Adaptive antioxidant response protects dermal fibroblasts from UVA-induced phototoxicity.

In response to the attack of reactive oxygen species (ROS) produced upon UV irradiation, the skin has developed a complex antioxidant defense system. Here we report that, in addition to the previously published induction of manganese superoxide dismutase (MnSOD) activity, single and, to a higher extent, repetitive low-dose UVA irradiation also leads to a substantial upregulation of glutathione peroxidase (GPx) activity. This concomitant adaptive response of two antioxidant enzymes acting in the same detoxification pathway coincided with the protection from high-UVA-dose-induced cytotoxicity conferred by low-dose UVA preirradiation. Whereas an interval of 24 h did not, an interval of 12 h did lead to the induction of MnSOD activity and, under selenium-supplemented conditions, of GPx activity as well, conferring definite cellular protection from UVA-induced phototoxicity. Moreover, under selenium-deficient conditions, which abrogate the UVA-mediated induction of GPx activity, adaptive protection against the cytotoxic effects of high UVA doses was significantly lower compared with selenium supplementation. Isolated 4.6-fold overexpression of MnSOD activity in stably transfected fibroblasts led to specific resistance from UVA-mediated phototoxicity under selenium-deficient conditions. Collectively, these data indicate that the concomitant induction of MnSOD and GPx activity is related to the optimal adaptive protection from photooxidative damage. This adaptive antioxidant protection clearly depends on the irradiation interval and a sufficient selenium concentration, findings that may have important implications for the improvement of photoprotective and phototherapeutic strategies in medicine.

Discrete papular mucinosis-a rare subtype of lichen myxoedematosus.

Lichen myxoedematosus is an uncommon and distinct disease entity characterized by cutaneous mucin deposition which, depending on the distribution and overall skin involvement, can be classified into several subtypes. We now describe the case of a discrete papular type of lichen myxoedematosus in a patient without any conspicious laboratory findings including normal thyroid function and the absence of any abnormal immunglobulins.

Treatment of pruritus by capsaicin in a patient with pityriasis rubra pilaris receiving RE-PUVA therapy.

Pityriasis rubra pilaris (PRP) is characterized by redness of the skin, scaling and a variable degree of pruritus. We present a patient with extremely itchy PRP successfully treated with oral retinoids and photochemotherapy with 8-methoxypsoralene (RE-PUVA) and topical capsaicin. The PRP-related pruritus which clearly preceded photochemotherapy and for which no other cause was apparent was relieved with capsaicin. This single case report provides evidence that topical capsaicin may be a useful therapeutic option in treating PRP-associated pruritus where antihistamines have been unsuccessful.

Stable overexpression of manganese superoxide dismutase in mitochondria identifies hydrogen peroxide as a major oxidant in the AP-1-mediated induction of matrix-degrading metalloprotease-1.

Reactive oxygen species (ROS) are important second messengers for the induction of several genes in a variety of physiological and pathological conditions. Here we addressed the question of whether isolated, unbalanced overexpression of the antioxidant enzyme manganese superoxide dismutase (Mn-SOD) may modulate signal transduction cascades, finally leading to connective tissue degradation, a hallmark in carcinogenesis and aging. Therefore, we generated stably Mn-SOD-overexpressing fibroblasts with an up to 4. 6-fold increase in Mn-SOD activity. The Mn-SOD-overexpressing cells revealed specific resistance to the superoxide anion (O-(2))-generating agent paraquat, whereas no resistance to UVA-generated oxidative stress was found. Treatment of the Mn-SOD-overexpressing cells with various ROS-generating systems resulted (due to the enhanced dismutation of superoxide anion to hydrogen peroxide) in an up to 9.5-fold increase in matrix-degrading metalloprotease-1 (MMP-1) mRNA levels. A similar increase in MMP-1 mRNA was also seen when the intracellular H(2)O(2) concentration was increased by the inhibition of different H(2)O(2)-detoxifying pathways. Furthermore, prooxidant conditions led to a strong induction of c-jun and c-fos mRNA levels resulting in a 4-fold higher transactivation of the transcription factor AP-1 in the Mn-SOD-overexpressing cells. Collectively, we have found that enhanced Mn-SOD activity, via an unbalanced H(2)O(2) overproduction and detoxification, induces MMP-1 mRNA levels, and this effect is at least partly mediated by the DNA recognition sequence AP-1.

Adaptive antioxidant response of manganese-superoxide dismutase following repetitive UVA irradiation.

In response to the attack of reactive oxygen species, the skin has developed a complex antioxidant defense system including among others the manganese-superoxide dismutase (MnSOD). MnSOD dismutates the superoxide anion (O2*-) derived from the reduction of molecular oxygen to hydrogen peroxide (H2O2), which is detoxified by glutathione peroxidase to water and molecular oxygen. We have addressed the question whether MnSOD is inducible upon UVA irradiation and whether repetitive UV exposure, as practiced for the light-hardening during phototherapy of various photodermatoses, can even enhance the adaptive antioxidant response. Single exposure of four different strains of fibroblasts to UVA irradiation resulted in a dose- and time-dependent increase in specific MnSOD mRNA levels. Interestingly, repetitive UVA exposure at days 1, 2, and 3 at a dose rate of 200 kJ per m2 resulted in a 5-fold induction of specific MnSOD mRNA levels following the third UVA exposure. Similar results were obtained for MnSOD activity. This adaptive response in terms of upregulation of the antioxidant enzyme MnSOD correlates with the protection against high UV doses, if cells were preexposed to sublethal UV doses. Importantly, MnSOD substantially differed between the tested individuals in both mRNA and activity levels. Taken together, we here provide evidence for the increasing induction of MnSOD upon repetitive UVA irradiation that may contribute to the effective adaptive UVA response of the skin during light hardening in phototherapy. Interindividual differences in the inducibility of MnSOD might account for differences in the susceptibility to develop photodermatologic disorders related to photosensitivity, photoaging, and skin cancer. The molecular basis for interindividual differences in the inducibility of antioxidant enzymes remains to be elucidated.

UVA-induced autocrine stimulation of fibroblast-derived collagenase/MMP-1 by interrelated loops of interleukin-1 and interleukin-6.

Previous work has shown that fibroblast-derived collagenase/matrix-metalloproteinase-1 (MMP-1), responsible for the breakdown of dermal interstitial collagen, was dose-dependently induced in vitro and in vivo by UVA irradiation and this induction was at least partly mediated by interleukin-6 (IL-6). We here provide evidence that UVA-induced IL-1 alpha and IL-1 beta play a central role in the induction of the synthesis both of IL-6 and collagenase/MMP-1. In contrast to the late increase of IL-1 alpha and IL-1 beta mRNA levels at 6 h postirradiation, bioactivity of IL-1 is already detectable at 1 h postirradiation. This early peak of IL-1 bioactivity appears to be responsible for the induction of IL-6 synthesis and together with IL-6 lead to an increase of the steady-state mRNA level of collagenase/MMP-1 as deduced from studies using IL-1 alpha and IL-1 beta antisense oligonucleotides or neutralizing antibodies against IL-1 alpha and IL-1 beta. Besides the early posttranslationally controlled release of intracellular IL-1, a latter pretranslationally controlled synthesis and release of IL-1 perpetuates the UV response. From these data we suggest a UV-induced cytokine network consisting of IL-1 alpha, IL-1 beta and IL-6, which via interrelated autocrine loops induce collagenase/MMP-1 and thus may contribute to the loss of interstitial collagen in cutaneous photoaging.