The production of immunomodulatory cytokines such as interleukin-10 (IL-10) from keratinocytes and other target cells in the skin plays a crucial role in UV-induced immunosuppression. Substantial evidence supports an association between DNA damage and immunomodulation. It is also known that small DNA fragments such as thymidine dinucleotides (pTpT) can mimic several UV-induced effects, including inhibition of the induction phase of the contact hypersensitivity response and up-regulation of tumor necrosis factor-alpha (TNF-alpha). To determine whether pTpT also induces IL-10 secretion by keratinocytes, and by inference whether IL-10 production after UV irradiation is a response to DNA damage, we compared the effects of pTpT with those of UV irradiation on primary human keratinocyte cultures. Subconfluent cultures of primary human keratinocytes were treated either with 10 micro M or 100 micro M pTpT or diluent alone, or exposed to solar-simulated light (100 J/m2 of UVB) or sham irradiated. An increase in IL-10 mRNA expression was observed 6-24 h after irradiation and at 24-48 h after treatment with pTpT. Detection of secreted IL-10 protein coincided with up-regulation of IL-10 gene expression at 48 and 72 h as determined by ELISA. Conditioned media from human keratinocytes treated with pTpT, like that from irradiated cells, significantly inhibited lymphocyte proliferation in the allogeneic-mixed lymphocyte reaction (MLR) assay. To determine whether pTpT mimics the suppressive influence of UVB on the elicitation phase of contact hypersensitivity, believed to result largely from IL-10 release, we compared the effects of topical application of pTpT with those of UVB irradiation on C57Bl/6 mice sensitized with dinitrofluorobenzene. Sensitized mice treated with pTpT or UVB irradiation showed markedly suppressed elicitation of ear-swelling responses. These results demonstrate that increased keratinocyte IL-10 mRNA level and IL-10 protein release are among the effects of pTpT and support the hypothesis that pTpT treatment triggers many of the biologic effects of UV irradiation by mimicking UV-induced DNA damage. Finally, regardless of mechanism, the data suggest that topical treatment with pTpT may provide a novel means of suppressing contact hypersensitivity or other lymphocyte-mediated reactions in skin.
The management of pediatric melanoma (PM) has largely been extrapolated from adult data. However, the behavior of PM appears to differ from its adult counterparts. Therefore, an international PM registry was created and analyzed.
Ultraviolet radiation is an important etiologic factor in skin cancer and a better understanding of how solar stimulated light (SSL) affects signal transduction pathways in human skin which is needed in further understanding activated networks that could be targeted for skin cancer prevention. We utilized Reverse Phase Protein Microarray Analysis (RPPA), a powerful technology that allows for broad-scale and quantitative measurement of the activation/phosphorylation state of hundreds of key signaling proteins and protein pathways in sun-protected skin after an acute dose of two minimal erythema dose (MED) of SSL. RPPA analysis was used to map the altered cell signaling networks resulting from acute doses of solar simulated radiation (SSL). To that end, we exposed sun-protected skin in volunteers to acute doses of two MED of SSL and collected biopsies pre-SSL and post-SSL irradiation. Frozen biopsies were subjected to laser capture microdissection (LCM) and then assessed by RPPA. The activation/phosphorylation or total levels of 128 key signaling proteins and drug targets were selected for statistical analysis. Coordinate network-based analysis was performed on specific signaling pathways that included the PI3k/Akt/mTOR and Ras/Raf/MEK/ERK pathways. Overall, we found early and sustained activation of the PI3K-AKT-mTOR and MAPK pathways. Cell death and apoptosis-related proteins were activated at 5 and 24 h. Ultimately, expression profile patterns of phosphorylated proteins in the epidermal growth factor receptor (EGFR), AKT, mTOR, and other relevant pathways may be used to determine pharmacodynamic activity of new and selective topical chemoprevention agents administered in a test area exposed to SSL to determine drug-induced attenuation or reversal of skin carcinogenesis pathways.
Sézary syndrome is one of the most common forms of cutaneous T cell lymphoma (CTCL). It is characterized by skin infiltration of malignant T cells. We examined interleukin-16, a potent T cell chemoattractant and cell-cycle regulator, as a prospective marker of disease onset and stage.
Experimental and observational studies continue to demonstrate conflicting results regarding the role of several commonly used drugs as melanoma chemopreventive agents. This case-control study was designed to assess the associations between cutaneous melanoma (CM) and exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and statins in current users. A total of 400 CM and 600 eligible age- and gender-matched community-based controls were prospectively recruited and interviewed. We assessed participants' demographic characteristics, CM risk factors, and current and previous use of medications. Multivariable conditional logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between NSAIDs and/or aspirin (ASA), statin exposure, and CM risk. Half of the subjects were men (mean age 60 years). After adjusting for confounders, use of any type of NSAIDs for more than 5 years significantly reduced the risk of melanoma development compared with the low-exposure group (adjusted OR=0.57; 95% CI=0.43-0.77). Subgroup analyses showed that the observed risk reduction was primarily driven by continuous ASA use (>5 years adjusted OR=0.51, 95% CI=0.35-0.75). No significant protective effect was observed with statin exposure (OR=0.97, 95% CI=0.73-1.29). Long-term use of NSAIDs, especially ASA, is associated with a significantly decreased risk of CM development. Clinical intervention studies are warranted to further investigate the potential role of ASA and other NSAIDs as chemopreventive agents for CM.
