Susceptibility to the biological effects of polyaromatic hydrocarbons is influenced by genes of the major histocompatibility complex

Elmets, Craig A.; Athar, Mohammad; Tubesing, Karen A.; Rothaupt, D; Xu, Hui; Mukhtar, Hasan

doi:10.1073/pnas.95.25.14915

Cited by 25 publications

(30 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition to activation by LPS signaling, TLR4 is also associated with signaling by many environmental chemicals, many of which are tumorigenic (23). Stimulation of TLRs by various ligands leads to signaling pathways that activate not only innate but also adaptive immunity by antigen-presenting cell (APC)-dependent or APC-independent mechanisms (5).…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Toll-like Receptor 4 during the Initiation Stage of Cutaneous Chemical Carcinogenesis

et al. 2008

Self Cite

View full text Add to dashboard Cite

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-; in C3H/HeN mice and by interleukin (IL)-17 in C3H/HeJ mice. Moreover, C3H/HeN mice had elevated circulating levels of IFN-; 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-; mediated may prove to be beneficial in the prevention of DMBA-induced cutaneous tumors. [Cancer Res 2008;68(2):615-22]

show abstract

Section: Discussionmentioning

confidence: 99%

Protective Role of Toll-like Receptor 4 during the Initiation Stage of Cutaneous Chemical Carcinogenesis

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…The development of that response is controlled by genes at the MHC class I and Ah receptor loci (15). Moreover, allergic contact hypersensitivity was associated with inhibition of tumor development, giving rise to the hypothesis that induction of the T cell-mediated immune response to DMBA protects an individual from the carcinogenic effects of that agent.…”

Section: Introductionmentioning

confidence: 99%

Antagonistic Roles of CD4+ and CD8+ T-Cells in 7,12-Dimethylbenz(a)anthracene Cutaneous Carcinogenesis

et al. 2008

Self Cite

View full text Add to dashboard Cite

The role that cell-mediated immune responses play during cutaneous carcinogenesis has received little attention. In this study, we evaluated the contribution of CD4 + and CD8 , CD8À/À , and WT mice were subjected to a standard two-stage DMBA/TPA cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (P < 0.001) in CD8 À/À mice than in WT mice.In contrast, the percentage of tumors was significantly less (P < 0.001) in CD4 À/À mice than in WT mice. Similar results were obtained when the data were evaluated as the number of tumors per mouse. These findings indicate that (a) CD8 +

show abstract

“…Strains of mice that were homozygous for the d allele (strains that are inefficient at metabolizing PAHs) uniformly failed to develop DMBA contact hypersensitivity (Anderson et al, 1995). Some strains that were homozygous for the b allele developed contact hypersensitivity to DMBA, but this was not universally the case, suggesting that other genetic factors were involved in the control of contact hypersensitivity to DMBA (Elmets et al, 1998). To further investigate the genetic component responsible for induction of cutaneous cell-mediated immune responses to PAH, strains of congenic mice that differed only at the major histocompatibility complex (MHC) were tested for their ability to develop this type of reaction.…”

Section: Strain Variation To the Development Of Cell-mediated Immunitmentioning

confidence: 99%

“…To further investigate the genetic component responsible for induction of cutaneous cell-mediated immune responses to PAH, strains of congenic mice that differed only at the major histocompatibility complex (MHC) were tested for their ability to develop this type of reaction. Those studies indicated that, in addition to the Ah receptor locus, proteins encoded by genes within the major histocompatibility locus also participated in the induction of this type of immune response (Elmets et al, 1998). Mice that possessed the H-2 k and closely related H-2 a loci had significantly greater contact hypersensitivity responses than mice with non-H-2 k or non-H-2 a loci.…”

Section: Strain Variation To the Development Of Cell-mediated Immunitmentioning

confidence: 99%

See 1 more Smart Citation

Acquired and innate immunity to polyaromatic hydrocarbons

Yusuf

Timares

Seibert

et al. 2007

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Polyaromatic hydrocarbons are ubiquitous environmental pollutants that are potent mutagens and carcinogens. Researchers have taken advantage of these properties to investigate the mechanisms by which chemicals cause cancer of the skin and other organs. When applied to the skin of mice, several carcinogenic polyaromatic hydrocarbons have also been shown to interact with the immune system, stimulating immune responses and resulting in the development of antigen specific T-cell mediated immunity. Development of cell-mediated immunity is strain specific and is governed by Ah receptor genes and by genes located within the major histocompatibility complex. CD8 + T-cells are effector cells in the response, whereas CD4 + T-cells down-regulate immunity. Development of an immune response appears to have a protective effect since strains of mice that develop a cell-mediated immune response to carcinogenic polyaromatic hydrocarbons are less likely to develop tumors when subjected to a polyaromatic hydrocarbon skin carcinogenesis protocol than mice that fail to develop an immune response. With respect to innate immunity, TLR4 deficient C3H/HeJ mice are more susceptible to polyaromatic hydrogen skin tumorigenesis than C3H/HeN mice in which TLR4 is normal. These findings support the hypothesis that immune responses, through their interactions with chemical carcinogens, play an active role in the prevention of chemical skin carcinogenesis during the earliest stages. Efforts to augment immune responses to the chemicals that cause tumors may be a productive approach to the prevention of tumors caused by these agents. Keywords polyaromatic hydrocarbon; contact hypersensitivity; skin carcinogenesis; dimethylbenz(a) anthracene; benzo(a)pyrene; immunotoxicology The polyaromatic hydrocarbons benzo(a)pyrene [B(a)P] 1 and dimethylbenz(a)anthracene (DMBA) are potent mutagens and carcinogens when applied to the skin. These chemicals are often employed to investigate the mechanisms by which xenobiotics cause cancer. A single application of DMBA or B(a)P results in the formation of stable adducts with the DNA of target cells, leading to mutations in the H-ras oncogene. Repeated exposure of the carcinogen treated skin to tumor promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA), benzoyl peroxide or mezerin produces epigenetic changes in the H-ras mutant cells that convert Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Skin tumors induced by carcinogenic polyaromatic hydrocarbons (PAHs) express tumor specific antigens that elicit a cell-mediated immune response. Immunotherapeutic app...

show abstract

Susceptibility to the biological effects of polyaromatic hydrocarbons is influenced by genes of the major histocompatibility complex

Cited by 25 publications

References 22 publications

Protective Role of Toll-like Receptor 4 during the Initiation Stage of Cutaneous Chemical Carcinogenesis

Protective Role of Toll-like Receptor 4 during the Initiation Stage of Cutaneous Chemical Carcinogenesis

Antagonistic Roles of CD4+ and CD8+ T-Cells in 7,12-Dimethylbenz(a)anthracene Cutaneous Carcinogenesis

Acquired and innate immunity to polyaromatic hydrocarbons

Contact Info

Product

Resources

About