Clarithromycin attenuates IL-13-induced periostin production in human lung fibroblasts
Kosaku Komiya1,2,3,4, Shoichiro Ohta1, Kazuhiko Arima1
1Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
Background:
Periostin is a biomarker indicating the presence of type 2 inflammation and submucosal fibrosis; serum periostin levels have been associated with asthma severity. Macrolides have immunomodulatory effects and are considered a potential therapy for patients with severe asthma. Therefore, we investigated whether macrolides can also modulate pulmonary periostin production.
Methods:
Using quantitative PCR and ELISA, we measured periostin production in human lung fibroblasts stimulated by interleukin-13 (IL-13) in the presence of two 14-member-ring macrolides-clarithromycin or erythromycin-or a 16-member-ring macrolide, josamycin. Phosphorylation of signal transducers and activators of transcription 6 (STAT6), downstream of IL-13 signaling, was evaluated by Western blotting. Changes in global gene expression profile induced by IL-13 and/or clarithromycin were assessed by DNA microarray analysis.
Results:
Clarithromycin and erythromycin, but not josamycin, inhibited IL-13-stimulated periostin production. The inhibitory effects of clarithromycin were stronger than those of erythromycin. Clarithromycin significantly attenuated STAT6 phosphorylation induced by IL-13. Global gene expression analyses demonstrated that IL-13 increased mRNA expression of 454 genes more than 4-fold, while decreasing its expression in 390 of these genes (85.9%), mainly "extracellular," "plasma membrane," or "defense response" genes. On the other hand, clarithromycin suppressed 9.8% of the genes in the absence of IL-13. Clarithromycin primarily attenuated the gene expression of extracellular matrix protein, including periostin, especially after IL-13.
Conclusions:
Clarithromycin suppressed IL-13-induced periostin production in human lung fibroblasts, in part by inhibiting STAT6 phosphorylation. This suggests a novel mechanism of the immunomodulatory effect of clarithromycin in asthmatic airway inflammation and fibrosis.
Insights
Clarithromycin and erythromycin, but not josamycin, reduced pulmonary periostin production in asthma models. This macrolide effect may offer new treatments for airway inflammation and fibrosis.
Area of Science:
- Pulmonary Medicine
- Immunology
- Pharmacology
Background:
- Periostin is a biomarker for type 2 inflammation and fibrosis in asthma.
- Serum periostin levels correlate with asthma severity.
- Macrolides possess immunomodulatory properties and are explored for severe asthma therapy.
Purpose of the Study:
- To investigate the effect of macrolides on pulmonary periostin production.
- To determine if macrolides can modulate periostin in the context of IL-13 stimulation.
Main Methods:
- Human lung fibroblasts were stimulated with IL-13 and treated with clarithromycin, erythromycin, or josamycin.
- Periostin production was measured using quantitative PCR and ELISA.
- STAT6 phosphorylation and global gene expression were analyzed via Western blotting and DNA microarray.
Main Results:
- Clarithromycin and erythromycin inhibited IL-13-induced periostin production; josamycin did not.
- Clarithromycin demonstrated stronger inhibition and significantly reduced STAT6 phosphorylation.
- Gene expression analysis revealed clarithromycin attenuated extracellular matrix protein gene expression, including periostin, particularly post-IL-13 stimulation.
Conclusions:
- Clarithromycin suppresses IL-13-induced periostin production in lung fibroblasts.
- Inhibition of STAT6 phosphorylation is a key mechanism for clarithromycin's effect.
- This suggests a novel immunomodulatory role for clarithromycin in asthmatic airway inflammation and fibrosis.
