Cyclosporin a inhibits directly in vivo keratinocyte proliferation of living human skin

Urabe, Atsumichi; Kanitakis, Jean; Viac, J.; Thivolet, J

doi:10.1016/0022-202x(89)90195-4

Cited by 37 publications

(10 citation statements)

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“…Several in vitro studies have reported a direct antiproliferative effect of CsA in cultures of proliferating epidermal keratocytes 1–4 . This is confirmed in the studies by Urabe et al 5 For example, CsA inhibits the proliferation of keratocytes and fibroblasts in culture at concentrations equivalent to those found in psoriatic plaques following CsA treatment 4–7 . It has been shown that CsA inhibits the induction of pro‐tumor sequencing and inflammatory hyperplastic response following topical application of the tumor‐promoting phorbol ester 12−O‐tetradecanoyl‐phorbol‐13‐acetate (TPA) 8–10 .…”

supporting

confidence: 57%

This article has been retracted: A preliminary examination of the role of NFAT 3 in human skin, cultured keratocytes and dermal fibroblasts

Al-Daraji

2010

J Cutan Pathol

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Retraction Retraction: The following article from Journal of Cutaneous Pathology, “A preliminary examination of the role of NFAT 3 in human skin, cultured keratocytes and dermal fibroblasts” by Wael I. Al‐Daraji, published online on 8 July, 2010 in Wiley Online Library (http://onlinelibrary.wiley.com), has been retracted by agreement between the journal Editor in Chief, Timothy McCalmont, and Blackwell Publishing Ltd. The retraction has been made as the manuscript was submitted for publication in breach of an agreement with the University of Newcastle upon Tyne due to the failure to provide appropriate acknowledgement of sources. Background: Ciclosporin A (CsA) is widely utilized for the treatment of inflammatory skin diseases such as psoriasis.The therapeutic effects of CsA are thought to be mediated via its immunosuppressive action on infiltrating lymphocytes in skin lesions. CsA and tacrolimus block T cell activation by inhibiting the phosphatase calcineurin and preventing translocation from the cytoplasm to the nucleus of the transcription factor Nuclear Factor of Activated T cells (NFAT). Methods: RT‐PCR and Western Analysis were used to investigate the presence of NFAT‐3 mRNA and protein in human keratocytes. Tissue culture of human keratocytes and immunostaining of cells on coverslips and confocal microscopy were used to assess the degree of nuclear localisation of NFAT‐3 in cultured cells. Keratome biopsies were taken from patients with psoriasis (lesional and non‐lesional skin) and normal skin and immunohistochemistry was used to assess the NFAT‐3 localisation in these biopsies using a well characterized anti‐NFAT‐3 antibody. Results: The NFAT‐3 mRNA and protein expression was demonstrated using RT‐PCR and Western blotting. The expression of NFAT‐3 in human keratocytes and response to different agonists provides perhaps a unique opportunity to examine the regulation, subcellular localization and kinetics of translocation of different NFATs in primary cultured human cells. As with NFAT 1, NFAT 2 and recently NFAT 5, differentiation‐promoting agents that increase intracellular calcium concentration induced nuclear translocation of NFAT‐3 in cultured keratocytes but with different kinetics. Conclusion: These data provide the first evidence of that NFAT‐3 is expressed in normal skin, psoriasis and that NFAT‐3 functionally active in human keratocytes and that nuclear translocation of NFAT‐3 in human skin cells has different kinetics than NFAT 1 suggesting that NFAT‐3 may play an important role in regulation of keratocytes proliferation and differentiation at a different stage. Inhibition of this pathway in human epidermal keratocytes many account, in part for the therapeutic effects of CsA and tacrolimus in skin disorders such as psoriasis. Al‐Daraji WI. A preliminary examination of the role of NFAT 3 in human skin, cultured keratocytes and dermal fibroblasts.

