title: UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome.
abstract: Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.
authors: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors: Kristin
authors: K
authors: Maier
authors: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors: Yinghong
authors: Y
authors: He
authors: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors: Ute
authors: U
authors: Wölfle
authors: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors: Philipp R
authors: PR
authors: Esser
authors: Institute of Molecular Medicine and Cell Research.|Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany.
authors: Tilman
authors: T
authors: Brummer
authors: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors: Christoph
authors: C
authors: Schempp
authors: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.|Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany.
authors: Leena
authors: L
authors: Bruckner-Tuderman
authors: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors: Cristina
authors: C
authors: Has
mesh_terms: D000975:Antioxidants / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001768:Blister / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004820:Epidermolysis Bullosa / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D047311:Luteolin / Q000008:administration & dosage*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D010510:Periodontal Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010787:Photosensitivity Disorders / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D000975:Antioxidants; C475301:FERMT1 protein, human; C477322:FERMT3 protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D047311:Luteolin