title: Macrolides increase the expression of 11β-hydroxysteroid dehydrogenase 1 in human sinonasal epithelium, contributing to glucocorticoid activation in sinonasal mucosa.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Hallym University, Chuncheon, Gangwon Do, South Korea.
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Kook
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Ha Kyun
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Sae Hee
authors.initials: SH
authors.lastname: Lim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Kyung Won
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Sang Hag
authors.initials: SH
authors.lastname: Lee
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003345:Corticosterone / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000187:drug effects* / Q000201:enzymology; D010256:Paranasal Sinuses / Q000187:drug effects* / Q000201:enzymology
chemical_list: D005938:Glucocorticoids; D018942:Macrolides; D003577:Cytochrome P-450 Enzyme System; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone