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To investigate the mechanism for LL-37 inducing MUC5AC mucin production in airway epithelial cells. The airway epithelial NCI-H292 cells were stimulated with various concentrations of LL-37 synthetic peptide and scrambled LL-37 (sLL-37) synthetic peptide ranged from 2.5 to 10 μg/mL. The effects of LL-37 and sLL-37 on TNF-α-converting enzyme (TACE) and EGFR activation and MUC5AC mucin production were evaluated by fluorescence resonance energy transfer (FRET) assay, Western blotting and ELISA respectively. Furthermore, we measured changes of transforming growth factor-alpha (TGF-α) in culture supernatants. A serious of inhibitors including TACE inhibitor TAPI-1, EGFR inhibitor AG1478, EGFR-neutralizing antibody, TGF-α-neutralizing antibody, amphiregulin (AR)-neutralizing antibody, and heparin binding-epidermal growth factor (HB-EGF)-neutralizing antibody were used to block the signaling pathway. Human serum and FBS were also used to investigate the effects of serum on LL-37-induced MUC5AC mucin production. LL-37 induced TACE and EGFR activation, as well as TGF-α and MUC5AC mucin production by NCI-H292 cells in a dose-dependent manner. EGFR-neutralizing antibody and AG1478 inhibited LL-37-induced EGFR activation and subsequent MUC5AC mucin production, whereas TGF-α-neutralizing antibody increased LL-37-induced TGF-α production. TAPI-1 inhibited LL-37-induced TGF-α production, EGFR activation and subsequent MUC5AC mucin production, whereas TGF-α-neutralizing antibody, but not AR- or HB-EGF-neutralizing antibody, inhibited LL-37-induced EGFR activation and subsequent MUC5AC mucin production in NCI-H292 cells. The sLL-37 had no effect on TACE and EGFR activation and MUC5AC mucin production. Additionally, Human serum, rather than FBS, inhibited LL-37-induced MUC5AC mucin production. LL-37 induces MUC5AC mucin production by airway epithelial cells via TACE-TGF-α-EGFR pathway.