Abstract
The human host defense peptide LL-37 influences double-stranded RNA signaling, but this process is not well understood. Here, we investigate synergistic actions of LL-37 and synthetic double-stranded RNA (poly I:C) on toll-like receptor 3 (TLR3) expression and signaling, and examine underlying mechanisms. In bronchial epithelial BEAS-2B cells, LL-37 potentiated poly I:C-induced TLR3 mRNA and protein expression demonstrated by qPCR and Western blot, respectively. Interestingly, these effects were associated with increased uptake of rhodamine-tagged poly I:C visualized by immunocytochemistry. The LL-37/poly I:C-induced upregulation of TLR3 mRNA expression was prevented by the endosomal acidification inhibitor chloroquine, indicating involvement of downstream TLR3 signaling. The glucocorticoid dexamethasone reduced LL-37/poly I:C-induced TLR3 expression on both mRNA and protein levels, and this effect was associated with increased IκBα protein expression, suggesting that dexamethasone acts via attenuation of NF-κB activity. We conclude that LL-37 potentiates poly I:C-induced upregulation of TLR3 through a mechanism that may involve enhanced import of poly I:C and that LL-37/poly I:C-induced TLR3 expression is associated with downstream TLR3 signaling and sensitive to inhibition of NF-κB activity.
Highlights
Toll-like receptors (TLRs) are important innate immune receptors that trigger defense and inflammatory responses in host cells in response to various microorganisms and pro-inflammatory agents [1]
We show that LL-37 potentiates Polycytidylic acid (poly I):C-induced upregulation of toll-like receptor 3 (TLR3) expression, and that this effect is associated with activation of TLR3 signaling and sensitive to pharmacological inhibition of NF-κB activity
We demonstrate on both transcript and protein levels that the host defense peptide LL-37 potentiates poly I:C-induced upregulation of TLR3 expression in human bronchial BEAS-2B epithelial cells, and that this effect is associated with LL-37evoked increase of cellular uptake of poly I:C
Summary
Toll-like receptors (TLRs) are important innate immune receptors that trigger defense and inflammatory responses in host cells in response to various microorganisms and pro-inflammatory agents [1]. The TLR family consists of about ten members of plasma membrane and intracellular receptors in humans, and their expression is largely dependent on cell type [2]. The activated TLR3 receptor increases expression of transcription factors interferon regulatory factor 3 and 7, and nuclear factor kappa B (NF-κB), leading to the production and secretion of type I interferons and pro-inflammatory cytokines [3–6]. The human host defense peptide LL-37 is part of the first line of defense against invading pathogens [7]. Besides showing activity against microorganisms, LL-37 modulates the immune system by acting as a chemoattractant for several types of immune cells and by promoting their expression of pro-inflammatory cytokines [13–16]
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