Fluticasone propionate and Salmeterol combination induces SOCS-3 expression in airway epithelial cells

Fluticasone propionate (FP) and Salmeterol (SAL) are commonly used in combination therapy for patients with Chronic obstructive pulmonary disease (COPD). Clinical studies show that FP/SAL used in combination therapy was found to inhibit airway inflammation in COPD patients. However, the mechanisms associated with FP/SAL induced anti-inflammatory effects were not clear. We have evaluated the effect of FP/SAL and tobacco smoke (TS) on SOCS-3 and interleukine-6 expression in bronchial airway epithelial cells (BAEpCs). Human BAEpCs were exposed to TS and subsequently treated with FP or SAL alone or in combinations in the presence and absence of mitogen activated protein kinase (MAPK) inhibitors for either Erk1/Erk2, or p38 or PI3 kinase. In BAEpCs, TS induced IL-6 expression via ERK1/ERK2 MAPK pathway and FP/SAL inhibited TS mediated IL-6 expression. TS down regulated the SOCS-3 expression via activation of Erk1/Erk2, and p38 MAPK signaling. When TS exposed BAEpCs were treated with FP/SAL SOCS-3 expression was restored. FP/SAL combinations induced significantly higher expression of SOCS-3 in BAEpCs when compared to individual drug. Pretreatment with Ly294002 a PI3 MAPK inhibitor significantly attenuated FP/SAL induced SOCS-3 expression in BAEpCs. Furthermore, FP/SAL blunted TS induced phosphorylation of Erk1/Erk2 and p38 MAPK in BAEpCs. Our study suggests that TS inhibits SOCS-3, combination of FP/SAL has a profound synergistic effect on SOCS-3 induction in BAEpCs and it is dependent on PI3 kinase signaling pathway. SOCS-3 may represent a potential biomarker for understanding the efficacy and a novel anti-inflammatory mechanism of FP/SAL combination therapy in the treatment of COPD.