of antimicrobial peptides in keratinocytes,” Journal of Investigative Dermatology, vol. 128, no. 11, pp. 2646–2654, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. L. A. Applegate, R. D. Ley, J. Alcalay, and M. L. Kripke, “Identification of the molecular target for the suppression of contact hypersensitivity by ultraviolet radiation,” Journal of Experimental Medicine, vol. 170, no. 4, pp. 1117–1131, 1989. View at Google Scholar · View at Scopus
  106. W. L. Morison, “Photoimmunology,” Journal of Investigative Dermatology, vol. 77, no. 1, pp. 71–76, 1981. View at Google Scholar · View at Scopus
  107. N. S. Scheinfeld, W. D. Tutrone, J. M. Weinberg, and V. A. Deleo, “Phototherapy of atopic dermatitis,” Clinics in Dermatology, vol. 21, no. 3, pp. 241–248, 2003. View at Publisher · View at Google Scholar · View at Scopus
  108. M. Gilliet, C. Conrad, M. Geiges et al., “Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors,” Archives of Dermatology, vol. 140, no. 12, pp. 1490–1495, 2004. View at Publisher · View at Google Scholar · View at Scopus
  109. A. Farkas, G. Tonel, and F. O. Nestle, “Interferon-α and viral triggers promote functional maturation of human monocyte-derived dendritic cells,” British Journal of Dermatology, vol. 158, no. 5, pp. 921–929, 2008. View at Publisher · View at Google Scholar · View at Scopus
  110. L. S. Miller, O. E. Sørensen, P. T. Liu et al., “TGF-α regulates TLR expression and function on epidermal keratinocytes,” Journal of Immunology, vol. 174, no. 10, pp. 6137–6143, 2005. View at Google Scholar · View at Scopus
  111. N. R. Seung, E. J. Park, C. W. Kim et al., “Comparison of expression of heat-shock protein 60, Toll-like receptors 2 and 4, and T-cell receptor γδ in plaque and guttate psoriasis,” Journal of Cutaneous Pathology, vol. 34, no. 12, pp. 903–911, 2007. View at Publisher · View at Google Scholar · View at Scopus
  112. A. A. Gaspari, “Innate and adaptive immunity and the pathophysiology of psoriasis,” Journal of the American Academy of Dermatology, vol. 54, no. 3, pp. S67–S80, 2006. View at Publisher · View at Google Scholar · View at Scopus
  113. C. Wu, C. Li, L. Wei, and Z. Zheng, “Innate immune modulation of keratinocytes by antikeratin 16 antibodies,” Experimental Dermatology, vol. 17, no. 8, pp. 645–652, 2008. View at Publisher · View at Google Scholar · View at Scopus
  114. M. A. Lowes, A. M. Bowcock, and J. G. Krueger, “Pathogenesis and therapy of psoriasis,” Nature, vol. 445, no. 7130, pp. 866–873, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. B. J. Nickoloff, J.-Z. Qin, and F. O. Nestle, “Immunopathogenesis of psoriasis,” Clinical Reviews in Allergy and Immunology, vol. 33, no. 1-2, pp. 45–56, 2007. View at Publisher · View at Google Scholar · View at Scopus
  116. B. S. Baker, A. F. Swain, L. Fry, and H. Valdimarsson, “Epidermal T lymphocytes and HLA-DR expression in psoriasis,” British Journal of Dermatology, vol. 110, no. 5, pp. 555–564, 1984. View at Google Scholar · View at Scopus
  117. L. M. Austin, M. Ozawa, T. Kikuchi, I. B. Walters, and J. G. Krueger, “The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-γ, interleukin-2, and tumor necrosis factor-α, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients,” Journal of Investigative Dermatology, vol. 113, no. 5, pp. 752–759, 1999. View at Publisher · View at Google Scholar · View at Scopus
