title: Iron sensitizes keratinocytes and fibroblasts to UVA-mediated matrix metalloproteinase-1 through TNF-α and ERK activation.
abstract: Oestrogen deficiency is regarded as the main causative factor in postmenopausal skin ageing and photoageing. While women after menopause experience low levels of oestrogen because of cease of ovarian function, they are also exposed to high levels of iron as a result of cessation of menstruation. In this study, we investigated whether this increase in iron presents a risk to the postmenopausal skin. Because of the lack of appropriate animal models to closely mimic the low oestrogen and high iron conditions, we tested the hypothesis in a high iron and low oestrogen culture model. Here, we showed that primary human dermal fibroblasts exposed to iron did not affect the baseline levels of matrix metalloproteinase-1 (MMP-1) activity. However, the iron-exposed fibroblasts were sensitized to UVA exposure, which resulted in a synergistic increase in MMP-1. UVA activated the three members of MAPK family: ERKs, p38, and JNKs. Additional activation of ERKs by iron contributed to the synergistic increases. Primary normal human epidermal keratinocytes (NHEK) did not respond to iron or UVA exposure as measured by MMP-1, but produced tumor necrosis factor-alpha (TNF-α) in the media, which then stimulated MMP-1 in fibroblasts. Our results indicate that iron and UVA increase MMP-1 activity in dermal fibroblasts not only directly through ERK activation but also by an indirect paracrine loop through TNF-α released by NHEK. We conclude that in addition to oestrogen deficiency, increased iron as a result of menopause could be a novel risk factor by sensitizing postmenopausal skin to solar irradiation.
authors.affiliation: Department of Environmental Medicine and Medicine, New York University, School of Medicine, New York, NY, USA.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Jian
authors.forename: Edward
authors.initials: E
authors.lastname: Pelle
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Nadine
authors.initials: N
authors.lastname: Pernodet
authors.forename: Daniel
authors.initials: D
authors.lastname: Maes
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001059:Apoproteins / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005293:Ferritins / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism* / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007501:Iron / Q000008:administration & dosage / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D014168:Transferrin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000906:Antibodies; D001059:Apoproteins; D017077:Culture Media, Conditioned; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D014168:Transferrin; D014409:Tumor Necrosis Factor-alpha; C028284:apotransferrin; C110714:holotransferrin; D004958:Estradiol; D005293:Ferritins; D007501:Iron; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D003676:Deferoxamine