title: The role of angiopoietin-like protein 2 in pathogenesis of dermatomyositis.
abstract: Dermatomyositis (DM) is an autoimmune disease marked by chronic inflammation of skin and muscle tissues and characterized clinically by proximal muscle weakness and skin eruption, including heliotrope rash, and Gottron's sign. Treatment with a non-specific immunosuppressive agent or anti-inflammatory corticosteroids is beneficial, although some patients are resistant to these therapies. Proinflammatory cytokines derived from infiltrating inflammatory cells and activated resident cells within skin and muscle tissues likely promote chronic inflammation in DM pathogenesis; however, molecular mechanisms underlying the disease are not completely defined. Here we show that mRNA and protein levels of angiopoietin-like protein 2 (Angptl2), a recently identified chronic inflammation mediator, are abundant in keratinocytes from DM patients' skin eruptions. To examine whether skin cell-derived Angptl2 promotes DM manifestations, we analyzed transgenic (Tg) mice expressing Angptl2 driven by the keratinocyte specific promoter K14 (K14-Angptl2) and therefore constitutively expressing Angptl2 in skin tissue. We found that K14-Angptl2 Tg mice exhibited skin phenotypes similar to those observed in DM patients. In addition, treatment of keratinocytes with exogenous Angptl2 activated the NF-κB inflammatory cascade, resulting in increased expression of the proinflammatory cytokines IL-1β and IL-6. We propose that keratinocyte-derived Angptl2 functions in DM pathogenesis by inducing chronic inflammation in skin tissue.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Ogata
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.forename: Jun
authors.initials: J
authors.lastname: Aoi
authors.forename: Otowa
authors.initials: O
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.forename: Zhe
authors.initials: Z
authors.lastname: Tian
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Jinnin
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D003882:Dermatomyositis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000096:biosynthesis; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology
chemical_list: C485792:ANGPTL2 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D016023:Integrins; D016328:NF-kappa B