14, 15員環マクロライド系抗菌薬の免疫調節作用とミトコンドリア代謝機能

抄録

The 14- and 15-membered macrolide antibiotics, such as erythromycin, clarithromycin （CAM）, and azithromycin, have immunomodulatory activity. Low-dose and long-term administration of the macrolides leads to symptom improvements of neutrophilic chronic inflammatory airway diseases, such as diffuse panbronchiolitis, chronic sinusitis, sinobronchial syndrome, cystic fibrosis, and chronic obstructive pulmonary disease. Suppression of proinflammatory cytokine and mucin production has been reported as a mechanism of the immunomodulating activity. Although the macrolides have beneficial immunomodulatory activity, there is a concern that the use of drugs other than antibacterial activity may lead to the development of resistant bacteria. Identifying target molecules is valuable and essential information for screening new immunomodulating drugs without antibacterial activity. We previously screened CAM-binding proteins in human airway respiratory cells. Mitochondrial proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal-associated protein 25-like （NIPSNAP）1 and 2 were identified. LPS-induced IL-8 production and mitochondria respiration/metabolism were suppressed by knockdown either NIPSNAP1 or 2 using siRNA and shRNA. Inhibition of mitochondria function by deferiprone or m-chlorophenylhydrazone reduced the LPS-induced IL-8 production. CAM inhibited mitochondria respiration and metabolism. Our observations indicate that mitochondrial proteins NIPSNAP1, 2 are a target molecule of CAM for immunomodulatory activity, and the immunomodulation links to mitochondria function, such as respiration and metabolism.