Christian Jantschitsch

Guidelines on the use of extracorporeal photopheresis

After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease.

Silencing the hsp25 Gene Eliminates Migration Capability of the Highly Metastatic Murine 4T1 Breast Adenocarcinoma Cell

The 25-kDa heat shock protein (Hsp25) is associated with various malignancies and is expressed at high levels in biopsies as well as circulating in the serum of breast cancer patients. In this study, we used RNA interference technology to silence the hsp25 gene in 4T1 breast adenocarcinoma cells, known as a poorly immunogenic, highly metastatic cell line. We demonstrate that transfection of 4T1 cells with short interference RNA-Hsp25 dramatically inhibits proliferation as compared with control transfected cells. In addition, we show that 4T1 cells transfected with short interference RNA-Hsp25 abrogates tumor migration potential by a mechanism that is in part due to the repression of matrix metalloproteinase 9 expression and a concomitant upregulation of its antagonist, tissue inhibitor metalloproteinase 1. Taken together, these findings provide a model system for the study of metastatic potential of tumors and are suggestive of an earlier unrecognized role for Hsp25 in tumor migration.

Infrared Radiation Confers Resistance to UV-Induced Apoptosis Via Reduction of DNA Damage and Upregulation of Antiapoptotic Proteins

Infrared radiation (IR) is increasingly used for wellness purposes. In this setting, it is frequently combined with UV radiation, primarily for tanning purposes. The impact of IR on UV-induced carcinogenesis is still unclear. Hence, we investigated the interplay between IR and UV with regard to UV-induced apoptosis. Pretreatment of murine keratinocytes with IR before UV reduced the apoptotic rate. Likewise, the number of sunburn cells was reduced in mice preexposed to IR before UV. The amounts of UV-induced DNA damage were reduced by IR both in vitro and in vivo. This was not observed in DNA repair-deficient mice. UV-induced downregulation of the antiapoptotic proteins FLIP(L) and BCL-X(L) was prevented by IR, whereas the proapoptotic protein BAX was downregulated. These data indicate that IR reduces UV-induced apoptosis that may be mediated by several pathways, including reduction of DNA damage and induction of antiapoptotic proteins. The antiapoptotic effects of IR may support the survival of UV-damaged cells and thus carcinogenesis. As, however, IR reduces UV-induced DNA damage, the balance between these two effects may be important. Thus, in vivo carcinogenesis studies are required to define the role of IR and its interaction with UV in photocarcinogenesis.

Hydrogen peroxide mediates EGCG-induced antioxidant protection in human keratinocytes

The beneficial health effects of (-)-epigallocatechin-3-gallate (EGCG), the main catechin of green tea, have been attributed to complex interactions with a focus on antioxidative properties. Susceptibility to autoxidation and production of cytotoxic reactive oxygen species (ROS), mostly H(2)O(2), have been suggested to occur in vitro but also in vivo. In this study, we address whether autoxidation-derived H(2)O(2) may be involved in the cytoprotective effects of EGCG. To that end we investigated keratinocyte-derived HaCat and HL-60 promyelocytic leukemia cells with significantly different sensitivities to H(2)O(2) (IC(50) 117.3 versus 58.3 μM, respectively) and EGCG (134.1 versus 84.1 μM). HaCat cells significantly resisted cytotoxicity and DNA damage based on enhanced H(2)O(2) clearance, improved DNA repair, and reduced intracellular ROS generation. Cumulative versus bolus EGCG and H(2)O(2) treatment and H(2)O(2) pretreatment before subsequent high-dose EGCG and vice versa significantly reduced DNA damage and cytotoxicity in HaCat cells only. Addition of catalase abolished the protective activities of low-dose H(2)O(2) and EGCG. In summary, our data suggest that autoxidative generation of low-dose H(2)O(2) is a significant player in the cell-type-specific cytoprotection mediated by EGCG and support the hypothesis that regular green tea consumption can contribute as a pro-oxidant to increased resistance against high-dose oxidative stressors.

Heat shock and UV-B-induced DNA damage and mutagenesis in skin

There is evidence that heat pre-treatment protects cultured human keratinocytes and normal murine and human skin from ultraviolet (UV) radiation-induced cell death. It has been suggested that heat-shock proteins (hsps), particularly hsp72, are involved in this effect. Hsps are expressed in response to various types of stress, such as UV radiation. Whether heat shock interferes with the repair of UV-induced DNA damage and whether this can be regarded as a protective mechanism is poorly understood and needs further experimental investigation. This review gives an overview of the current state of research in the area.

