Green tea phenol extracts reduce UVB-induced DNA damage in human cells via interleukin-12.

Green tea chemoprevention has been a focus of recent research, as a polyphenolic fraction from green tea (GTP) has been suggested to prevent UV radiation-induced skin cancer. Recently, it was demonstrated that GTP reduced the risk for skin cancer in a murine photocarcinogenesis model. This was accompanied by a reduction in UV-induced DNA damage. These effects appeared to be mediated via interleukin (IL)-12, which was previously shown to induce DNA repair. Therefore, we studied whether GTP induction of IL-12 and DNA repair could also be observed in human cells. KB cells and normal human keratinocytes were exposed to GTP 5 h before and after UVB. UVB-induced apoptosis was reduced in UVB-exposed cells treated with GTP. GTP induced the secretion of IL-12 in keratinocytes. The reduction in UV-induced cell death by GTP was almost completely reversed upon addition of an anti-IL-12-antibody, indicating that the reduction of UV-induced cell death by GTP is mediated via IL-12. The ability of IL-12 to reduce DNA damage and sunburn cells was confirmed in "human living skin equivalent" models. Hence the previously reported UV-protective effects of GTP appear to be mediated in human cells via IL-12, most likely through induction of DNA repair.

Norepinephrine modulates human dendritic cell activation by altering cytokine release.

Norepinephrine (NE) can modulate dendritic cell (DC) activation in animal models, but the response of human DC to NE and other response modifiers is as yet not completely understood. Here we report the effect of NE on the cytokine response of a mixed population of human DC cells to extracellular stimuli. These cells were obtained by differentiating human cord blood CD34+ precursor cells. NE inhibited the lipopolysaccharide (LPS)-stimulated production of interleukin (IL)-23, IL-12 p40, tumor necrosis factor (TNF)-alpha and IL-6 whereas the expression of IL-10 was not significantly affected. Thus, human cord blood-derived DC respond to NE in a manner similar to mouse Langerhans cells (LC). Furthermore, forskolin also inhibited the LPS-induced levels of TNF-alpha, IL-12 p40, IL-23 p19 and IL-6, supporting the hypothesis that the effects of NE are mediated by cAMP. Data from experiments using inhibitors of adrenergic receptors suggest that NE acts through beta-adrenergic receptors. As IL-23 promotes the differentiation of CD4+ T cells required for T(H)1-mediated immunity, we suggest that NE decreases the differentiation of CD4+ T cells needed for T(H)1-mediated contact hypersensitivity and that NE is a candidate regulator of human DC functions in the skin.

A synthetic superoxide dismutase/catalase mimetic (EUK-134) inhibits membrane-damage-induced activation of mitogen-activated protein kinase pathways and reduces p53 accumulation in ultraviolet B-exposed primary human keratinocytes.

Salen-manganese complexes exhibit powerful superoxide dismutase and catalase activity, with pharmacologic efficacy in several oxidative-stress-associated disease models. Ultraviolet (UV) B not only induces direct DNA damage, but also generates oxidative stress. EUK-134, a salen-manganese complex, might therefore confer a direct protection against UVB-induced oxidative stress and consequently alleviate UVB-damage-induced signal transduction. We investigated the effect of EUK-134 on the UVB-induced accumulation and stabilization of the p53 protein. p53 plays a central role in the UVB response, both as sensor of UVB damage and as a mediator of a protective response. Cells treated with EUK-134 before UVB irradiation showed a significantly lower accumulation of the p53 protein in a concentration-dependent fashion. Furthermore, EUK-134 severely reduced N-terminal phosphorylation of p53. The extracellular signal-regulated kinase ERK and the stress-activated kinases JNK and p38 have been implicated in the UVB-induced N-terminal phosphorylation and accumulation of p53. Pre-treatment with EUK-134 inhibited the UVB-induced activation of these mitogen-activated protein kinase (MAPK) pathways. We hypothesize that EUK-134, by direct protection of the membrane from UVB-induced oxidative damage, reduces oxidative stress induced MAPK signaling and consequently lowers the level of p53 induction. The protection conferred by EUK-134 resulted in a significant increase in cell survival following UVB irradiation.

Age-dependent response of energy metabolism of human skin to UVA exposure: an in vivo study by 31P nuclear magnetic resonance spectroscopy.

PURPOSE: The aim of our study was to evaluate the in vivo energy metabolism of human skin as a function of age, in conditions of rest and after a mild stress caused by a suberythemal UVA irradiation. METHODS: The kinetics of UVA-induced modifications in high-energy phosphorylated metabolites of young and old skins were non-invasively monitored over a period of 24 h using 31P nuclear magnetic resonance spectroscopy. In vivo 31P spectra were obtained on the ventral aspect of the wrist, using a NMR Imaging Spectrometer equipped with a double-tuned surface coil. Concentrations of phosphocreatine, inorganic phospate, adenosine tri-phosphate, phosphomono and phosphodiesters were calculated from the spectra and results were expressed as relative concentrations. A total of 20 subjects were enrolled in this study (n = 10 for the age group below 25 years and n = 10 for the age group above 55 years). A second experiment was then performed on 10 old subjects (mean age 60) who were treated on one wrist, twice a day for one month prior to UVA irradiation, with a product that contained active ingredients to restore barrier function and modulate the inflammatory response, the other wrist being an untreated control. RESULTS: Baseline levels of phosphorylated metabolites were similar in young and old skins. A suberythemal dose of UVA (6 J.cm-2) led to a significant decrease in the PCr/Pi ratio (index of energy status) and a significant increase in the PME/PDE ratio (index of cellular turnover rate of lipid-related metabolites) within 1 h. The observed variations were transient and the recovery was complete at T + 24 h post-UVA, although recovery was significantly slower in the older group. The disturbances were significantly reduced after treatment of the older skin with a formula that restored barrier function of the stratum corneum and modulated the inflammatory response. CONCLUSION: (i) baseline levels of energy metabolites in skin do not seem to vary with age; (ii) low dose UVA irradiation induces a rapid response in the energy metabolism of the skin; (iii) the kinetics of the response and recovery after an aggression by UVA suggest that older skin has significantly less energy rebound after a stress situation than younger skin; (iv) the energy reserve in older skin can be protected efficiently against UVA-induced stress by restoring barrier function and modulating the inflammatory response.