Macrolides increase the expression of 11β-hydroxysteroid dehydrogenase 1 in human sinonasal epithelium, contributing to glucocorticoid activation in sinonasal mucosa

Se Jin Park, Jin Ho Kook, Ha Kyun Kim, Sung Hoon Kang, Sae Hee Lim, Hyun Jin Kim, Kyung Won Kim, Tae-Hoon Kim, Sang Hag Lee

Research output: Contribution to journalArticle

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Abstract

Background and Purpose The anti-inflammatory and immunomodulatory effects of macrolides include the ability to decrease mucus secretion and inhibit inflammatory mediators in chronic rhinosinusitis. Nevertheless, their mechanisms of action remain to be determined. Here we have investigated the effects of macrolide antibiotics (clarithromycin, azithromycin and josamycin; representating the 14-, 15- and 16-membered macrolides) on endogenous steroids in human sinonasal epithelial cells and mouse nasal mucosa. Experimental Approach The effects of macrolides on the expression of steroid-converting enzymes [11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2)], steroid-synthesizing enzymes (3β-HSD, CYP21, CYP11B1 and CYP11A1) and cortisol levels were assessed in cultured human epithelial cells. In control and adrenalectomized mice, these enzymes and corticosterone levels were evaluated in nasal mucosa and serum after administration of macrolides. Key Results The expression levels of 3β-HSD, CYP21, 11β-HSD1 and CYP11B1 increased in human epithelial cells treated with clarithromycin and azithromycin, whereas the expression levels of 11β-HSD2 and CYP11A1 were not affected. Josamycin had no effects on the expression of these enzymes. Cortisol levels increased in epithelial cells treated with clarithromycin or azithromycin. The expression of 3β-HSD, CYP11A1, CYP21, CYP11B1 and 11β-HSD1 was upregulated in nasal mucosa of mice treated with clarithromycin or azithromycin, but not in adrenalectomized mice. Conclusions and Implications This study provides evidence that 14- and 15-membered macrolide antibiotics may affect the expression of steroid-synthesizing and steroid-converting enzymes in human sinonasal epithelial cells and mouse nasal mucosa, increasing the endogenous cortisol levels in sinonasal mucosa.

Original languageEnglish
Pages (from-to)5083-5095
Number of pages13
JournalBritish Journal of Pharmacology
Volume172
Issue number21
DOIs
Publication statusPublished - 2015 Nov 1

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11-beta-Hydroxysteroid Dehydrogenases
Macrolides
Glucocorticoids
Mucous Membrane
Azithromycin
Clarithromycin
Epithelium
Nasal Mucosa
Steroid 11-beta-Hydroxylase
Cholesterol Side-Chain Cleavage Enzyme
Epithelial Cells
Steroids
Josamycin
Enzymes
Hydrocortisone
Anti-Bacterial Agents
Mucus
Corticosterone
Anti-Inflammatory Agents
Serum

ASJC Scopus subject areas

  • Pharmacology

Cite this

Macrolides increase the expression of 11β-hydroxysteroid dehydrogenase 1 in human sinonasal epithelium, contributing to glucocorticoid activation in sinonasal mucosa. / Park, Se Jin; Kook, Jin Ho; Kim, Ha Kyun; Kang, Sung Hoon; Lim, Sae Hee; Kim, Hyun Jin; Kim, Kyung Won; Kim, Tae-Hoon; Lee, Sang Hag.

In: British Journal of Pharmacology, Vol. 172, No. 21, 01.11.2015, p. 5083-5095.

Research output: Contribution to journalArticle

Park, Se Jin ; Kook, Jin Ho ; Kim, Ha Kyun ; Kang, Sung Hoon ; Lim, Sae Hee ; Kim, Hyun Jin ; Kim, Kyung Won ; Kim, Tae-Hoon ; Lee, Sang Hag. / Macrolides increase the expression of 11β-hydroxysteroid dehydrogenase 1 in human sinonasal epithelium, contributing to glucocorticoid activation in sinonasal mucosa. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 21. pp. 5083-5095.
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abstract = "Background and Purpose The anti-inflammatory and immunomodulatory effects of macrolides include the ability to decrease mucus secretion and inhibit inflammatory mediators in chronic rhinosinusitis. Nevertheless, their mechanisms of action remain to be determined. Here we have investigated the effects of macrolide antibiotics (clarithromycin, azithromycin and josamycin; representating the 14-, 15- and 16-membered macrolides) on endogenous steroids in human sinonasal epithelial cells and mouse nasal mucosa. Experimental Approach The effects of macrolides on the expression of steroid-converting enzymes [11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2)], steroid-synthesizing enzymes (3β-HSD, CYP21, CYP11B1 and CYP11A1) and cortisol levels were assessed in cultured human epithelial cells. In control and adrenalectomized mice, these enzymes and corticosterone levels were evaluated in nasal mucosa and serum after administration of macrolides. Key Results The expression levels of 3β-HSD, CYP21, 11β-HSD1 and CYP11B1 increased in human epithelial cells treated with clarithromycin and azithromycin, whereas the expression levels of 11β-HSD2 and CYP11A1 were not affected. Josamycin had no effects on the expression of these enzymes. Cortisol levels increased in epithelial cells treated with clarithromycin or azithromycin. The expression of 3β-HSD, CYP11A1, CYP21, CYP11B1 and 11β-HSD1 was upregulated in nasal mucosa of mice treated with clarithromycin or azithromycin, but not in adrenalectomized mice. Conclusions and Implications This study provides evidence that 14- and 15-membered macrolide antibiotics may affect the expression of steroid-synthesizing and steroid-converting enzymes in human sinonasal epithelial cells and mouse nasal mucosa, increasing the endogenous cortisol levels in sinonasal mucosa.",
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AU - Park, Se Jin

AU - Kook, Jin Ho

AU - Kim, Ha Kyun

AU - Kang, Sung Hoon

AU - Lim, Sae Hee

AU - Kim, Hyun Jin

AU - Kim, Kyung Won

AU - Kim, Tae-Hoon

AU - Lee, Sang Hag

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AB - Background and Purpose The anti-inflammatory and immunomodulatory effects of macrolides include the ability to decrease mucus secretion and inhibit inflammatory mediators in chronic rhinosinusitis. Nevertheless, their mechanisms of action remain to be determined. Here we have investigated the effects of macrolide antibiotics (clarithromycin, azithromycin and josamycin; representating the 14-, 15- and 16-membered macrolides) on endogenous steroids in human sinonasal epithelial cells and mouse nasal mucosa. Experimental Approach The effects of macrolides on the expression of steroid-converting enzymes [11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2)], steroid-synthesizing enzymes (3β-HSD, CYP21, CYP11B1 and CYP11A1) and cortisol levels were assessed in cultured human epithelial cells. In control and adrenalectomized mice, these enzymes and corticosterone levels were evaluated in nasal mucosa and serum after administration of macrolides. Key Results The expression levels of 3β-HSD, CYP21, 11β-HSD1 and CYP11B1 increased in human epithelial cells treated with clarithromycin and azithromycin, whereas the expression levels of 11β-HSD2 and CYP11A1 were not affected. Josamycin had no effects on the expression of these enzymes. Cortisol levels increased in epithelial cells treated with clarithromycin or azithromycin. The expression of 3β-HSD, CYP11A1, CYP21, CYP11B1 and 11β-HSD1 was upregulated in nasal mucosa of mice treated with clarithromycin or azithromycin, but not in adrenalectomized mice. Conclusions and Implications This study provides evidence that 14- and 15-membered macrolide antibiotics may affect the expression of steroid-synthesizing and steroid-converting enzymes in human sinonasal epithelial cells and mouse nasal mucosa, increasing the endogenous cortisol levels in sinonasal mucosa.

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