  118. C. N. Ellis, D. C. Gorsulowsky, and T. A. Hamilton, “Cyclosporine improves psoriasis in a double-blind study,” Journal of the American Medical Association, vol. 256, no. 22, pp. 3110–3116, 1986. View at Google Scholar · View at Scopus
  119. J. Prinz, O. Braun-Falco, M. Meurer et al., “Chimaeric CD4 monoclonal antibody in treatment of generalised pustular psoriasis,” The Lancet, vol. 338, no. 8762, pp. 320–321, 1991. View at Google Scholar · View at Scopus
  120. J. R. Abrams, S. L. Kelley, E. Hayes et al., “Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells,” Journal of Experimental Medicine, vol. 192, no. 5, pp. 681–693, 2000. View at Publisher · View at Google Scholar · View at Scopus
  121. M. Sugiyama, P. M. Speight, S. S. Prime, and F. M. Watt, “Comparison of integrin expression and terminal differentiation capacity in cell lines derived from oral squamous cell carcinomas,” Carcinogenesis, vol. 14, no. 10, pp. 2171–2176, 1993. View at Google Scholar · View at Scopus
  122. S. L. Gottlieb, P. Gilleaudeau, R. Johnson et al., “Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis,” Nature Medicine, vol. 1, no. 5, pp. 442–447, 1995. View at Publisher · View at Google Scholar · View at Scopus
  123. M. P. Schon, “Animal models of psoriasis—what can we learn from them?” Journal of Investigative Dermatology, vol. 112, no. 4, pp. 405–410, 1999. View at Publisher · View at Google Scholar · View at Scopus
  124. J. A. Snowden and D. C. Heaton, “Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity,” British Journal of Dermatology, vol. 137, no. 1, pp. 130–132, 1997. View at Google Scholar · View at Scopus
  125. J. L. Curry, J.-Z. Qin, B. Bonish et al., “Innate immune-related receptors in normal and psoriatic skin,” Archives of Pathology and Laboratory Medicine, vol. 127, no. 2, pp. 178–186, 2003. View at Google Scholar · View at Scopus
  126. K. Kis, L. Bodai, H. Polyanka et al., “Budesonide, but not tacrolimus, affects the immune functions of normal human keratinocytes,” International Immunopharmacology, vol. 6, no. 3, pp. 358–368, 2006. View at Publisher · View at Google Scholar · View at Scopus
  127. K. Rappersberger, M. Komar, M.-E. Ebelin et al., “Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated,” Journal of Investigative Dermatology, vol. 119, no. 4, pp. 876–887, 2002. View at Publisher · View at Google Scholar · View at Scopus
  128. N. H. R. Litjens, M. Rademaker, B. Ravensbergen et al., “Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated TH1 lymphocyte responses,” European Journal of Immunology, vol. 34, no. 2, pp. 565–575, 2004. View at Publisher · View at Google Scholar · View at Scopus
  129. L. A. J. O'Neill, “Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases,” Current Opinion in Pharmacology, vol. 3, no. 4, pp. 396–403, 2003. View at Publisher · View at Google Scholar · View at Scopus
  130. A. J. Thody and S. Shuster, “Control and function of sebaceous glands,” Physiological Reviews, vol. 69, no. 2, pp. 383–416, 1989. View at Google Scholar · View at Scopus
  131. C. C. Zouboulis, “Acne and sebaceous gland function,” Clinics in Dermatology, vol. 22, no. 5, pp. 360–366, 2004. View at Publisher · View at Google Scholar · View at Scopus
  132. P. Georgel, K. Crozat, X. Lauth et al., “A toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria,” Infection and Immunity, vol. 73, no. 8, pp. 4512–4521, 2005. View at Publisher · View at Google Scholar · View at Scopus
