Sensitization of H2O2-induced TRPM2 activation and subsequent interleukin-8 (CXCL8) production by intracellular Fe2+ in human monocytic U937 cells |
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| Affiliation: | 1. Laboratory of Pharmacology, Department of Clinical Pharmacy, Yokohama College of Pharmacy, Yokohama 245-0066, Japan;2. Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo 164-8530, Japan;3. Division of Physiology and Pathology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, Tokyo 142-8555, Japan;4. Department of Pharmacogenomics, Showa University School of Pharmacy, Tokyo 142-8555, Japan;5. Department of Molecular Cell Biology and Medicine, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8505, Japan;6. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan;1. Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland;2. Department of Biology, University of Copenhagen, 2200 Copenhagen N, Denmark;3. Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 803-8555, Japan;1. Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan;2. Department of Physiological Sciences, The University of Advanced Studies, Okazaki, Aichi 444-8585, Japan;1. Departments of Ophthalmology, Neurobiology, and Bioengineering, University of Utah, Salt Lake City, USA;2. Institute of Physiology, Faculty of Medicine, Christian-Albrechts-University Kiel, Germany;3. Experimental Ophthalmology, Department of Ophthalmology, Charité – Universitätsmedizin Berlin, a Corporate Member of Freie Universität, Humboldt-University, The Berlin Institute of Health, Berlin, Germany;1. Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan;2. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan;1. Key Laboratory of Regenerative Biology, Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China;2. Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan 410013, China |
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| Abstract: | Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress-sensitive Ca2+-permeable channel. In monocytes/macrophages, H2O2-induced TRPM2 activation causes cell death and/or production of chemokines that aggravate inflammatory diseases. However, relatively high concentrations of H2O2 are required for activation of TRPM2 channels in vitro. Thus, in the present study, factors that sensitize TRPM2 channels to H2O2 were identified and subsequent physiological responses were examined in U937 human monocytes. Temperature increase from 30 °C to 37 °C enhanced H2O2-induced TRPM2-mediated increase in intracellular free Ca2+ ([Ca2+]i) in TRPM2-expressing HEK 293 cells (TRPM2/HEK cells). The H2O2-induced TRPM2 activation enhanced by the higher temperature was dramatically sensitized by intracellular Fe2+-accumulation following pretreatment with FeSO4. Thus intracellular Fe2+-accumulation sensitizes H2O2-induced TRPM2 activation at around body temperature. Moreover, intracellular Fe2+-accumulation increased poly(ADP-ribose) levels in nuclei by H2O2 treatment, and the sensitization of H2O2-induced TRPM2 activation were almost completely blocked by poly(ADP-ribose) polymerase inhibitors, suggesting that intracellular Fe2+-accumulation enhances H2O2-induced TRPM2 activation by increase of ADP-ribose production through poly(ADP-ribose) polymerase pathway. Similarly, pretreatment with FeSO4 stimulated H2O2-induced TRPM2 activation at 37 °C in U937 cells and enhanced H2O2-induced ERK phosphorylation and interleukin-8 (CXCL8) production. Although the addition of H2O2 to cells under conditions of intracellular Fe2+-accumulation caused cell death, concentration of H2O2 required for CXCL8 production was lower than that resulting in cell death. These results indicate that intracellular Fe2+-accumulation sensitizes TRPM2 channels to H2O2 and subsequently produces CXCL8 at around body temperature. It is possible that sensitization of H2O2-induced TRPM2 channels by Fe2+ may implicated in hemorrhagic brain injury via aggravation of inflammation, since Fe2+ is released by heme degradation under intracerebral hemorrhage. |
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| Keywords: | TRPM2 channel Hydrogen peroxide Ferrous iron CXCL8 U937 cells |
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