Abstract
ObjectiveThe importance of human host defense peptide LL-37 in vascular innate immunity is not understood. Here, we assess the impact of LL-37 on double-stranded RNA (dsRNA) signaling in human vascular smooth muscle cells.Materials and methodsCellular import of LL-37 and synthetic dsRNA (poly I:C) were investigated by immunocytochemistry and fluorescence imaging. Transcript and protein expression were determined by qPCR, ELISA and Western blot. Knockdown of TLR3 was performed by siRNA.ResultsLL-37 was rapidly internalized, suggesting that it has intracellular actions. Co-stimulation with poly I:C and LL-37 enhanced pro-inflammatory IL-6 and MCP-1 transcripts several fold compared to treatment with poly I:C or LL-37 alone. Poly I:C increased IL-6 and MCP-1 protein production, and this effect was potentiated by LL-37. LL-37-induced stimulation of poly I:C signaling was not associated with enhanced import of poly I:C. Treatment with poly I:C and LL-37 in combination increased expression of dsRNA receptor TLR3 compared to stimulation with poly I:C or LL-37 alone. In TLR3 knockdown cells, treatment with poly I:C and LL-37 in combination had no effect on IL-6 and MCP-1 expression, showing loss of function.ConclusionsLL-37 potentiates dsRNA-induced cytokine production through up-regulation of TLR3 expression representing a novel pro-inflammatory mechanism.
Highlights
The human host defense peptide (HDP) LL-37 belongs to the cathelicidin family of HDPs and is well-recognized as an important part of the innate immune response [1,2,3]
We demonstrate that LL-37 potentiates double-stranded RNA (dsRNA)-induced production of the pro-inflammatory cytokines interleukin 6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1) via up-regulation of the dsRNA receptor TLR3, offering a novel mechanism by which LL-37 may modulate vascular innate immunity
We show that LL-37 potentiates dsRNA-induced stimulation of pro-inflammatory IL-6 and MCP-1 production in Human coronary artery smooth muscle cells (hCASMCs) through a mechanism that involves up-regulation of the dsRNA receptor TLR3
Summary
The human host defense peptide (HDP) LL-37 belongs to the cathelicidin family of HDPs and is well-recognized as an important part of the innate immune response [1,2,3]. LL-37 is produced by white blood cells and epithelial cells and formed as the pro-protein hCAP18 which is encoded by one single gene, named CAMP [4]. The hCAP18 protein is secreted and processed extracellularly to LL-37 in a reaction catalysed by serine protease 3 and kallikrein 5 [5, 6]. LL-37 kills bacteria through permeabilization of the Inflammation is regarded to play an important role in the etiology and progression of atherosclerosis, and both interleukin 6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1) seem to be associated with this process [16]. The atherosclerotic plaques contain smooth muscle cells which represent a major cell type of the plaque, and LL-37 produced by the macrophages may affect the functional properties of
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