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-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) E(2), proliferating cell nuclear antigen, cyclin D1 and the proinflammatory cytokines (tumor necrosis factor-alpha, IL-1beta 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 PGE(2) 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.
Sharma
Som D
SD
Department of Dermatology, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall 557, Birmingham, AL 35294, USA.
Meeran
Syed M
SM
Katiyar
Nandan
N
Tisdale
George B
GB
Yusuf
Nabiha
N
Xu
Hui
H
Elmets
Craig A
CA
Katiyar
Santosh K
SK
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D019938:Cyclin D1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000172:deficiency / Q000235:genetics*; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D002273:Carcinogens; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D018809:Proliferating Cell Nuclear Antigen; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D015127:9,10-Dimethyl-1,2-benzanthracene; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate