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Upregulation of P2Y2 receptors by retinoids in normal human epidermal keratinocytes.

Fujishita K, Koizumi S, Inoue K - Purinergic Signal. (2006)

Bottom Line: The DNA microarray analysis also revealed that ATRA upregulates various genes involved in the differentiation of NHEKs.Our present results suggest that retinoids, at least in part, exert their proliferative effects by upregulating P2Y2 receptors in NHEKs.This effect of retinoids may be closely related to their therapeutic effect against various ailments or aging events in skins such as over-keratinization, pigmentation and re-modeling.

View Article: PubMed Central - PubMed

Affiliation: Division of Biosignaling, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo, Japan.

ABSTRACT
Retinoids, vitamin A derivatives, are important regulators of the growth and differentiation of skin cells. Although retinoids are therapeutically used for several skin ailments, little is known about their effects on P2 receptors, known to be involved in various functions in the skin. DNA array analysis showed that treatment of normal human epidermal keratinocytes (NHEKs) with all-trans-retinoic acid (ATRA), an agonist to RAR (retinoic acid receptor), enhanced the expression of mRNA for the P2Y2 receptor, a metabotropic P2 receptor that is known to be involved in the proliferation of the epidermis. The expression of other P2 receptors in NHEKs was not affected by ATRA. ATRA increased the mRNA for the P2Y2 receptor in a concentration-dependent fashion (1 nM to 1 muM). Am80, a synthesized agonist to RAR, showed a similar enhancement, whereas 9-cis-retinoic acid (9-cisRA), an agonist to RXR (retinoid X receptor), enhanced P2Y2 gene expression to a lesser extent. Ca(2+) imaging analysis showed that ATRA also increased the function of P2Y2 receptors in NHEKs. Retinoids are known to enhance the turnover of the epidermis by increasing both proliferation and terminal differentiation. The DNA microarray analysis also revealed that ATRA upregulates various genes involved in the differentiation of NHEKs. Our present results suggest that retinoids, at least in part, exert their proliferative effects by upregulating P2Y2 receptors in NHEKs. This effect of retinoids may be closely related to their therapeutic effect against various ailments or aging events in skins such as over-keratinization, pigmentation and re-modeling.

No MeSH data available.


Related in: MedlinePlus

Time- and concentration-dependency of three different retinoids-induced changes in mRNAs in NHEKs. Diagram shows the quantity of P2Y2 mRNAs detected by real-time RT-PCR after treatment with 0.001–1 µM ATRA (A), Am80 (B) and 9-cisRA (C) for 2–24 h. The P2Y2 mRNA levels in cells treated with various concentrations of retinoids were normalized by those in retinoids-untreated control cells at each incubation period (2, 6, 12 and 24 h), and expressed as “percentage (%) of control.” All these retinoids, and especially Am80, caused a linear increase in P2Y2 mRNAs in a concentration- and time-dependent fashion. Asterisks show significant difference in the P2Y2 mRNA levels from control groups (*P < 0.05; **P < 0.01). Data were obtained from at least three independent experiments.
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Fig2: Time- and concentration-dependency of three different retinoids-induced changes in mRNAs in NHEKs. Diagram shows the quantity of P2Y2 mRNAs detected by real-time RT-PCR after treatment with 0.001–1 µM ATRA (A), Am80 (B) and 9-cisRA (C) for 2–24 h. The P2Y2 mRNA levels in cells treated with various concentrations of retinoids were normalized by those in retinoids-untreated control cells at each incubation period (2, 6, 12 and 24 h), and expressed as “percentage (%) of control.” All these retinoids, and especially Am80, caused a linear increase in P2Y2 mRNAs in a concentration- and time-dependent fashion. Asterisks show significant difference in the P2Y2 mRNA levels from control groups (*P < 0.05; **P < 0.01). Data were obtained from at least three independent experiments.

Mentions: We next investigated the time-course and concentration dependency of changes in the mRNA expression for P2Y2 receptors induced by ATRA, its stereo-isomer 9-cis retinoic acid (9-cisRA) and the synthetic RAR agonist Am80. All these retinoids tested caused significant and drastic increases in the mRNA expression in a concentration- and incubation time-dependent manner (Figure 2). After treatment with 1 µM ATRA and Am80 for 24 h, the expression level reached to 768.4 ± 458.1 and 862.2 ± 24.7% of control, respectively (Figure 2A, B). 9-cisRA, an agonist to RXRs and possibly to RARs, showed a moderate but significant rise in P2Y2 receptor mRNA in NHEKs (Figure 2C). These results suggest that the upregulation of P2Y2 receptors by retinoids would be mainly mediated by RARs in NHEKs.Figure 2


Upregulation of P2Y2 receptors by retinoids in normal human epidermal keratinocytes.

Fujishita K, Koizumi S, Inoue K - Purinergic Signal. (2006)

Time- and concentration-dependency of three different retinoids-induced changes in mRNAs in NHEKs. Diagram shows the quantity of P2Y2 mRNAs detected by real-time RT-PCR after treatment with 0.001–1 µM ATRA (A), Am80 (B) and 9-cisRA (C) for 2–24 h. The P2Y2 mRNA levels in cells treated with various concentrations of retinoids were normalized by those in retinoids-untreated control cells at each incubation period (2, 6, 12 and 24 h), and expressed as “percentage (%) of control.” All these retinoids, and especially Am80, caused a linear increase in P2Y2 mRNAs in a concentration- and time-dependent fashion. Asterisks show significant difference in the P2Y2 mRNA levels from control groups (*P < 0.05; **P < 0.01). Data were obtained from at least three independent experiments.
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Related In: Results  -  Collection

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Fig2: Time- and concentration-dependency of three different retinoids-induced changes in mRNAs in NHEKs. Diagram shows the quantity of P2Y2 mRNAs detected by real-time RT-PCR after treatment with 0.001–1 µM ATRA (A), Am80 (B) and 9-cisRA (C) for 2–24 h. The P2Y2 mRNA levels in cells treated with various concentrations of retinoids were normalized by those in retinoids-untreated control cells at each incubation period (2, 6, 12 and 24 h), and expressed as “percentage (%) of control.” All these retinoids, and especially Am80, caused a linear increase in P2Y2 mRNAs in a concentration- and time-dependent fashion. Asterisks show significant difference in the P2Y2 mRNA levels from control groups (*P < 0.05; **P < 0.01). Data were obtained from at least three independent experiments.
Mentions: We next investigated the time-course and concentration dependency of changes in the mRNA expression for P2Y2 receptors induced by ATRA, its stereo-isomer 9-cis retinoic acid (9-cisRA) and the synthetic RAR agonist Am80. All these retinoids tested caused significant and drastic increases in the mRNA expression in a concentration- and incubation time-dependent manner (Figure 2). After treatment with 1 µM ATRA and Am80 for 24 h, the expression level reached to 768.4 ± 458.1 and 862.2 ± 24.7% of control, respectively (Figure 2A, B). 9-cisRA, an agonist to RXRs and possibly to RARs, showed a moderate but significant rise in P2Y2 receptor mRNA in NHEKs (Figure 2C). These results suggest that the upregulation of P2Y2 receptors by retinoids would be mainly mediated by RARs in NHEKs.Figure 2

Bottom Line: The DNA microarray analysis also revealed that ATRA upregulates various genes involved in the differentiation of NHEKs.Our present results suggest that retinoids, at least in part, exert their proliferative effects by upregulating P2Y2 receptors in NHEKs.This effect of retinoids may be closely related to their therapeutic effect against various ailments or aging events in skins such as over-keratinization, pigmentation and re-modeling.

View Article: PubMed Central - PubMed

Affiliation: Division of Biosignaling, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo, Japan.

ABSTRACT
Retinoids, vitamin A derivatives, are important regulators of the growth and differentiation of skin cells. Although retinoids are therapeutically used for several skin ailments, little is known about their effects on P2 receptors, known to be involved in various functions in the skin. DNA array analysis showed that treatment of normal human epidermal keratinocytes (NHEKs) with all-trans-retinoic acid (ATRA), an agonist to RAR (retinoic acid receptor), enhanced the expression of mRNA for the P2Y2 receptor, a metabotropic P2 receptor that is known to be involved in the proliferation of the epidermis. The expression of other P2 receptors in NHEKs was not affected by ATRA. ATRA increased the mRNA for the P2Y2 receptor in a concentration-dependent fashion (1 nM to 1 muM). Am80, a synthesized agonist to RAR, showed a similar enhancement, whereas 9-cis-retinoic acid (9-cisRA), an agonist to RXR (retinoid X receptor), enhanced P2Y2 gene expression to a lesser extent. Ca(2+) imaging analysis showed that ATRA also increased the function of P2Y2 receptors in NHEKs. Retinoids are known to enhance the turnover of the epidermis by increasing both proliferation and terminal differentiation. The DNA microarray analysis also revealed that ATRA upregulates various genes involved in the differentiation of NHEKs. Our present results suggest that retinoids, at least in part, exert their proliferative effects by upregulating P2Y2 receptors in NHEKs. This effect of retinoids may be closely related to their therapeutic effect against various ailments or aging events in skins such as over-keratinization, pigmentation and re-modeling.

No MeSH data available.


Related in: MedlinePlus