title: Mechanistic insight into the norepinephrine-induced fibrosis in systemic sclerosis.
abstract: Raynaud's phenomenon is frequently observed in systemic sclerosis (SSc) patients, and cold- or stress-induced norepinephrine (NE) has been speculated to be associated with vasoconstriction. Objective was to elucidate the role of NE in fibrosis in SSc. IL-6 is a potent stimulator of collagen production in fibroblasts. NE enhanced IL-6 production and proliferation more significantly in SSc fibroblasts than in normal fibroblasts. Furthermore, the production of IL-6 and phosphorylation of p38 in SSc fibroblasts was enhanced by adrenergic receptor (AR)β agonist, isoproterenol, but not ARα agonist, oxymetazoline. ARβ blocker, propranolol, inhibited NE-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. NE-induced IL-6 was significantly inhibited by p38 inhibitor, SB203580, suggesting that NE-induced phosphorylation of p38 via ARβ enhances IL-6 production in SSc fibroblasts. NE-induced phosphorylation of ERK1/2 via ARα inhibited IL-6 production in SSc fibroblasts. Combined treatment with NE and endothelin-1 resulted in an additive increase in IL-6 production in SSc fibroblasts. NE-induced IL-6/IL-6 receptor trans-signaling increased the production of collagen type I in SSc fibroblasts, and both propranolol and SB203580 inhibited NE-induced collagen production. These results suggest that cold exposure and/or emotional stress-induced NE might contribute to the skin fibrosis via potentiation of IL-6 production from fibroblasts in SSc.
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Uehara
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Sei-Ichiro
authors.initials: S
authors.lastname: Motegi
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Uchiyama
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Buddhini
authors.initials: B
authors.lastname: Perera
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Toki
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ogino
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishikawa
mesh_terms: D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D009638:Norepinephrine / Q000009:adverse effects* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D048051:p38 Mitogen-Activated Protein Kinases; D009638:Norepinephrine