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Keratinocyte differentiation induced by calcium, phorbol ester or interferon-γ elicits distinct changes in the retinoid signalling pathways
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
2010 (English)In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 57, no 3, p. 207-213Article in journal (Refereed) Published
Abstract [en]

Background: Retinoids influence keratinocyte proliferation and differentiation via binding to nuclear retinoic acid receptors (RARα, -γ) and retinoid X receptor α (RXRα). The effect of keratinocyte differentiation on expression of nuclear retinoid receptors and on the conversion of retinol into retinoic acid has not been examined earlier in depth. Objectives: Our aim was to examine the expression of retinoid receptors and a retinoid-regulated gene CRABPII, as well as the metabolism of exogenous [3H]retinol in cultured human keratinocytes induced to differentiate by exposure to either calcium, phorbol 12-myristate 13-acetate (PMA), or interferon-γ (IFNγ). Methods: Normal human keratinocytes were cultured and exposed to differentiation-inducing agents. The mRNA and protein expression of retinoid receptors were examined using real-time PCR and Western blot. [3H]Retinol uptake and metabolism was monitored by HPLC with on-line radioactivity detection. Results: In calcium-exposed cells, increased expression of RARγ and RXRα, enhanced metabolism of [3H]retinol to 3,4-didehydro-RA (ddRA), and an induction of CRABPII mRNA and protein was noted. In contrast, treatment with PMA and IFNγ reduced the RARγ and RXRα protein expression (preventable by the proteasome inhibitor MG132), increased the accumulation of [3H]RA and/or [3H]ddRA in the cells, and changed the CRABPII transcription. Conclusions: Retinoid signalling is profoundly altered upon differentiation of keratinocytes and the effects depend on how cellular differentiation is initiated.

Place, publisher, year, edition, pages
2010. Vol. 57, no 3, p. 207-213
Keywords [en]
Differentiation, Interferon-γ, Keratinocyte, Phorbol ester, Retinoic acid, Retinoid receptor
National Category
Medical and Health Sciences
Research subject
Dermatology and Venerology
Identifiers
URN: urn:nbn:se:uu:diva-89862DOI: 10.1016/j.jdermsci.2009.12.013ISI: 000275232200009PubMedID: 20122816OAI: oai:DiVA.org:uu-89862DiVA, id: diva2:161684
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. p. 63
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1155
Keywords
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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