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Topical retinoic acid alters the expression of cellular retinoic acid-binding protein-I and cellular retinoic acid-binding protein-II in non-lesional but not lesional psoriatic skin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2002 (English)In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 11, no 2, 143-152 p.Article in journal (Refereed) Published
Abstract [en]

Therapeutic retinoids have profound effects on psoriatic skin pathology but their interactions with various retinoid-binding proteins in lesional vs non-lesional skin have not been investigated. Using quantitative real-time PCR the mRNA expression of cellular retinol-binding protein I (CRBPI) and retinoic acid-binding protein I/II (CRABPI/CRABPII) was studied in psoriatic and healthy control (=normal) skin after 4 days of occlusive RA/vehicle treatment (n=6). Untreated psoriatic lesions showed a markedly elevated CRABPII/CRABPI ratio, while the CRBPI level was reduced in lesional and non-lesional skin as compared to normal skin. In RA-treated normal and non-lesional skin, the mRNA expression of CRBPI was unaltered while that of CRABPI and CRABPII was reduced by approximately 80% and increased approximately 5-fold, respectively, as compared to vehicle-treated skin. In contrast, lesional skin exposed to RA showed an almost 90% increase in CRBPI transcripts but unaltered expression of CRABPI and CRABPII, yet, the mRNA expression of several inflammatory mediators, e.g. inducible nitric oxide synthase, interferon-gamma and interleukin-1beta, was clearly reduced. Immunohistochemistry localized CRABPII to suprabasal keratinocytes in normal skin and revealed markedly elevated levels in lesional skin. RA treatment induced CRABPII protein expression in normal and non-lesional skin, to similar levels as in untreated lesions. The results indicate that the effects of RA differ in normal/non-lesional psoriatic skin and lesional skin. Whether the high expression of CRABPII in psoriatic skin lesions is due to increased amounts of endogenous retinoids in lesional skin or reflects an abnormal regulation of the CRABPII gene in psoriasis remains to be studied.

Place, publisher, year, edition, pages
2002. Vol. 11, no 2, 143-152 p.
Keyword [en]
quantitative real-time PCR, psoriasis, CRBP, keratinocyte, CRABP
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89861DOI: 10.1034/j.1600-0625.2002.110206.xPubMedID: 11994141OAI: oai:DiVA.org:uu-89861DiVA: diva2:161683
Available from: 2002-05-03 Created: 2002-05-03 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Studies on Vitamin A Signaling in Psoriasis: A Comparison Between Normal and Lesional Keratinocytes
Open this publication in new window or tab >>Studies on Vitamin A Signaling in Psoriasis: A Comparison Between Normal and Lesional Keratinocytes
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Vitamin A and metabolites (retinoids) are crucial for normal epidermal maturation. Physiological effects are mediated by retinoic acid (RA) that activates nuclear retinoic acid receptors (RARs) in complexes with retinoid X receptors (RXRs), resulting in altered gene transcription.

Psoriasis is a common disease with unknown etiology. Lesions display inflammation, hyperproliferation, and disturbed epidermal maturation. Treatments include topical or oral synthetic retinoids that allegedly bind to and activate the RARs.

The mRNA expression of retinoid receptors RARα/γ and RXRα was studied in normal and psoriatic skin samples. RARα and RXRα were significantly reduced in psoriatic plaques as compared to non-lesional and normal skin. In situ immunofluorescence detection revealed altered distribution patterns of the receptor proteins in lesional skin. All three receptor proteins were more intensely detected in the lower half of the epidermis but were significantly reduced in the superficial epidermis compared to both normal and non-lesional skin.

In order to evaluate the retinoid signaling system in psoriatic lesions, we compared the effect of topical RA on the expression of the cellular RA-binding protein II (CRABPII) in psoriatic and normal skin. CRABPII was induced by RA on mRNA and protein level in non-lesional and normal skin but not in lesional skin, where the basal expression of CRABPII was already up-regulated.

Changes in retinoid signaling during keratinocyte differentiation in vitro were studied by measuring retinoid receptor and RAR-ligand levels. Exposure to differentiation-inducing levels of calcium, phorbol myristate acetate (PMA) or interferon-γ (IFNγ) led to increased RAR-ligand levels but PMA and IFNγ caused receptor protein loss due to increased proteasomal degradation. Since an increased IFNγ level is a hallmark of psoriatic inflammation, this might be a cause of altered retinoid signaling in lesional epidermis.

Conclusion: Keratinocyte differentiation is accompanied by alterations in the retinoid signaling system. In psoriatic lesions, this system appears to be dysfunctioning due to reduced retinoid receptor levels, which might be an important event in the pathogenesis of the disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 63 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1155
Keyword
Medical sciences, Psoriasis, vitamin A, retinoids, retinoid receptor, differentiation, keratinocyte, skin, MEDICIN OCH VÅRD
National Category
Medical and Health Sciences
Research subject
Dermatology and Venerology
Identifiers
urn:nbn:se:uu:diva-2037 (URN)91-554-5317-1 (ISBN)
Public defence
2002-05-28, Rosénsalen, UAS, ing 95/96, Uppsala, 13:15
Opponent
Available from: 2002-05-03 Created: 2002-05-03Bibliographically approved

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