Protective Role of Toll-like Receptor 4 during the Initiation Stage of Cutaneous Chemical Carcinogenesis
Open Access
- 15 January 2008
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (2), 615-622
- https://doi.org/10.1158/0008-5472.can-07-5219
Abstract
Toll-like receptors (TLR) activate multiple steps in inflammatory reactions in innate immune responses. They also activate signals that are critically involved in the initiation of adaptive immune responses. Many tumorigenic chemicals have been associated with endotoxin hypersensitivity mediated through TLR4. To determine the role of TLR4 in cutaneous skin carcinogenesis, we treated TLR4-deficient C3H/HeJ mice and the TLR4-normal C3H/HeN mice with the carcinogenic polyaromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA). TLR4-deficient C3H/HeJ mice developed more tumors relative to the TLR4-normal C3H/HeN mice. Both C3H/HeN and C3H/HeJ mice developed a T-cell–mediated immune response to topically applied DMBA. Interestingly, the cell-mediated immune response was mediated by IFN-γ in C3H/HeN mice and by interleukin (IL)-17 in C3H/HeJ mice. Moreover, C3H/HeN mice had elevated circulating levels of IFN-γ following topical application of DMBA, whereas IL-17 was elevated in C3H/HeJ mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA skin tumorigenesis and that this is associated with differences in the T-cell subtype activated. Efforts to divert the cell-mediated immune response from one that is IL-17 mediated to one that is IFN-γ mediated may prove to be beneficial in the prevention of DMBA-induced cutaneous tumors. [Cancer Res 2008;68(2):615–22]Keywords
This publication has 29 references indexed in Scilit:
- Acquired and innate immunity to polyaromatic hydrocarbonsToxicology and Applied Pharmacology, 2007
- Cooperation of Toll-like receptor signals in innate immune defenceNature Reviews Immunology, 2007
- Human Keratinocytes Express Functional Toll-Like Receptor 3, 4, 5, and 9Journal of Investigative Dermatology, 2007
- Human Keratinocyte Toll-like Receptors Promote Distinct Immune ResponsesJournal of Investigative Dermatology, 2007
- Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?British Journal of Cancer, 2006
- Pathogen Recognition and Innate ImmunityCell, 2006
- Toll-like receptor control of the adaptive immune responsesNature Immunology, 2004
- Differential Expression and Function of Toll-like Receptors in Langerhans Cells: Comparison with Splenic Dendritic CellsJournal of Investigative Dermatology, 2004
- Inflammation and cancerNature, 2002
- Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor.The Journal of Experimental Medicine, 1992