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1 Department of Pediatrics and Physiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
* To whom correspondence should be addressed. E-mail: brubin{at}wfubmc.edu.
Macrolide antibiotics decrease pro-inflammatory cytokine production in airway cells from subjects with chronic airway inflammation. However in subjects with COPD, short-term azithromycin therapy causes a transient early increase in the blood neutrophil oxidative burst followed by a decrease in inflammatory markers with longer administration. We studied the effects of clarithromycin (CAM) and azithromycin (AZM) on proinflammatory cytokine production from normal human bronchial epithelial (NHBE) cells. CAM decreased IL-8 over the first 6 hours, and then significantly increased interleukin (IL)-8 at 12 - 72 hours after exposure (p < 0.0001). AZM also increased IL-8 at 24 and 48 hours and CAM increased GM-CSF at 48 hours. In the presence of LPS, both CAM and AZM dose-dependently increased IL-8 secretion over 24 hours but after 5 days of exposure to CAM 10 µg/ml there is suppression of IL-8 (p < 0.001). PD 98059, an inhibitor of MAP kinase/ERK kinase inhibited CAM-induced IL-8 (p < 0.0001) and GM-CSF (p < 0.01) release. The p38 MAP kinase inhibitor, SB 203580, increased CAM-induced IL-8 release (p < 0.001) and the c-jun N-terminal kinase (JNK) inhibitor, SP 600125, had no effect on IL-8. At 120 minutes and 6 hours CAM increased phospho-ERK1/2 (pERK) but not phospho-p38 or phospho-JNK. Over the first 90 min, CAM at 10 µg/ml inhibited pERK, and then increased pERK in parallel with measured IL-8 secretion. After daily exposure to CAM for 5 days, both IL-8 and pERK returned to baseline. The p38 MAP kinase inhibitor, SB 203580 increased ERK phosphorylation and IL-8 secretion. These results suggest that macrolide antibiotics can differentially modulate pro-inflammatory cytokine secretion in NHBE cells, in part through ERK.
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