The CYP26 inhibitor R115866 potentiates the effects of all-<i>trans</i>retinoic acid on cultured human epidermal keratinocytes

Giltaire, Séverine; Herphelin, Françoise; Frankart, Aurélie; Hérin, Michel; Stoppie, P.; Poumay, Yves

doi:10.1111/j.1365-2133.2008.08960.x

Cited by 29 publications

(24 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RA also increased HAS2 expression, thus completely reversing the changes in HAS1, HAS2, and HAS3 expression observed under spontaneous differentiation. Interestingly, RA was also found to increase HB-EGF expression (Giltaire et al, 2009), suggesting that HB-EGF could explain the increase in HAS3 expression as observed in other models (Monslow et al, 2009). In addition, treatment of RHE with HB-EGF decreased the HAS1/HAS3 ratio 50-fold.…”

Section: Discussionmentioning

confidence: 84%

“…To probe the potential link between keratinocyte differentiation and expressions of specific HASs, confluent cultures were incubated for 18 hours with various concentrations of all-trans RA, a well-known inducer of epidermal dedifferentiation (Poumay et al, 1999;Giltaire et al, 2009). This treatment strongly downregulates keratin 10 (KRT10) and upregulates involucrin (IVL) ( Figure 1g).…”

Section: Production Of Ha By Human Keratinocytes Correlates With Exprmentioning

confidence: 99%

See 1 more Smart Citation

Hyaluronan Metabolism in Human Keratinocytes and Atopic Dermatitis Skin Is Driven by a Balance of Hyaluronan Synthases 1 and 3

Malaisse

Bourguignon

Vuyst

et al. 2014

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Hyaluronan (HA) is a glycosaminoglycan synthesized directly into the extracellular matrix by three hyaluronan synthases (HAS1, HAS2, and HAS3). HA is abundantly synthesized by keratinocytes but its epidermal functions remain unclear. We used culture models to grow human keratinocytes as autocrine monolayers or as reconstructed human epidermis (RHE) to assess HA synthesis and HAS expression levels during the course of keratinocyte differentiation. In both the models, epidermal differentiation downregulates HAS3 mRNA expression while increasing HAS1 without significant changes in hyaluronidase expression. HA production correlates with HAS1 mRNA expression level during normal differentiation. To investigate the regulation of HAS gene expression during inflammatory conditions linked to perturbed differentiation, lesional and non-lesional skin biopsies of atopic dermatitis (AD) patients were analyzed. HAS3 mRNA expression level increases in AD lesions compared with healthy and non-lesional skin. Simultaneously, HAS1 expression decreases. Heparin-binding EGF-like growth factor (HB-EGF) is upregulated in AD epidermis. An AD-like HAS expression pattern is observed in RHE incubated with HB-EGF. These results indicate that HAS1 is the main enzyme responsible for HA production by normal keratinocytes and thus, must be considered as an actor of normal keratinocyte differentiation. In contrast, HAS3 can be induced by HB-EGF and seems mainly involved in AD epidermis.

show abstract

Section: Discussionmentioning

confidence: 84%

Section: Production Of Ha By Human Keratinocytes Correlates With Exprmentioning

confidence: 99%

Hyaluronan Metabolism in Human Keratinocytes and Atopic Dermatitis Skin Is Driven by a Balance of Hyaluronan Synthases 1 and 3

Malaisse

Bourguignon

Vuyst

et al. 2014

Journal of Investigative Dermatology

View full text Add to dashboard Cite

show abstract

“…Since MAPK p38 plays major roles in cellular responses to environmental and physiological stresses [14,15,20,32] and MAPK ERK 1/2 promotes cellular proliferation needed for tissue reconstruction [24], phosphorylation of both MAPK's was investigated in our model. RHE was exposed for 1, 2, 4, 8 or 22 h to DNFB (0.250 mg/ml) as a prototype sensitizing chemical, then tissue extracts were analyzed by Western blot in order to detect phosphorylated forms of p38 and ERK 1/2 MAPK's (Fig.…”

Section: Exposure Of Rhe To Sensitizing Chemicals Induces Early Transmentioning

confidence: 99%

Studies of cell signaling in a reconstructed human epidermis exposed to sensitizers: IL-8 synthesis and release depend on EGFR activation

Frankart

Coquette²,

Schroeder

et al. 2012

Arch Dermatol Res

View full text Add to dashboard Cite

Models of reconstructed human epidermis (RHE) holding proliferating and fully differentiated cultured keratinocytes allow in vitro investigation of early molecular and cellular epidermal events during the complex response of keratinocytes at the onset of allergic contact dermatitis (ACD) or sensitization. In this study, data collected on RHE exposed to well-characterized sensitizing chemicals, such as dinitrofluorobenzene, oxazolone, cinnamaldehyde and isoeugenol, revealed a transient expression of IL-8 mRNA in association with abundant IL-8 cell release. Investigations of keratinocyte signaling illustrate transient activation by tissue exposure to sensitizing chemicals of the epidermal growth factor receptor (EGFR). This activation of EGFR tyrosine kinase is involved in the expression and release of IL-8. The IL-8 release appears also to be partially dependent on p38 and ERK 1/2 MAPK activation. Moreover, data suggest that heparin-binding EGF-like growth factor (HB-EGF) expression and release induced after exposure of RHE to sensitizing chemicals are also under the control of EGFR tyrosine kinase activity, independently of the IL-8 expression and release. Mechanistic approach of keratinocyte responses in the context of RHE underlying regulation of expression and release of epidermal cytokines and growth factors after topical application of sensitizing chemicals is proposed to identify biomarkers which could then be analysed for in vitro toxicological screening of new or undefined compounds.

show abstract

“…Based on this information, the effects of talarozole were studied in cultured human epidermal keratinocytes when co-administered with low concentrations of ATRA [135]. The aim was to determine whether talarozole could be useful in the treatment of dermatological conditions such as psoriasis, ichthyosis and acne.…”

Section: Pharmacological Effects Of Inhibitors Of Retinoic Acid Hymentioning

confidence: 99%

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Nelson¹,

Buttrick²,

Isoherranen³

2013

CTMC

View full text Add to dashboard Cite

Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulating cell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatological diseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity, and resistance to treatment emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids, RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450 (CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors of RA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance. This makes CYP26 enzymes an attractive target for the development of novel therapeutics for cancer and dermatological conditions. The basic principle of development of CYP26 inhibitors is that endogenous RA concentrations will be increased in the presence of a CYP26 inhibitor, thus, potentiating the activity of endogenous RA in a cell-type specific manner. This will reduce side effects compared to administration of RA and allow for more targeted therapy. In clinical trials, inhibitors of RA metabolism have been effective in treatment of psoriasis and other dermatological conditions as well as in some cancers. However, no CYP26 inhibitor has yet been approved for clinical use. This review summarizes the history of development of RAMBAs, the clinical and preclinical studies with the various structural series and the available knowledge of structure activity relationships of CYP26 inhibitors.

show abstract

The CYP26 inhibitor R115866 potentiates the effects of all-transretinoic acid on cultured human epidermal keratinocytes

Abstract: These results strongly suggest that R115866 potentiates the effects of RA on epidermal keratinocytes when RA is present at low concentrations.

Cited by 29 publications

References 19 publications

Hyaluronan Metabolism in Human Keratinocytes and Atopic Dermatitis Skin Is Driven by a Balance of Hyaluronan Synthases 1 and 3

Hyaluronan Metabolism in Human Keratinocytes and Atopic Dermatitis Skin Is Driven by a Balance of Hyaluronan Synthases 1 and 3

Studies of cell signaling in a reconstructed human epidermis exposed to sensitizers: IL-8 synthesis and release depend on EGFR activation

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Contact Info

Product

Resources

About