IL-12 deficiency suppresses 12-O-tetradecanoylphorbol-13-acetate-induced skin tumor development in 7,12-dimethylbenz(a)anthracene-initiated mouse skin through inhibition of inflammation

Interleukin (IL)-12 deficiency exacerbates tumorigenesis in ultraviolet (UV) radiation-induced skin. Here, we assessed the effects of IL-12 deficiency on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mouse skin. Using this two-s...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2009-11, Vol.30 (11), p.1970-1977
Main Authors: Sharma, Som D., Meeran, Syed M., Katiyar, Nandan, Tisdale, George B., Yusuf, Nabiha, Xu, Hui, Elmets, Craig A., Katiyar, Santosh K.
Format: Article
Language:English
Subjects:
9,10-Dimethyl-1,2-benzanthracene - toxicity
Animals
Carcinogenesis
Carcinogens - toxicity
Cyclin D1 - biosynthesis
Cyclooxygenase 2 - biosynthesis
Cytokines - biosynthesis
Female
Inflammation - genetics
Inflammation - immunology
Interleukin-12 Subunit p40 - deficiency
Interleukin-12 Subunit p40 - genetics
Interleukin-6 - biosynthesis
Mice
Mice, Knockout
Proliferating Cell Nuclear Antigen - biosynthesis
Skin Neoplasms - chemically induced
Skin Neoplasms - genetics
Skin Neoplasms - immunology
Skin Neoplasms - pathology
Tetradecanoylphorbol Acetate - toxicity
Tumor Necrosis Factor-alpha - biosynthesis
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Summary:Interleukin (IL)-12 deficiency exacerbates tumorigenesis in ultraviolet (UV) radiation-induced skin. Here, we assessed the effects of IL-12 deficiency on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mouse skin. Using this two-stage chemical carcinogenesis protocol, we found that the development of DMBA/TPA-induced skin tumors was diminished in IL-12p40-knockout mice than in their wild-type counterparts. At the termination of the experiment (at 24 weeks), the skin tumor incidence and tumor multiplicity were significantly lower (P < 0.005) in interleukin-12-knockout (IL-12 KO) mice than in their wild-type counterparts, as was the malignant transformation of DMBA/TPA-induced papillomas to carcinomas (P < 0.01). Analysis of samples collected at the termination of the experiments for biomarkers of inflammation by immunohistochemical analysis, western blotting, enzyme-linked immunosorbent assay and real-time polymerase chain reaction revealed significantly lower levels of cyclooxygenase-2 (COX-2), prostaglandin (PG) E2, proliferating cell nuclear antigen, cyclin D1 and the proinflammatory cytokines (tumor necrosis factor-α, IL-1β and IL-6) in the DMBA/TPA-treated tumors and tumor-uninvolved skin of IL-12 KO mice than the skin and tumors of DMBA/TPA-treated wild-type mice. Analysis of the skin 6 h after TPA treatment showed that the TPA-induced promotion of skin edema, inflammatory leukocyte infiltration, COX-2 expression and PGE2 production was significantly lower in the skin of the IL-12-KO mice than their wild-type counterparts. These results indicate that DMBA/TPA-induced skin tumor development differs from UVB-induced skin tumor development in that endogenous IL-12 acts to inhibit UVB-induced skin tumor development and malignant progression of the skin tumors to carcinoma. In the case of DMBA/TPA-induced skin tumor development, the endogenous IL-12 modulates the tumor promoter stimulation of inflammatory responses.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgp228