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.
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) gamma and interleukin (IL) 2 in the DLN and IL1beta, IL10, tumor necrosis factor (TNF) alpha, and IL4 mRNAs in the skin of mice treated with 200 nmol of DB[a,l]P were in remarkable agreement with established profiles in mice treated with conventional contact sensitizers, e.g., oxazolone or dinitrochlorobenzene. Strong upregulation of DLN IFNgamma mRNA coupled with little change in IL 2 mRNA suggested a CD8(+) T-cell response characteristic of CHS induction. Coordinate expression of epidermal IL1beta, TNFalpha, and IL10 mRNAs, 24 h after DB[a,l]P treatment, was also characteristic of CHS induction. IL1beta and IL10 are upregulated by allergens and not by chemical irritants. Time-response profiles of epidermal IL1beta, TNFalpha, 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,l]P induces epidermal hyperplasia, a requirement for tumor promotion in mouse skin.
Casale
G P
GP
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68198-6805, USA. gpcasale@UNMC.edu
Cheng
Z
Z
Liu
J n
Jn
Cavalieri
E L
EL
Singhal
M
M
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000276:immunology / Q000494:pharmacology*; D000279:Administration, Cutaneous; D000818:Animals; D001580:Benzopyrenes / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003877:Dermatitis, Contact / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000187:drug effects / Q000473:pathology*; D005260:Female; D006965:Hyperplasia; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018632:Mice, Inbred SENCAR; D012333:RNA, Messenger / Q000096:biosynthesis*; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D001580:Benzopyrenes; D002273:Carcinogens; D016207:Cytokines; D012333:RNA, Messenger; D015127:9,10-Dimethyl-1,2-benzanthracene; C041517:dibenzo(a,l)pyrene