Anti-Inflammatory Effects of EM900 on Cultured Human Nasal Epithelial Cells

Abstract

Objectives: Macrolide therapy is an important conservative therapy for chronic rhinosinusitis, especially in Japan. The mechanism underlying this therapy involves anti-inflammatory and not antimicrobial activity. However, the administration of long-term low-dose macrolides (LTLMs) causes an increase in the number of antibiotic-resistant bacteria. EM900 is a derivative of erythromycin (EM), with antiinflammatory but not antibacterial effects. It does not induce macrolide-resistant bacteria as shown by LTLM. In the present study, we analyzed the inhibitory effects of EM900 in comparison with those of clarithromycin (CAM) on inflammatory cytokine production in human nasal epithelial cells (HNEpCs). Methods: After HNEpCs were cultured for 4 days, CAM or EM900 was added into the culture, followed by stimulation with tumor necrosis factor (TNF)-α. Interleukin (IL)-8 and vascular endothelial growth factor (VEGF) levels were measured using real-time polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). Results: Both the ELISA and RT-PCR showed that EM900 and CAM significantly inhibited IL-8 production in HNEpCs. In contrast, EM900 and CAM did not suppress the increased VEGF production when HNEpCs were stimulated with TNF-α. Conclusion: EM900 showed an anti-inflammatory effect, such as that of CAM, due to the inhibitory effect on IL-8 production in HNEpCs.

Erythromycin reduces nasal inflammation by inhibiting immunoglobulin production, attenuating mucus secretion, and modulating cytokine expression

“…Sadamatsu et al 36 treated asthmatic mice with a macrolide EM900 (a derivative of EM without antibacterial effects) and found significantly lower levels of IL-5, IL-13, RANTES, and IL-17A in their bronchoalveolar lavage. EM 900 also demonstrated inhibitory effect on IL-8 on culture human nasal epithelial cells in another in vitro study 37 . Pukhyalsky et al 38 studied patients with cystic fibrosis after prolonged treatments of clarithromycin.…”

Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development

“…AP-1, activator protein-1; ATF2, activating transcription factor-2; DAG, diacylglycerol; IP3, inositol trisphosphate; JNK, c-Jun N-terminal kinases; LEF, lymphoid enhancer factor; mTOR, mammalian target of rapamycin; Nrf2, nuclear factor-erythroid factor 2-related factor 2; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; RAC-1, ras-related C3 botulinum toxin substrate 1; SMAD2, mothers against DPP homolog 2; SRF, serum response factor. expression of proinflammatory cytokines and the MUC5AC gene in the A549 epithelial cell line, inhibits epithelial mucus secretion, and is comparable to clarithromycin as an inhibitor of the generation of the neutrophil-chemotactic cytokine IL-8 from human nasal epithelial cells in vitro (Otsu et al, 2011;Tojima et al, 2015;Wakayama et al, 2018). Moreover, given both before and after in vitro infection of human primary airway epithelial cells with rhinovirus (RV), EM900 inhibited both RV titers and viral RNA, as well as inflammatory cytokine generation by this cell type, apparently by reducing the expression of the intercellular adhesion molecule-1, which acts as a receptor for the RV (Lusamba Kalonji et al, 2015).…”

“…In studies related to effects on epithelial cells, AZM features most prominently, but roxithromycin and several other macrolides have also been reported to have similar effects. For example, roxithromycin had cytoprotective effects on airway epithelia after sulfurmustard exposure (Gao et al, 2007), and the nonantibiotic erythromycin derivative EM900 suppressed cytokine expression (Tojima et al, 2015;Wakayama et al, 2018) and reduced rhinovirus infection in respiratory epithelial cells (Lusamba Kalonji et al, 2015). Several review articles cover these effects in airway and gingival epithelium in detail (Lopez-Boado and Rubin, 2008;Kanoh and Rubin, 2010;Fujita et al, 2018).…”

Non-antimicrobial effects of macrolides: literature review

“…MUC5AC в эпителиальных клетках линии A549, подавляет секрецию слизи и сопоставим с кларитромицином в качестве ингибитора ИЛ-8, также известного как хемотаксический фактор нейтрофилов, в эпителиальных клетках носа человека в условиях in vitro [64]. В отличие от кларитромицина, EM900 также оказывает положительное влияние на выживаемость мышей, инфицированных вирусом гриппа H1N1: предположительно, посредством воздействия на воспалительную активность в макрофагах [65].…”