IL-23 Antagonizes UVR-Induced Immunosuppression through Two Mechanisms: Reduction of UVR-Induced DNA Damage and Inhibition of UVR-Induced Regulatory T Cells

UVR-induced DNA damage is the major molecular trigger for photoimmunosuppression. The cytokines IL-12 and IL-18, which reduce DNA damage through induction of DNA repair, prevent UVR-induced immunosuppression. IL-12 but not IL-18 can break established UVR-induced immunotolerance through modulation of regulatory T cells (Treg). IL-23 is related to IL-12 by sharing the p40 subunit. Hence, we studied whether (i) IL-23 can reduce UVR-induced DNA damage and thereby prevent UVR-induced immunosuppression and (ii) can suppress the activity of Treg. IL-23 reduced UVR-induced apoptosis of keratinocytes. Injection of IL-23 into UVR-exposed mice diminished the number of apoptotic keratinocytes and the amounts of DNA damage. This was not observed in DNA repair-deficient xeroderma pigmentosum A knock-out mice (Xpa-KO mice), implying that IL-23 reduces DNA damage through induction of DNA repair. Similarly, UVR-mediated suppression of the induction of contact hypersensitivity was prevented on injection of IL-23 in wild-type but not in Xpa-KO mice. However, in contrast to IL-18, IL-23 inhibited the activity of UVR-induced Treg as demonstrated by adoptive transfer experiments. Our data indicate that IL-23, similar to IL-12 and IL-18, can reduce UVR-induced DNA damage and thereby prevent immunosuppression. IL-23 shares with IL-12 the still unique capacity to restore suppressed immune responses because of its effect on Treg.

Infrared radiation does not enhance the frequency of ultraviolet radiation-induced skin tumors, but their growth behaviour in mice

Abstract:  There is increasing concern about the interaction between infrared radiation (IR) and ultraviolet radiation (UVR) with regard to carcinogenesis because prolonged solar exposure is associated with an increased cumulative load not only of UVR but also of IR. We recently demonstrated that IR‐pretreatment reduces UVR‐induced apoptosis. As this might support the survival of UVR‐damaged cells and thus carcinogenesis, we performed an in vivo photocarcinogenesis study. One group of mice were treated with IR prior to each UVR exposure; additional groups were treated with IR or UVR alone. IR alone did not induce skin cancer. UVR‐induced tumor formation was not enhanced in IR‐pretreated mice, but, in contrast, seemed to occur with delay. This correlated with a reduction of p53 mutated clones in the skin. However, once developed, tumors in IR‐pretreated mice grew faster which was confirmed by their enhanced Ki‐67 expression. The enhanced aggressiveness of tumors derived from IR‐pretreated mice was associated with a higher prevalence of sarcomas than epithelial tumors. Hence, the impact of IR on UVR‐induced carcinogenesis has to be interpreted with caution. Although IR may delay the onset of UVR‐induced tumors, it might contribute to a worse outcome by shifting these tumors into a more aggressive phenotype.

IL-12 and IL-23 Affect Photocarcinogenesis Differently

Induction of DNA damage by UVR is the key event in photocarcinogenesis. IL-12 and IL-23 are related heterodimeric cytokines consisting of a common p40 unit and a p35/IL-12 and a p19/IL-23 chain, respectively. Both exert immunomodulatory activities but are also found to reduce UVR-induced DNA damage presumably via induction of DNA repair. As both cytokines are also produced in the skin, they may mitigate the risk to develop UVR-induced skin cancer. This appears to be the case as mice lacking p40 were previously shown to be at higher risk for skin tumors upon chronic UVR exposure. As these mice express neither IL-12 nor IL-23, the individual effects of IL-12 or IL-23 could not be evaluated. Thus, mice lacking p35 (IL-12p35-/-) or p19 (IL-23p19-/-) were subjected to chronic UVR exposure. The Kaplan-Meier analysis indicated a significantly increased probability of tumor development in IL-23p19-/- but not in IL-12p35-/- mice. Taken together, in our model, loss of IL-23, but not of IL-12, enhances development of UVR-induced skin tumors, indicating that IL-23 but not IL-12 may counteract photocarcinogenesis. This may have impact on the development of future strategies utilizing antibodies against IL-12 and IL-23, respectively, for the treatment of inflammatory dermatoses.

Severe scombroid fish poisoning: An underrecognized dermatologic emergency

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Infrared A radiation promotes survival of human melanocytes carrying ultraviolet radiation-induced DNA damage.

The link between solar radiation and melanoma is still elusive. Although infrared radiation (IR) accounts for over 50% of terrestrial solar energy, its influence on human skin is not well explored. There is increasing evidence that IR influences the expression patterns of several molecules independently of heat. A previous in vivo study revealed that pretreatment with IR might promote the development of UVR‐induced non‐epithelial skin cancer and possibly of melanoma in mice. To expand on this, the aim of the present study was to evaluate the impact of IR on UVR‐induced apoptosis and DNA repair in normal human epidermal melanocytes. The balance between these two effects is a key factor of malignant transformation. Human melanocytes were exposed to physiologic doses of IR and UVR. Compared to cells irradiated with UVR only, simultaneous exposure to IR significantly reduced the apoptotic rate. However, IR did not influence the repair of UVR‐induced DNA damage. IR partly reversed the pro‐apoptotic effects of UVR via modification of the expression and activity of proteins mainly of the extrinsic apoptotic pathway. In conclusion, IR enhances the survival of melanocytes carrying UVR‐induced DNA damage and thereby might contribute to melanomagenesis.