Profiles of cytokine mRNAs in the skin and lymph nodes of SENCAR mice treated epicutaneously with dibenzo[a,l]pyrene or dimethylbenz[a]anthracene reveal a direct correlation between carcinogen-induced contact hypersensitivity and epidermal hyperplasia

George P Casale, Zhao Cheng, Jia Nuo Liu, Ercole Cavalieri, Maria Singhal

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19 Citations (Scopus)

Abstract

The potent carcinogenicity of dibenzo[a,l]pyrene (DB[a,l]P) in mouse skin is associated with an inflammatory response and a striking epidermal hyperplasia. The mechanism of these tissue responses is not known. However, a recent study has shown DB[a,l]P to be a contact sensitizer. In view of the programmed expression of cytokines during induction of contact hypersensitivity (CHS) and elicitation of CHS reactions, we analyzed cytokine mRNAs in treated skin and draining lymph nodes of SENCAR mice, at selected times after a single, epicutaneous application of DB[a,l]P or dimethylbenz[a]anthracene (DMBA), a substantially weaker carcinogen and a weaker contact sensitizer than DB[a,l]P. Cytokine mRNAs were quantified by first-strand DNA synthesis with reverse transcriptase (RT) and DNA amplification by the polymerase chain reaction (PCR). Histopathology of treated skin was determined in the same experiments. Time-response profiles of interferon (IFN) γ and interleukin (IL) 2 in the DLN and IL1β, IL10, tumor necrosis factor (TNF) α, and IL4 mRNAs in the skin of mice treated with 200 nmol of DB[a,I]P were in remarkable agreement with established profiles in mice treated with conventional contact sensitizers, e.g., oxazolone or dinitrochlorobenzene. Strong upregulation of DLN IFNγ mRNA coupled with little change in IL 2 mRNA suggested a CD8+ T-cell response characteristic of CHS induction. Coordinate expression of epidermal IL1β, TNFα, and IL10 mRNAs, 24 h after DB[a,I]P treatment, was also characteristic of CHS induction. IL1β and IL10 are upregulated by allergens and not by chemical irritants. Time-response profiles of epidermal IL1β, TNFα, IL10, and IL4 mRNAs, 3-14 d after DB[a,l]P treatment, corresponded with expression of these cytokines during elicitation of CHS reactions. Epidermal IL4 is specifically upregulated during CHS reactions. Cytokine mRNA responses were dose-dependent (50, 100, and 200 nmol of DB[a,l]P) and markedly weaker in animals treated with 400 nmol of DMBA. Significantly, the intensity of epidermal hyperplasia correlated with the strength of the cytokine mRNA signals in DLN and skin. In conclusion, our data support carcinogen-specific CHS as a mechanism by which the very potent carcinogen DB[a,I]P induces epidermal hyperplasia, a requirement for tumor promotion in mouse skin. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)125-140
Number of pages16
JournalMolecular Carcinogenesis
Volume27
Issue number2
DOIs
StatePublished - Feb 23 2000

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Inbred SENCAR Mouse
Contact Dermatitis
Carcinogens
Hyperplasia
Lymph Nodes
Cytokines
Messenger RNA
Skin
Interleukin-10
Interleukin-4
Tumor Necrosis Factor-alpha
Interferons
Interleukin-2
Oxazolone
dibenzo(a,l)pyrene
anthracene
Dinitrochlorobenzene
Irritants
RNA-Directed DNA Polymerase
DNA-Directed DNA Polymerase