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confidence: 57%

This article has been retracted: A preliminary examination of the role of NFAT 3 in human skin, cultured keratocytes and dermal fibroblasts

Al-Daraji

2010

J Cutan Pathol

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“…This is suggested by the effectiveness of cyclo sporin in the treatment of established psoriasis. An inhib itory effect of cyclosporin on kcratinocytes [29,[32][33][34] and antigen-presenting cell function [35][36][37] has also been reported, but it is probable that its major site of action in psoriasis is on activated CD4+ T cells, which appear to play a central role in the pathogenesis of psoriasis.…”

Section: Cyclosporin and The Pathogenesis Of Psoriasismentioning

confidence: 99%

Cyclosporin in Psoriasis: Pathophysiology and Experimental Data

Mozzanica¹,

Pigatto²,

Finzi³

1993

Dermatology

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Cyclosporin has been used efficaciously in recent years for the management of severe psoriasis. The remarkable efficacy of this drug and its known immunosuppressive properties have indicated even more strongly the involvement of the immune system in the induction and maintenance of psoriasis. The present review summarizes the role of cellular immunity in the pathogenesis of psoriasis and possible mechanisms of action of cyclosporin in psoriasis, and describes the laboratory studies performed in our Department under two headings, changes in lesional immune infiltrate (evaluated immunohistologically) and changes in neutrophil chemotaxis during cyclosporin treatment. Our immunohistological study showed that the psoriatic plaques contained an infiltrate composed mainly of activated CD4+ T cells. Cyclosporin treatment significantly decreased T cells and normalized the distribution and antigen expression of intraepidermal Langerhans cells, increasing the number of CD1+ dendritic cells. Our studies on neutrophil chemotaxis showed that cyclosporin reduced the chemotactic activity of neutrophilic polymorphonuclear leukocytes (in vivo but not in vitro), seemingly as a consequence of blocking the production of chemoattracting cytokines by psoriatic monocytes.

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“…The first of these metabolites, ciclosporin (CsA) was isolated from cultures of the fungus Tolypocladium inflatum Gams and has enjoyed widespread clinical use in organ transplanta tion by virtue of its potent immunosuppres sive, T-cell-directed properties [1], However, CsA has more recently been shown to exert also biological activities on a wider range of cell types, including endothelial [2], fibro blastic [3] and epithelial ones. In this respect, CsA has been shown to exert in vitro an anti proliferative effect on cultured human and animal interfollicular epidermal keratino cytes (EK), evaluated by both a decrease in the total cell number at the end of the culture and the percent of S-phase (5-bromo-2'-deoxyuridine or 3H-thymidine incorporat ing) cells [for a review, see 4], The same effect was also shown by us in vivo on nor mal human skin xenografted onto athymie mice [5], By now more than 46 CsA analogues have been studied. As shown by Wenger [6], chemical alterations involving the amino…”

mentioning

confidence: 84%

Nonimmunosuppressive Ciclosporin H Inhibits the Growth and DNA Synthesis of Cultured Normal Human Epidermal Keratinocytes

Ramírez-Boscá

Kanitakis

Haftek

et al. 1989

Skin Pharmacol Physiol

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Ciclosporin H (CsH) is an epimer (11-D-N-methyl-L-valine) of ciclosporin A (CsA) devoid of immunosuppressive properties. The known antiproliferative effect of CsA on epidermal keratinocytes (EK) grown in vitro prompted us to study the effect of CsH (at the doses of 0.5, 1, 3.5 and 5 µg/ml) on the growth and DNA synthesis (5-bromo-2’-deoxy-uridine incorporation). CsH was observed to reduce both the number and DNA synthesis of EK in a statistically significant manner at the dosage of 5 µg/ml after 24, 48 and 72 h in culture. These results show that the immunosuppressive properties of the ciclosporins (Cs) are dissociated from the antiproliferative ones on EK and highlight the interest of further in vivo studies that may lead to therapeutic applications of Cs in hyperproliferative epidermal diseases requiring no immunosuppression.

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Cyclosporin a inhibits directly in vivo keratinocyte proliferation of living human skin

Cited by 37 publications

References 14 publications

This article has been retracted: A preliminary examination of the role of NFAT 3 in human skin, cultured keratocytes and dermal fibroblasts

This article has been retracted: A preliminary examination of the role of NFAT 3 in human skin, cultured keratocytes and dermal fibroblasts

Cyclosporin in Psoriasis: Pathophysiology and Experimental Data

Nonimmunosuppressive Ciclosporin H Inhibits the Growth and DNA Synthesis of Cultured Normal Human Epidermal Keratinocytes

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