uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Retinoids Reduce Formation of Keratin Aggregates in Heat-stressed Immortalized Keratinocytes from an Epidermolytic Ichthyosis Patient with a KRT10 Mutation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
2013 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 93, no 1, 44-49 p.Article in journal (Refereed) Published
Abstract [en]

Epidermolytic ichthyosis (EI) is an autosomal dominant epidermal skin fragility disorder caused by mutations in keratin 1 and 10 (K1 and K10) genes. Mutated keratins form characteristic aggregates in vivo and in vitro. Some patients benefit from retinoid therapy, although the mechanism is not fully understood. Our aim was to demonstrate whether retinoids affect the formation of keratin aggregates in immortalized EI cells in vitro. EI keratinocytes were seeded on cover slips, pre-treated or not with retinoids, heat-stressed, and keratin aggregate formation monitored. K10 aggregates were detected in 5% of cells in the resting state, whereas heat stress increased this proportion to 25%. When cells were pre-incubated with all-trans-retinoic acid (ATRA) or retinoic acid receptor (RAR)-α agonists the aggregates decreased in a dose-dependent manner. Furthermore, ATRA decreased the KRT10 transcripts 200-fold as well as diminished the ratio of mutant to wild-type transcripts from 0.41 to 0.35, thus providing a plausible rational for retinoid therapy of EI due to K10 mutations.

Place, publisher, year, edition, pages
2013. Vol. 93, no 1, 44-49 p.
National Category
Dermatology and Venereal Diseases
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-172436DOI: 10.2340/00015555-1368ISI: 000313373300009OAI: oai:DiVA.org:uu-172436DiVA: diva2:514673
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2017-12-07Bibliographically approved
In thesis
1. In vitro Studies of Genodermatoses Affecting Cytoskeletal Integrity and Lipid Processing in Human Epidermis: Pathogenic Mechanisms and Effects of Retinoid Therapy
Open this publication in new window or tab >>In vitro Studies of Genodermatoses Affecting Cytoskeletal Integrity and Lipid Processing in Human Epidermis: Pathogenic Mechanisms and Effects of Retinoid Therapy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autosomal dominant epidermolytic ichthyosis (EI) is a rare disease characterized by intra-epidermal blistering due to mutations in either of two keratin genes, KRT1 and KRT10, expressed by suprabasal keratinocytes. Autosomal recessive congenital ichthyosis (ARCI) is a non-blistering, hyperkeratotic disease caused by mutations in one of the following genes: ABCA12, ALOX12B, ALOXE3, TGM1, CYP4F22, NIPAL4 and SLC27A4, which are all essential for skin barrier homeostasis. ARCI and EI often respond well to treatment with retinoids, but the mechanism of action is unclear. The aim of this thesis was to increase the knowledge of pathogenic pathways in ichthyosis and to find new explanations to the effect of retinoids.

In vitro studies of immortalized keratinocytes from EI patients showed an abnormal keratin aggregation after heat stress, that could be partially inhibited by pre-treatment with all-trans retinoic acid (ATRA) or retinoic acid receptor α-agonists. ATRA treatment also reduced the relative expression of mutated vs wildtype KRT10. The clearance of ATRA in human keratinocytes was found to be mediated by CYP26B1.

In skin biopsies from ARCI patients, immunofluorescence analysis of 12R-LOX, eLOX-3, TGM1, ichthyin and FATP4 showed altered expression, not only of the mutated protein, but also of the other proteins. These observations are consistent with a feedback regulatory mechanism by which the loss of one protein results in an up-regulation of other proteins. Furthermore, 12R-LOX, eLOX-3 and TGM1 were intimately co-localized in stratum corneum, as were ichthyin and FATP4, suggesting that the proteins are linked to the same metabolic pathway. When treated with a CYP26 inhibitor known to raise the endogenous ATRA level of the skin, two patients with NIPAL4 mutations, initially exhibiting increased co-localization signals for 12R-LOX and eLOX-3, displayed normalized lipoxygenase expressions and showed clinical improvement.

In conclusion, mechanisms are proposed by which pathogenic keratin aggregations in EI and epidermal protein deficiencies in ARCI patients may be mitigated by retinoids. Furthermore, the vivid crosstalk between proteins incriminated in ARCI suggests that these enzymes operate along a common metabolic pathway essential for producing barrier lipids in stratum corneum. Any abrogation of this production may cause barrier failure, hence resulting in a compensatory hyperkeratosis characteristic of congenital ichthyosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 43 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 769
Keyword
Congenital Ichthyosiform Erythroderma, Epidermolytic Hyperkeratosis, Ceramides, Keratins, Retinoids, Molecular Probe Techniques, Transglutaminases, Lipoxygenases, Fatty Acid Transporter Proteins, Keratinocytes, Epidermis
National Category
Dermatology and Venereal Diseases
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-172863 (URN)978-91-554-8352-4 (ISBN)
Public defence
2012-06-04, Rosensalen, Akademiska sjukhuset entrance 95/96, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-05-14 Created: 2012-04-16 Last updated: 2012-08-01Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full texthttp://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1368&preview=1

Authority records BETA

Li, HaoTörmä, Hans

Search in DiVA

By author/editor
Li, HaoTörmä, Hans
By organisation
Dermatology and Venereology
In the same journal
Acta Dermato-Venereologica
Dermatology and Venereal Diseases

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 448 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf