Low concentrations of LL-37 alter IL-8 production by keratinocytes and bronchial epithelial cells in response to proinflammatory stimuli

The immunomodulatory cationic host defence peptide LL-37 plays an important role in epithelial innate immunity; at higher concentrations (20-50 mu g mL(-1)) associated with inflammation, LL-37 elicits the production of cytokines and chemokines. It was demonstrated here that lower, physiologically relevant LL-37 concentrations (2-3 mu g mL(-1)) altered epithelial cell responses to proinflammatory stimuli. In combination with interleukin-1 beta (IL-1 beta) and the Toll-like receptor-5 (TLR5) agonist flagellin, these low concentrations of LL-37 synergistically increased IL-8 production by both proliferating and differentiated keratinocytes and by bronchial epithelial cells. In combination with the TLR2/1 agonist PAM3CSK4, LL-37 synergistically induced transcription and the release of both IL-8 and IL-6 from primary bronchial epithelial cells; the IL-8 response was demonstrated to be regulated by epidermal growth factor receptor signalling. Treatment of bronchial epithelial cells with LL-37 and the TLR3 agonist polyI:C resulted in synergistic increases in IL-8 release and cytotoxicity. These data indicate that low concentrations of LL-37 may alter epithelial responses to infecting microorganisms in vivo.