Abstract
The role of dendritic cells (DCs) in directing the immune response is due in part to their capacity to produce a range of cytokines. Importantly, DCs are a source of cytokines, which can promote T cell survival and T helper cell differentiation. While it has become evident that soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptors (SNAREs) are involved in membrane fusion and ultimately cytokine release, little is known about which members of this family facilitate the secretion of specific cytokines from DCs. We profiled mRNA of 18 SNARE proteins in DCs in response to activation with a panel of three Toll-like receptors (TLR) ligands and show differential expression of SNAREs in response to their stimulus and subsequent secretion patterns. Of interest, STX3 mRNA was up-regulated in response to TLR4 and TLR7 activation but not TLR2 activation. This correlated with secretion of IL-6 and MIP-1α. Abolishment of STX3 from DCs by RNAi resulted in the attenuation of IL-6 levels and to some extent MIP-1α levels. Analysis of subcellular location of STX3 by confocal microscopy showed translocation of STX3 to the cell membrane only in DCs secreting IL-6 or MIP-1α, indicating a role for STX3 in trafficking of these immune mediators. Given the role of IL-6 in Th17 differentiation, these findings suggest the potential of STX3 as therapeutic target in inflammatory disease.
Highlights
Since the discovery of soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptors (SNAREs) in the 1980s they have been defined to have an essential role for the trafficking of molecules and membranes within cells [1]
SNARE mRNA EXPRESSION IN dendritic cells (DCs) FOLLOWING ACTIVATION WITH A PANEL OF Toll-like receptors (TLR) LIGANDS Using RT-quantitative polymerase chain reaction we analyzed the expression of Qa SNAREs (STX2, STX3, STX4, STX5, STX7, STX11, STX12, and STX16) (Figure 1), Qb SNARES (Vti1a and Vti1b), Qbc SNARE (SNAP23), Qc SNARE (STX6)(Figure 2), and R SNAREs (VAMP1, VAMP2, VAMP3, VAMP4, VAMP7, and VAMP8)(Figure 3) in JAWS II DCs following stimulation with 100 ng/ml LPS, 1 mM Loxoribine, or 5 μg/ml PGN
Several studies have addressed the role of SNAREs in cytokine release from immune cells, little is still known about the specific SNAREs involved in cytokine or chemokine secretion by DCs
Summary
Since the discovery of soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptors (SNAREs) in the 1980s they have been defined to have an essential role for the trafficking of molecules and membranes within cells [1]. Dendritic cells are essential for the generation of a functional immune response They do so by the capture and processing of antigens, expression of surface co-stimulatory molecules, migration to lymphoid organs, and secretion of cytokines and chemokines [4]. Understanding these actions, such as their ability to drive T helper cell responses makes the dendritic cells (DC) a powerful tool for manipulating the immune system. The cytokines they secrete are associated with the pathogenesis of a wide range of inflammatory diseases [5]. As DCs act as a link between innate and adaptive immunity and secrete cytokines, which are important in inflammatory diseases, investigating how DCs secrete these cytokines may provide us with new therapeutic targets in these diseases
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