Induction of phenotype modifying cytokines by
            <i>FERMT1</i>
            mutations

Heinemann, Anja; He, Yinghong; Зимина, Е. П.; Boerries, Melanie; Busch, Hauke; Chmel, Nadja; Kurz, Thorsten; Bruckner‐Tuderman, Leena; Has, Cristina

doi:10.1002/humu.21449

Cited by 33 publications

(36 citation statements)

References 42 publications

(47 reference statements)

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“…Although all individuals with KS caused by null mutations exhibit skin blistering, poikiloderma, and photosensitivity, the variability of clinical presentation is evident, suggesting a role for environmental and/or epigenetic factors. We have recently shown that the cumulative effect of cell stress-inducing events may play a decisive role in the outcome of the disease Heinemann et al, 2011]. Kindlin-1 deficient keratinocytes respond to cell stress by upregulating the expression of cytokines, for example, IL-20, IL-24, and TGF-β2.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

Kindler syndrome: Extension of FERMT1 mutational spectrum and natural history

et al. 2011

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Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.

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Section: Genotype-phenotype Correlationmentioning

confidence: 99%

Kindler syndrome: Extension of FERMT1 mutational spectrum and natural history

et al. 2011

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“…Real-time quantitative PCR (RT-qPCR) was carried out as described. 6 In brief, the reaction was performed in a 20-lL volume containing 750 ng of cDNA, ready-to-use iQ-SYBR Green Supermix (BioRad, Mü nchen, Germany), and IL-20 primers (forward primer 5¢-tttgcaagacacaaagcctg-3¢, reverse primer 5¢-tggtaagaaaggaattggcg-3¢). The expression levels were calculated relative to those of glyceraldehyde-3-phosphate dehydrogenase (GAPDH).…”

Section: Rna Extraction and Real-time Quantitative Pcrmentioning

confidence: 99%

“…15 Normal human dermal fibroblasts (NHDFs) were isolated from human foreskin as described 6 and routinely used between passages 3 and 6.…”

Section: Cell Culturementioning

confidence: 99%

“…5 Furthermore, we have shown that the IL-20 receptors IL20Ra and IL-20Rb are expressed on human dermal fibroblasts. 6 Therefore, we hypothesize that solar light-induced IL-20 production in keratinocytes might contribute to aging processes in the dermis.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have shown that IL-20, an early proinflammatory cytokine, is also released by keratinocytes in response to UVB irradiation, 6 whereas UV irradiation did not induce IL-20 expression in human fibroblasts (data not shown). When HaCaT keratinocytes were treated with 8 lg/mL luteolin before irradiation with a solar simulator, IL-6 expression (Fig.…”

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confidence: 99%

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Luteolin Prevents Solar Radiation-Induced Matrix Metalloproteinase-1 Activation in Human Fibroblasts: A Role for p38 Mitogen-Activated Protein Kinase and Interleukin-20 Released from Keratinocytes

Wölfle

Heinemann

Esser

et al. 2012

Rejuvenation Research

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Human skin is continuously exposed to solar radiation, which can result in photoaging, a process involving both dermal and, to a lesser extent, epidermal structures. Previously, we have shown that the flavonoid luteolin protects the epidermis from ultraviolet (UV)-induced damage by a combination of UV-absorbing, antioxidant, and antiinflammatory properties. The aim of the present study was to determine direct and indirect effects of luteolin on dermal fibroblasts as major targets of photoaging. Stimulation of fibroblasts with UVA light or the proinflammatory cytokine interleukin-20 (IL-20) is associated with wrinkled skin, increased IL-6 secretion, matrix metalloproteinase (MMP-1) expression, and hyaluronidase activity. All of these targets were inhibited by luteolin via interference with the p38 mitogen-activated protein kinase (MAPK) pathway. Next, we assessed the role of conditioned supernatants from keratinocytes irradiated with solar-simulated radiation (SSR) on nonirradiated dermal fibroblasts. In keratinocytes, luteolin inhibited SSR-induced production of IL-20, also via interference with the p38 MAPK pathway. Similarly, keratinocyte supernatant-induced IL-6 and MMP-1 expression in fibroblasts was reduced by pretreatment of keratinocytes with luteolin. Finally, these results were confirmed ex vivo on skin explants treated with luteolin before UV irradiation. Our results suggest that SSRmediated production of soluble factors in keratinocytes is modulated by luteolin and may attenuate photoaging in dermal fibroblasts.

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