IL-12: Cell Protection from UVB

IL-12 is a disulfide-linked heterodimeric glycoprotein that is essentially integrated in the immune system. The pleiotropic functions of IL-12 on T cells and NK cells include stimulation of cytotoxic activity, proliferation, and promotion of Th1 development.^1,2 Schwarz et al. illustrate a function beyond the immune system; IL-12 inhibits UV-induced apoptosis and initiates DNA repair in UV-damaged keratinocytes, which ultimately protect the cells from malignancy.³

Skin exposure to UVB (290-320 nm) radiation can cause two forms of DNA damage: cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts. These types of mutations result in DNA structure deformities and hence altered replication efficiencies.⁴ Depending on the severity of the DNA damage following UVB-exposure, keratinocytes could progress to either apoptosis^5-8 or DNA repair^7,9 pathways. If the DNA damage is irreparable, the keratinocyte cell cycle is arrested, and it is transformed into a sunburn cell (SC), an initial morphological indicator of epidermal cell apoptosis.^6,7 Alternatively, the keratinocyte could suspend its cell cycle and begin DNA repair.^8,9 Prevention of apoptosis and pyrimidine dimer repair can be accomplished by the highly conserved DNA repair system, nucleotide excision repair (NER). This process employs an array of excinucleases, which intricately detect a DNA lesion, remove the adduct, and reinstate the correct nucleotides.^10,11 Apoptosis and DNA repair are both clearly adaptive, as they allow the organism either to discard genomic instability or to maintain and preserve the cell, respectively. However, the dysregulation of either process could result in cancer proneness.^{6, 8, 12-15}

Figure 1. UVB-exposure can lead to DNA damage. Depending on the severity, keratinocytes progress to either DNA repair or apoptotic pathways. IL-12 treatment leads to a significant upregulation of nucleotide excision repair (NER) genes and a bias toward DNA repair and cell survival.

Schwartz et al. theorized cytokine-stimulated cell protection and demonstrated IL-12 suppression of apoptosis and promotion of NER in vitro and in vivo.³ These authors incubated epithelial cells and keratinocytes in IL-12 prior to UVB exposure in vitro and observed an increase of cell survival and a decrease in CPDs and apoptotic cells. These data were confirmed in vivo as immunohistochemical analysis of IL-12-treated, UVB-exposed mice exhibited considerably fewer CPDs and SCs. To further examine the association of IL-12 to UVB-induced NER, these authors analyzed NER gene expression. IL-12-treated, UVB-exposed cells not only exhibited a decisive upregulation of NER genes but also enhanced overall gene expression. Next, Schwartz et al. utilized an Xpa knockout mouse model, which presents characteristics identical to the human autosomal recessive disorder xermoderma pigmentosum (XP).³ Individuals afflicted with XP possess an inoperative NER system resulting in hypersensitivity of the skin to sunlight and increased susceptibility to skin cancer.^14,15 Xpa knockout mice display a marked increase in the quantity of apoptotic epidermal cells upon UVB exposure compared to wild-type controls.⁷ Expectedly, IL-12 treatment had no effect on UVB-exposed Xpa knockout mice. Further, Schwartz et al. tested UVB-exposed peripheral blood mononuclear cells from an XP patient and a healthy control with and without IL-12 treatment and observed a reduction in CPDs in IL-12-treated healthy control cells and no effect on XP cells.³ Taken together, these results suggest that the DNA damage caused by UVB-exposure, which could lead to skin cancer, may be warded off by the NER-promoting effects of IL-12, implicating it as a potential therapeutic drug.

References

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