  133. B. R. Vowels, S. Yang, and J. J. Leyden, “Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne,” Infection and Immunity, vol. 63, no. 8, pp. 3158–3165, 1995. View at Google Scholar · View at Scopus
  134. D.-Y. Lee, K. Yamasaki, J. Rudsil et al., “Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill Propionibacterium acnes,” Journal of Investigative Dermatology, vol. 128, no. 7, pp. 1863–1866, 2008. View at Publisher · View at Google Scholar · View at Scopus
  135. M. Toyoda, M. Nakamura, and M. Morohashi, “Neuropeptides and sebaceous glands,” European Journal of Dermatology, vol. 12, no. 5, pp. 422–427, 2002. View at Google Scholar · View at Scopus
  136. R. Ganceviciene, S. Fimmel, E. Glass, and C. C. Zouboulis, “Psoriasin and follicular hyperkeratinization in acne comedones,” Dermatology, vol. 213, no. 3, pp. 270–272, 2006. View at Publisher · View at Google Scholar · View at Scopus
  137. C. M. T. Chronnell, L. R. Ghali, R. S. Ali et al., “Human β defensin-1 and -2 expression in human pilosebaceous units: upregulation in acne vulgaris lesions,” Journal of Investigative Dermatology, vol. 117, no. 5, pp. 1120–1125, 2001. View at Publisher · View at Google Scholar · View at Scopus
  138. I. Nagy, A. Pivarcsi, K. Kis et al., “Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes,” Microbes and Infection, vol. 8, no. 8, pp. 2195–2205, 2006. View at Publisher · View at Google Scholar · View at Scopus
  139. D. K. Chalker, J. L. Lesher Jr., and J. G. Smith Jr., “Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: results of a multicenter, double-blind investigation,” Journal of the American Academy of Dermatology, vol. 17, no. 2, pp. 251–254, 1987. View at Google Scholar · View at Scopus
  140. J. S. Weiss, “Current options for the topical treatment of acne vulgaris,” Pediatric Dermatology, vol. 14, no. 6, pp. 480–488, 1997. View at Google Scholar · View at Scopus
  141. S. Gibbs, C. Backendorf, and M. Ponec, “Regulation of keratinocyte proliferation and differentiation by all-trans-retinoic acid, 9-cis-retinoic acid and 1,25-dihydroxy vitamin D3,” Archives of Dermatological Research, vol. 288, no. 12, pp. 729–738, 1996. View at Publisher · View at Google Scholar · View at Scopus
  142. P. T. Liu, S. R. Krutzik, J. Kim, and R. L. Modlin, “Cutting edge: all-trans retinoic acid down-regulates TLR2 expression and function,” Journal of Immunology, vol. 174, no. 5, pp. 2467–2470, 2005. View at Google Scholar · View at Scopus
  143. P. A. Grange, C. Chéreau, J. Raingeaud et al., “Production of superoxide anions by keratinocytes initiates P. acnes-induced inflammation of the skin,” PLoS Pathogens, vol. 5, no. 7, Article ID e1000527, pp. 1–14, 2009. View at Publisher · View at Google Scholar · View at Scopus
  144. P. A. Grange, J. Raingeaud, V. Calvez, and N. Dupin, “Nicotinamide inhibits Propionibacterium acnes-induced IL-8 production in keratinocytes through the NF-κB and MAPK pathways,” Journal of Dermatological Science, vol. 56, no. 2, pp. 106–112, 2009. View at Publisher · View at Google Scholar · View at Scopus
  145. L. Bianchi, A. Costanzo, E. Campione, S. Nisticò, and S. Chimenti, “Superficial and nodular basal cell carcinomas treated with an immune response modifier: a report of seven patients,” Clinical and Experimental Dermatology, Supplement, vol. 28, no. 1, supplement, pp. 24–26, 2003. View at Google Scholar · View at Scopus
  146. H. G. Kaporis, E. Guttman-Yassky, M. A. Lowes et al., “Human basal cell carcinoma is associated with Foxp3+ T cells in a Th2 dominant microenvironment,” Journal of Investigative Dermatology, vol. 127, no. 10, pp. 2391–2398, 2007. View at Publisher · View at Google Scholar · View at Scopus
  147. A. S. Weinberg, C. A. Ogle, and E. K. Shim, “Metastatic cutaneous squamous cell carcinoma: an update,” Dermatologic Surgery, vol. 33, no. 8, pp. 885–899, 2007. View at Publisher · View at Google Scholar · View at Scopus
  148. A. I. Rubin, E. H. Chen, and D. Ratner, “Basal-cell carcinoma,” The New England Journal of Medicine, vol. 353, no. 21, pp. 2262–2269, 2005. View at Publisher · View at Google Scholar · View at Scopus
  149. F. I. Ezughah, A. G. Affleck, A. Evans, S. H. Ibbotson, and C. J. Fleming, “Confirmation of histological clearance of superficial basal cell carcinoma with multiple serial sectioning and Mohs' micrographic surgery following treatment with imiquimod 5% cream,” Journal of Dermatological Treatment, vol. 19, no. 3, pp. 156–158, 2008. View at Publisher · View at Google Scholar · View at Scopus
  150. H.-J. Schulze, B. Cribier, L. Requena et al., “Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe,” British Journal of Dermatology, vol. 152, no. 5, pp. 939–947, 2005. View at Publisher · View at Google Scholar · View at Scopus
  151. Y. Vun and G. Siller, “Use of 5% imiquimod cream in the treatment of facial basal cell carcinoma: a 3-year retrospective follow-up study,” Australasian Journal of Dermatology, vol. 47, no. 3, pp. 169–171, 2006. View at Publisher · View at Google Scholar · View at Scopus
  152. M. J. Bluth, L. C. Zaba, D. Moussai et al., “Myeloid dendritic cells from human cutaneous squamous cell carcinoma are poor stimulators of T-cell proliferation,” Journal of Investigative Dermatology, vol. 129, no. 10, pp. 2451–2462, 2009. View at Publisher · View at Google Scholar · View at Scopus
  153. R. Marks, “Squamous cell carcinoma,” The Lancet, vol. 347, no. 9003, pp. 735–738, 1996. View at Publisher · View at Google Scholar · View at Scopus
  154. J. Garcia-Zuazaga and S. M. Olbricht, “Cutaneous squamous cell carcinoma,” Advances in Dermatology, vol. 24, pp. 33–57, 2008. View at Publisher · View at Google Scholar · View at Scopus
  155. H. Sadek, N. Azli, J. L. Wendling et al., “Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin,” Cancer, vol. 66, no. 8, pp. 1692–1696, 1990. View at Google Scholar · View at Scopus
  156. U. Wollina, G. Hansel, A. Koch, and E. Köstler, “Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin,” Journal of Cancer Research and Clinical Oncology, vol. 131, no. 5, pp. 300–304, 2005. View at Publisher · View at Google Scholar · View at Scopus
  157. J. C. Muhrer, “Melanoma: current incidence, diagnosis, and preventive strategies,” Journal for Nurse Practitioners, vol. 5, no. 1, pp. 35–41, 2009. View at Publisher · View at Google Scholar · View at Scopus
  158. A. A. Smith, A. B. Cole, and S. W. Fosko, “Melanoma from the dermatologist's perspective,” Facial Plastic Surgery Clinics of North America, vol. 11, no. 2, pp. 277–286, 2003. View at Google Scholar · View at Scopus
  159. A. R. Doben and D. C. MacGillivray, “Current concepts in cutaneous melanoma: malignant melanoma,” Surgical Clinics of North America, vol. 89, no. 3, pp. 713–725, 2009. View at Publisher · View at Google Scholar · View at Scopus
  160. A. S. Lonsdorf, H. Kuekrek, B. V. Stern, B. O. Boehm, P. V. Lehmann, and M. Tary-Lehmann, “Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity,” Journal of Immunology, vol. 171, no. 8, pp. 3941–3946, 2003. View at Google Scholar · View at Scopus
  161. D. E. Speiser, D. Liénard, N. Rufer et al., “Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909,” Journal of Clinical Investigation, vol. 115, no. 3, pp. 739–746, 2005. View at Publisher · View at Google Scholar · View at Scopus
  162. J. N. Kochenderfer, C. D. Chien, J. L. Simpson, and R. E. Gress, “Maximizing CD8+ T cell responses elicited by peptide vaccines containing CpG oligodeoxynucleotides,” Clinical Immunology, vol. 124, no. 2, pp. 119–130, 2007. View at Publisher · View at Google Scholar · View at Scopus
  163. A. M. Krieg, “Development of TLR9 agonists for cancer therapy,” Journal of Clinical Investigation, vol. 117, no. 5, pp. 1184–1194, 2007. View at Publisher · View at Google Scholar · View at Scopus
  164. M. Pashenkov, G. Goëss, C. Wagner et al., “Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma,” Journal of Clinical Oncology, vol. 24, no. 36, pp. 5716–5724, 2006. View at Publisher · View at Google Scholar · View at Scopus
  165. A. Steinmann, J. O. Funk, G. Schuler, and P. Von den Driesch, “Topical imiquimod treatment of a cutaneous melanoma metastasis,” Journal of the American Academy of Dermatology, vol. 43, no. 3, pp. 555–556, 2000. View at Google Scholar · View at Scopus
  166. N. P. Peet, L. E. Baugh, S. Sunder, and J. E. Lewis, “Synthesis and antiallergic activity of some quinolinones and imidazoquinolinones,” Journal of Medicinal Chemistry, vol. 28, no. 3, pp. 298–302, 1985. View at Google Scholar · View at Scopus
  167. M. J. Reiter, T. L. Testerman, R. L. Miller, C. E. Weeks, and M. A. Tomai, “Cytokine induction in mice by the immunomodulator imiquimod,” Journal of Leukocyte Biology, vol. 55, no. 2, pp. 234–240, 1994. View at Google Scholar · View at Scopus
  168. M. P. Schön and M. Schön, “Imiquimod: mode of action,” British Journal of Dermatology, vol. 157, no. 2, pp. 8–13, 2007. View at Publisher · View at Google Scholar · View at Scopus
  169. H. Hemmi, T. Kaisho, O. Takeuchi et al., “Small-antiviral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway,” Nature Immunology, vol. 3, no. 2, pp. 196–200, 2002. View at Publisher · View at Google Scholar · View at Scopus
  170. D. H. Dockrell and G. R. Kinghorn, “Imiquimod and resiquimod as novel immunomodulators,” Journal of Antimicrobial Chemotherapy, vol. 48, no. 6, pp. 751–755, 2001. View at Google Scholar · View at Scopus
  171. R. Skinner, “Role of topical therapies in the management of cutaneous disease,” Journal of Cutaneous Medicine and Surgery, vol. 8, no. 3, supplement, pp. 22–31, 2004. View at Publisher · View at Google Scholar · View at Scopus
  172. J. E. McInturff, R. L. Modlin, and J. Kim, “The role of toll-like receptors in the pathogenesis and treatment of dermatological disease,” Journal of Investigative Dermatology, vol. 125, no. 1, pp. 1–8, 2005. View at Publisher · View at Google Scholar · View at Scopus
  173. M. Urosevic, R. Dummer, C. Conrad et al., “Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment,” Journal of the National Cancer Institute, vol. 97, no. 15, pp. 1143–1153, 2005. View at Publisher · View at Google Scholar · View at Scopus
  174. H. Y. Kang, T. J. Park, and S. H. Jin, “Imiquimod, a Toll-like receptor 7 agonist, inhibits melanogenesis and proliferation of human melanocytes,” The Journal of Investigative Dermatology, vol. 129, no. 1, pp. 243–246, 2009. View at Publisher · View at Google Scholar · View at Scopus
  175. S. Adams, D. W. O'Neill, D. Nonaka et al., “Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant,” Journal of Immunology, vol. 181, no. 1, pp. 776–784, 2008. View at Google Scholar · View at Scopus
  176. S. Garantziotis, J. W. Hollingsworth, A. K. Zaas, and D. A. Schwartz, “The effect of toll-like receptors and toll-like receptor genetics in human disease,” Annual Review of Medicine, vol. 59, pp. 343–359, 2008. View at Publisher · View at Google Scholar · View at Scopus
  177. F. Heil, P. Ahmad-Nejad, H. Hemmi et al., “The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily,” European Journal of Immunology, vol. 33, no. 11, pp. 2987–2997, 2003. View at Publisher · View at Google Scholar · View at Scopus
  178. S. S. Agarwala, J. M. Kirkwood, and J. Bryant, “Phase I, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer,” Cytokines, Cellular and Molecular Therapy, vol. 6, no. 4, pp. 171–176, 2000. View at Google Scholar · View at Scopus
  179. E. Lotzova, C. A. Savary, A. Khan, and D. A. Stringfellow, “Stimulation of natural killer cells in two random-bred strains of athymic rats by interferon-inducing pyrimidinone,” Journal of Immunology, vol. 132, no. 5, pp. 2566–2570, 1984. View at Google Scholar · View at Scopus
  180. S. Euvrard, C. Ulrich, and N. Lefrancois, “Immunosuppressants and skin cancer in transplant patients: focus on rapamycin,” Dermatologic Surgery, vol. 30, no. 4, pp. 628–633, 2004. View at Google Scholar · View at Scopus
  181. N. J. Reynolds and W. I. Al-Daraji, “Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology,” Clinical and Experimental Dermatology, vol. 27, no. 7, pp. 555–561, 2002. View at Publisher · View at Google Scholar · View at Scopus
  182. B. C. Wulff, D. F. Kusewitt, A. M. Vanbuskirk, J. M. Thomas-Ahner, F. J. Duncan, and T. M. Oberyszyn, “Sirolimus reduces the incidence and progression of UVB-induced skin cancer in SKH mice even with co-administration of cyclosporine A,” Journal of Investigative Dermatology, vol. 128, no. 10, pp. 2467–2473, 2008. View at Publisher · View at Google Scholar · View at Scopus
  183. Z. Wang, J. Zhou, J. Fan et al., “Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma,” Journal of Cancer Research and Clinical Oncology, vol. 135, no. 5, pp. 715–722, 2009. View at Publisher · View at Google Scholar · View at Scopus
  184. R. P. Hickerson, D. Leake, L. N. Pho, S. A. Leachman, and R. L. Kaspar, “Rapamycin selectively inhibits expression of an inducible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients,” Journal of Dermatological Science, vol. 56, no. 2, pp. 82–88, 2009. View at Publisher · View at Google Scholar · View at Scopus
  185. T. Mathew, H. Kreis, and P. Friend, “Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies,” Clinical Transplantation, vol. 18, no. 4, pp. 446–449, 2004. View at Publisher · View at Google Scholar · View at Scopus
  186. U. Nadiminti and J. L. Arbiser, “Rapamycin (sirolimus) as a steroid-sparing agent in dermatomyositis,” Journal of the American Academy of Dermatology, vol. 52, no. 2, supplement 1, pp. S17–S19, 2005. View at Publisher · View at Google Scholar · View at Scopus
  187. A. F. Javier, Z. Bata-Csorgo, C. N. Ellis, S. Kang, J. J. Voorhees, and K. D. Cooper, “Rapamycin (Sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells,” Journal of Clinical Investigation, vol. 99, no. 9, pp. 2094–2099, 1997. View at Google Scholar · View at Scopus
  188. NIH, http://clinicaltrials.gov.