Lipopolysaccharide regulates thymic stromal lymphopoietin expression via TLR4/MAPK/Akt/NF-κB‒signaling pathways in nasal fibroblasts: differential inhibitory effects of macrolide and corticosteroid

Background: Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinonasal mucosa. Thymic stromal lymphopoietin (TSLP) is associated with T-helper 2 (Th2) response and induced by pathogen, allergen, toll-like receptor (TLR) ligands, and cytokines. Fibroblasts are known to be modulators of wound-healing, from inflammation to tissue remodeling. We examined effect of lipopolysaccharide (LPS) on TSLP production and the underlying mechanisms. We aimed to determine whether the effects of commonly used medications in CRS, namely corticosteroids, and macrolides, are related to LPS-induced TSLP in nasal fibroblasts. Methods: Fibroblasts were isolated from inferior turbinate tissues of CRS patients. TSLP and TLR4 expressions were determined by reverse transcript‒polymerase chain reaction (RT-PCR), Western blot, enzyme-linked immunoassay, and immunofluorescence staining. Mitogen-activated protein kinase (MAPK), protein kinase B (Akt), and nuclear factor-kappaB (NF-κB) phosphorylation was determined by Western blot and/or luciferase assay. Results: LPS increased TSLP expression in a dose- and time-dependent manner. LPS antagonist and corticosteroids inhibited TLR4 expression in LPS-stimulated fibroblasts. LPS-RS, macrolides, corticosteroids, and specific inhibitors suppressed LPS-induced alterations. Ex vivo culture showed similar results. Conclusion: LPS induces TSLP production via the TLR4, MAPK, Akt, and NF-κB pathways. The effects of corticosteroids and macrolides are related to LPS-induced TSLP expression. We explored new treatment modalities targeting LPS-induced TSLP production that could replace the currently used corticosteroid and macrolides for treatment of CRS.