Clarithromycin Modulates Neutrophilic Inflammation Induced by Prevotella intermedia in Human Airway Epithelial Cells

<b>Objectives:</b> In the present study, we aimed to clarify the mechanisms by which periodontal pathogens, particularly <i>Prevotella intermedia</i>, induce severe neutrophilic inflammation. In addition, we aimed to test the efficacy of macrolides, which has not been resolved in the neutrophilic inflammation induced by <i>P. intermedia</i>. <b>Methods:</b> NCl-H292 human airway epithelial cells were pre-incubated with clarithromycin for 2 h before incubation with <i>P. intermedia</i> supernatants. Then, C-X-C motif chemokine ligand 8 (<i>CXCL8</i>) transcription and interleukin (IL)-8 production were measured. To elucidate the signaling pathway, mitogen-activated protein kinase inhibitors were added to the cell culture, and the cells were subjected to Western blotting. <b>Results:</b><i>P. intermedia</i> supernatants promoted <i>CXCL8</i> transcription and IL-8 production, and the reactions were significantly suppressed by clarithromycin pretreatment. Only trametinib, the selective mitogen-activated extracellular signal-regulated kinase inhibitor, downregulated <i>CXCL8</i> transcription and IL-8 production. Furthermore, Western blotting revealed that stimulation with <i>P. intermedia</i> supernatants specifically induces extracellular signal-regulated kinases (ERK) 1/2 phosphorylation, which is suppressed by clarithromycin pretreatment. Notably, the interference analysis revealed that ERK3 might be dispensable for IL-8 production under the stimulation of <i>P. intermedia</i> supernatants. <b>Conclusions:</b> Our results provide new insight into the mechanism underlying <i>P. intermedia</i>-induced production of IL-8 from human airway epithelial cells. Furthermore, macrolides might have therapeutic potential in regulating periodontal pathogen-induced neutrophilic inflammation in the lungs.