title: CCK8 negatively regulates the TLR9-induced activation of human peripheral blood pDCs by targeting TRAF6 signaling.
abstract: Plasmacytoid dendritic cells (pDCs) are specialized in rapid and massive secretion of type I interferon in response to foreign nuclei acids. Combined with their antigen presentation capacity, this powerful functionality enables pDCs to orchestrate innate and adaptive immune responses. Cholecystokinin octapeptide (CCK8) is a potent immunomodulator, whose role in pDCs function is unknown. In this study, we found that two different cholecystokinin receptors, CCK1R and CCK2R, are expressed on human peripheral blood pDCs. Exogenous CCK8 was able to modulate the TLR-induced activation of pDCs, including phenotypic maturation, IFN-α synthesis and secretion, and could also regulate the potential of pDCs to induce adaptive immune responses in vitro. CCK8 inhibited TLR9-induced activation of tumor-necrosis factor receptor-associated factor 6, which is an important adapter protein in activation of interferon-regulatory factor (IRF)5 and IRF7, possibly through CCK2R, by evoking the activity of protein kinase (PK)A and reducing the activity of PKC. All these results indicate that CCK8 can inhibit the TLR9-induced phenotypic maturation and activation of pDCs, acting through CCK2R by modulating the tumor-necrosis factor receptor-associated factor 6 signaling pathways.
authors.affiliation: Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.
authors.forename: Xianxian
authors.initials: X
authors.lastname: Jia
authors.forename: Bin
authors.initials: B
authors.lastname: Cong
authors.forename: Jingge
authors.initials: J
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Liu
authors.forename: Heping
authors.initials: H
authors.lastname: Chang
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.forename: Chunling
authors.initials: C
authors.lastname: Ma
mesh_terms: D003713:Dendritic Cells / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D043886:