Steroids inhibit vascular endothelial growth factor expression via TLR4/Akt/NF-kappa B pathway in chronic rhinosinusitis with nasal polyp

Abstract

Vascular endothelial growth factor (VEGF) is elevated in chronic rhinosinusitis with nasal polyps. Steroids have anti-inflammatory properties and are ideal candidates for treating chronic inflammatory airways. The aims of this study were to identify the inhibitory effects and mechanisms of steroids on lipopolysaccharide (LPS)-induced VEGF expression in nasal polyps. Nasal polyp-derived fibroblasts (NPDFs) were stimulated with LPS alone or with both LPS and steroids were used to determine the expression levels of toll-like receptor (TLR)-4, myeloid differentiation primary response gene 88 (MyD88), and VEGF by using reverse transcription-polymerase chain reaction (RT-PCR). VEGF protein level was analyzed by immunocytochemical staining and enzyme-linked immunosorbent assay (ELISA). Small interfering RNA (siRNA) for TLR4 was transfected to down-regulate TLR4 expression. Activation of Akt and nuclear factor kappa B (NF-kappa B) pathway on VEGF expression was determined by Western blot analysis, immunocytochemical staining, and ELISA. Nasal polyp organ cultures were stimulated with LPS alone or in conjunction with steroids or LPS-RS (TLR4 inhibitor) and accessed the expression of VEGF. Steroids decreased the expressions of TLR4, MyD88, and VEGF mRNA and VEGF protein in LPS-stimulated NPDFs. Steroids inhibited LPS-induced VEGF expression levels in dose-dependent manner. The suppression of TLR4 transcription by siRNA treatment reduced LPS-induced expression of both TLR4 and VEGF in NPDFs. Furthermore, steroids inhibited the production of VEGF by blocking Akt and NF-kB activation and preventing with NF-kappa B translocation. Also, steroid and TLR4 inhibitor decreased VEGF expression in nasal polyp organ cultures. These results indicate that steroids inhibit LPS-induced VEGF expression through the TLR4/Akt/NF-kappa B signaling pathway in chronic rhinosinusitis with nasal polyp.