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.

Abstract

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.

• Authors: Som D Sharma, Syed M Meeran, Nandan Katiyar, George B Tisdale, Nabiha Yusuf, Hui Xu, Craig A Elmets, Santosh K Katiyar
• Journal: Carcinogenesis (Carcinogenesis) Vol. 30 Issue 11 Pg. 1970-7 (Nov 2009) ISSN: 1460-2180 [Electronic] England
• PMID: 19759192 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carcinogens
• Cytokines
• Interleukin-12 Subunit p40
• Interleukin-6
• Proliferating Cell Nuclear Antigen
• Tumor Necrosis Factor-alpha
• Cyclin D1
• 9,10-Dimethyl-1,2-benzanthracene
• Cyclooxygenase 2
• Tetradecanoylphorbol Acetate

Topics

• 9,10-Dimethyl-1,2-benzanthracene (toxicity)
• Animals
• Carcinogens (toxicity)
• Cyclin D1 (biosynthesis)
• Cyclooxygenase 2 (biosynthesis)
• Cytokines (biosynthesis)
• Female
• Inflammation (genetics, immunology)
• Interleukin-12 Subunit p40 (deficiency, genetics)
• Interleukin-6 (biosynthesis)
• Mice
• Mice, Knockout
• Proliferating Cell Nuclear Antigen (biosynthesis)
• Skin Neoplasms (chemically induced, genetics, immunology, pathology)
• Tetradecanoylphorbol Acetate (toxicity)
• Tumor Necrosis Factor-alpha (biosynthesis)