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

Abstract

BACKGROUND AND PURPOSEThe 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 APPROACHThe 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 RESULTSThe 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 IMPLICATIONSThis 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. IntroductionAlthough considered an infectious process induced by bacteria, viruses and fungi, chronic rhinosinusitis (CRS) with and without nasal polyps is accepted as an example of persistent mucosal inflammation resulting from multiple causes (Benninger et al., 2003;Adriaensen and Fokkens, 2013). Thus, the therapeutic potential of treatment that targets the common pathways of mucosal inflammation has resulted in significant interest in glucocorticoids and macrolides (Benninger et al., 2003;Adriaensen and Fokkens, 2013). Glucocorticoids and macrolides share some similarities in their pharmacological action, including antiinflammatory and immunomodulatory properties and both classes of compounds have been shown to improve the symptoms and signs of CRS and are recommended for the treatment of CRS by the European Position Paper on Rhinosinusitis and Nasal Polyposis (Fokkens et al., 2012).Macrolides are known to have many diverse biological activities, including the ability to modulate inflammation (Kanoh and Rubin, 2010). A recent study has indicated that macrolide antibiotics inhibit pro-inflammatory cytokine production in vitro and show similar potential to prednisolone (Wallwork et al., 2002). A study comparing the clinic...

Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy

“… 38 We additionally speculate that one of the possible mechanisms of improved time to ROSC in the azithromycin-treated group could be via an effect on steroid synthesis. Azithromycin has been shown to enhance corticosterone and cortisol levels 39 as early as 60 minutes after administration. 40 Studies investigating this mechanism are ongoing.…”