Keywords

  • Carcinogenesis
  • Cytokine
  • Hyperplasia
  • Hypersensitivity
  • Promotion

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

@article{24f70a14119e4b60b4aa5b8bd23589dc,
title = "Profiles of cytokine mRNAs in the skin and lymph nodes of SENCAR mice treated epicutaneously with dibenzo[a,l]pyrene or dimethylbenz[a]anthracene reveal a direct correlation between carcinogen-induced contact hypersensitivity and epidermal hyperplasia",
abstract = "The potent carcinogenicity of dibenzo[a,l]pyrene (DB[a,l]P) in mouse skin is associated with an inflammatory response and a striking epidermal hyperplasia. The mechanism of these tissue responses is not known. However, a recent study has shown DB[a,l]P to be a contact sensitizer. In view of the programmed expression of cytokines during induction of contact hypersensitivity (CHS) and elicitation of CHS reactions, we analyzed cytokine mRNAs in treated skin and draining lymph nodes of SENCAR mice, at selected times after a single, epicutaneous application of DB[a,l]P or dimethylbenz[a]anthracene (DMBA), a substantially weaker carcinogen and a weaker contact sensitizer than DB[a,l]P. Cytokine mRNAs were quantified by first-strand DNA synthesis with reverse transcriptase (RT) and DNA amplification by the polymerase chain reaction (PCR). Histopathology of treated skin was determined in the same experiments. Time-response profiles of interferon (IFN) γ and interleukin (IL) 2 in the DLN and IL1β, IL10, tumor necrosis factor (TNF) α, and IL4 mRNAs in the skin of mice treated with 200 nmol of DB[a,I]P were in remarkable agreement with established profiles in mice treated with conventional contact sensitizers, e.g., oxazolone or dinitrochlorobenzene. Strong upregulation of DLN IFNγ mRNA coupled with little change in IL 2 mRNA suggested a CD8+ T-cell response characteristic of CHS induction. Coordinate expression of epidermal IL1β, TNFα, and IL10 mRNAs, 24 h after DB[a,I]P treatment, was also characteristic of CHS induction. IL1β and IL10 are upregulated by allergens and not by chemical irritants. Time-response profiles of epidermal IL1β, TNFα, IL10, and IL4 mRNAs, 3-14 d after DB[a,l]P treatment, corresponded with expression of these cytokines during elicitation of CHS reactions. Epidermal IL4 is specifically upregulated during CHS reactions. Cytokine mRNA responses were dose-dependent (50, 100, and 200 nmol of DB[a,l]P) and markedly weaker in animals treated with 400 nmol of DMBA. Significantly, the intensity of epidermal hyperplasia correlated with the strength of the cytokine mRNA signals in DLN and skin. In conclusion, our data support carcinogen-specific CHS as a mechanism by which the very potent carcinogen DB[a,I]P induces epidermal hyperplasia, a requirement for tumor promotion in mouse skin. (C) 2000 Wiley-Liss, Inc.",
keywords = "Carcinogenesis, Cytokine, Hyperplasia, Hypersensitivity, Promotion",
author = "Casale, {George P} and Zhao Cheng and Liu, {Jia Nuo} and Ercole Cavalieri and Maria Singhal",
year = "2000",
month = "2",
day = "23",
doi = "10.1002/(SICI)1098-2744(200002)27:2<125::AID-MC8>3.0.CO;2-0",
language = "English (US)",
volume = "27",
pages = "125--140",
journal = "Molecular Carcinogenesis",
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TY - JOUR

T1 - Profiles of cytokine mRNAs in the skin and lymph nodes of SENCAR mice treated epicutaneously with dibenzo[a,l]pyrene or dimethylbenz[a]anthracene reveal a direct correlation between carcinogen-induced contact hypersensitivity and epidermal hyperplasia

AU - Casale, George P

AU - Cheng, Zhao

AU - Liu, Jia Nuo

AU - Cavalieri, Ercole

AU - Singhal, Maria

PY - 2000/2/23

Y1 - 2000/2/23

N2 - The potent carcinogenicity of dibenzo[a,l]pyrene (DB[a,l]P) in mouse skin is associated with an inflammatory response and a striking epidermal hyperplasia. The mechanism of these tissue responses is not known. However, a recent study has shown DB[a,l]P to be a contact sensitizer. In view of the programmed expression of cytokines during induction of contact hypersensitivity (CHS) and elicitation of CHS reactions, we analyzed cytokine mRNAs in treated skin and draining lymph nodes of SENCAR mice, at selected times after a single, epicutaneous application of DB[a,l]P or dimethylbenz[a]anthracene (DMBA), a substantially weaker carcinogen and a weaker contact sensitizer than DB[a,l]P. Cytokine mRNAs were quantified by first-strand DNA synthesis with reverse transcriptase (RT) and DNA amplification by the polymerase chain reaction (PCR). Histopathology of treated skin was determined in the same experiments. Time-response profiles of interferon (IFN) γ and interleukin (IL) 2 in the DLN and IL1β, IL10, tumor necrosis factor (TNF) α, and IL4 mRNAs in the skin of mice treated with 200 nmol of DB[a,I]P were in remarkable agreement with established profiles in mice treated with conventional contact sensitizers, e.g., oxazolone or dinitrochlorobenzene. Strong upregulation of DLN IFNγ mRNA coupled with little change in IL 2 mRNA suggested a CD8+ T-cell response characteristic of CHS induction. Coordinate expression of epidermal IL1β, TNFα, and IL10 mRNAs, 24 h after DB[a,I]P treatment, was also characteristic of CHS induction. IL1β and IL10 are upregulated by allergens and not by chemical irritants. Time-response profiles of epidermal IL1β, TNFα, IL10, and IL4 mRNAs, 3-14 d after DB[a,l]P treatment, corresponded with expression of these cytokines during elicitation of CHS reactions. Epidermal IL4 is specifically upregulated during CHS reactions. Cytokine mRNA responses were dose-dependent (50, 100, and 200 nmol of DB[a,l]P) and markedly weaker in animals treated with 400 nmol of DMBA. Significantly, the intensity of epidermal hyperplasia correlated with the strength of the cytokine mRNA signals in DLN and skin. In conclusion, our data support carcinogen-specific CHS as a mechanism by which the very potent carcinogen DB[a,I]P induces epidermal hyperplasia, a requirement for tumor promotion in mouse skin. (C) 2000 Wiley-Liss, Inc.

AB - The potent carcinogenicity of dibenzo[a,l]pyrene (DB[a,l]P) in mouse skin is associated with an inflammatory response and a striking epidermal hyperplasia. The mechanism of these tissue responses is not known. However, a recent study has shown DB[a,l]P to be a contact sensitizer. In view of the programmed expression of cytokines during induction of contact hypersensitivity (CHS) and elicitation of CHS reactions, we analyzed cytokine mRNAs in treated skin and draining lymph nodes of SENCAR mice, at selected times after a single, epicutaneous application of DB[a,l]P or dimethylbenz[a]anthracene (DMBA), a substantially weaker carcinogen and a weaker contact sensitizer than DB[a,l]P. Cytokine mRNAs were quantified by first-strand DNA synthesis with reverse transcriptase (RT) and DNA amplification by the polymerase chain reaction (PCR). Histopathology of treated skin was determined in the same experiments. Time-response profiles of interferon (IFN) γ and interleukin (IL) 2 in the DLN and IL1β, IL10, tumor necrosis factor (TNF) α, and IL4 mRNAs in the skin of mice treated with 200 nmol of DB[a,I]P were in remarkable agreement with established profiles in mice treated with conventional contact sensitizers, e.g., oxazolone or dinitrochlorobenzene. Strong upregulation of DLN IFNγ mRNA coupled with little change in IL 2 mRNA suggested a CD8+ T-cell response characteristic of CHS induction. Coordinate expression of epidermal IL1β, TNFα, and IL10 mRNAs, 24 h after DB[a,I]P treatment, was also characteristic of CHS induction. IL1β and IL10 are upregulated by allergens and not by chemical irritants. Time-response profiles of epidermal IL1β, TNFα, IL10, and IL4 mRNAs, 3-14 d after DB[a,l]P treatment, corresponded with expression of these cytokines during elicitation of CHS reactions. Epidermal IL4 is specifically upregulated during CHS reactions. Cytokine mRNA responses were dose-dependent (50, 100, and 200 nmol of DB[a,l]P) and markedly weaker in animals treated with 400 nmol of DMBA. Significantly, the intensity of epidermal hyperplasia correlated with the strength of the cytokine mRNA signals in DLN and skin. In conclusion, our data support carcinogen-specific CHS as a mechanism by which the very potent carcinogen DB[a,I]P induces epidermal hyperplasia, a requirement for tumor promotion in mouse skin. (C) 2000 Wiley-Liss, Inc.

KW - Carcinogenesis

KW - Cytokine

KW - Hyperplasia

KW - Hypersensitivity

KW - Promotion

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U2 - 10.1002/(SICI)1098-2744(200002)27:2<125::AID-MC8>3.0.CO;2-0

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