Profiles of cytokine mRNAs in the skin and lymph nodes of SENCAR mice treated epicutaneously with dibenzo[a,I]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 i s associated with an inflammatory response and a striking epidermal hyperpl asia. The mechanism of these tissue responses is not known. However, a rece nt study has shown DB[a,l]P to be a contact sensitizer. In view of the prog rammed expression of cytokines during induction of contact hypersensitivity (CHS) and elicitation of CHS reactions, we analyzed cytokine mRNAs in trea ted 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 t han DB[a,l]P. Cytokine mRNAs were quantified by first-strand DNA synthesis with reverse transcriptase (RT) and DNA amplification by the polymerase cha in reaction (PCR). Histopathology of treated skin was determined in the sam e experiments. Time-response profiles of interferon (IFN)gamma and interleu kin (IL)2 in the DLN and IL1 beta, IL10, tumor necrosis factor (TNF) alpha, and IL4 mRNAs in the skin of mice treated with 200 nmol of DB[a,l]P were i n remarkable agreement with established profiles in mice treated with conve ntional contact sensitizers, e.g., oxazolone or dinitrochlorobenzene. Stron g upregulation of DLN IFN gamma mRNA coupled with little change in IL 2 mRN A suggested a CD8(+) T-cell response characteristic of CHS induction. Coord inate expression of epidermal IL1 beta, TNF alpha, and IL10 mRNAs, 24 h aft er DB[a,l]P treatment, was also characteristic of CHS induction. IL1 beta a nd IL10 are upregulated by allergens and not by chemical irritants. Time-re sponse profiles of epidermal IL1 beta, TNF alpha, 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 upregul ated 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 co rrelated with the strength of the cytokine mRNA signals in DLN and skin. In conclusion, our data support carcinogen-specific CHS as a mechanism by whi ch the very potent carcinogen DB[a,l]P induces epidermal hyperplasia, a req uirement for tumor promotion in mouse skin. (C) 2000 Wiley-Liss, Inc.