Effectiveness of atorvastatin in suppressing MUC5AC gene expression in human airway epithelial cells.

Abstract

We recently reported that chronic cholesterol depletion in NCI-H292 cells by lovastatin suppresses interleukin (IL)-1β-induced MUC5AC gene expression. However, as there are numerous statins affect MUC5AC expression, we sought to determine which statin is most effective in reducing MUC5AC expression, and whether this activity of statins is related to IL-1 receptor (IL-1RI) and mitogen-activated protein kinase (MAPK) activity. Four statins, namely atorvastatin, fluvastatin, lovastatin, and simvastatin, were tested. Cholesterol depletion was measured via modified microenzymatic fluorescence assay and filipin staining. NCI-H292 cells were pretreated with 10 μM of each statin for 1 hour, 10 ng/mL of IL-1β was added, and cells were then co-incubated with statin and IL-1β for 24 hours. MUC5AC mRNA expression was measured via real-time polymerase chain reaction (PCR). The phosphorylation levels were assayed by Western blot. Cholesterol in the plasma membrane was markedly decreased by all 4 statins, of which atorvastatin was the most potent. IL-1β-induced MUC5AC messenger RNA (mRNA) expression was most significantly decreased by 10 μM atorvastatin, to 1.4 ± 0.2-fold of the level of the untreated control group, as opposed to an increase to 4.7 ± 0.5-fold for IL-1β alone, and this suppression of MUC5AC expression was dose-dependent. This decrease in MUC5AC expression by atorvastatin was mediated via the IL-1 receptor and the MAPK pathway, including both phospho-p38 MAPK and phospho-extracellular signal-regulated kinase (phospho-ERK). These results suggest that atorvastatin is the most potent of the assayed statins with respect to suppression of IL-1β-induced MUC5AC mRNA expression, and may be considered as an anti-hypersecretory agent.