Manganese Superoxide Dismutase Is Induced by Endoplasmic Reticulum Stress through IRE1-Mediated Nuclear Factor (NF)-κB and AP-1 Activation

Manganese superoxide dismutase (MnSOD) is an antioxidative enzyme that scavenges superoxide radicals and is localized in the mitochondrial matrix. MnSOD is induced by a variety of stimuli through nuclear factor (NF)-κB and AP-1 activation. We investigated the expression of MnSOD in HeLa cells exposed to various agents interfering with endoplasmic reticulum (ER) functions. All agents caused an increase in the mRNA and protein levels of MnSOD. Although ER stress-responsive genes often are up-regulated by ATF6, IRE1 and XBP1, which are ER stress-related transcription factors/transducers, the overexpression of neither molecule affected the levels of MnSOD mRNA and protein. Furthermore, we showed that ER stress reagents induced NF-κB and AP-1 activation that were inhibited by a dominant-negative IRE1 mutant. We finally demonstrated that ER stress-induced MnSOD expression was reduced by the IRE1 mutant. These results suggest that the MnSOD expression is controlled by ER stress through IRE1-mediated NF-κB and AP-1 activation.This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technalogy, Japan

Melatonin attenuates the detrimental effects of UVA

Background People living in Mediterranean countries are mostly exposed to solar ultraviolet (UV) radiation that damages skin and results in photoaging which involves activation of epidermal growth factor receptor (EGFR) and downstream signal transduction through mitogen-activated protein kinases (MAPKs) in fibroblasts. Generation of reactive oxygen/nitrogen species by UV radiation is also critical for EGFR and MAPKs activation. MAPKs are responsible for activation of AP-1 subunits in the nucleus which induce matrix metalloproteinases. Melatonin, along with its metabolites, are known to be the most effective free radical scavenger and protective agent due to its ability to react with various radicals, lipophilic/hydrophilic structures. Objectives In this study, we investigated the effects of melatonin on UVA-irradiated primary human dermal fibroblasts (HDFs) by following the alteration of molecules from cell membrane to the nucleus and oxidative/nitrosative damage status of the cells in a time-dependent manner which have not been clearly elucidated yet. Methods To mimic UVA dosage in Mediterranean countries, HDFs were exposed to UVA with sub-cytotoxic dosage (20 J/cm(2)) after pretreatment with melatonin (1 mu mol/L) for 1 hour. Changes in the activation of the molecules and oxidative/nitrosative stress damage were analyzed at different time points. Results Our results clearly show that melatonin decreases UVA-induced oxidative/nitrosative stress damage in HDFs. It also suppresses phosphorylation of EGFR, activation of MAPK/AP-1 signal transduction pathway and production of matrix metalloproteinases in a time-dependent manner. Conclusion Melatonin can be used as a protective agent for skin damage against intracellular detrimental effects of relatively high dosage of UVA irradiation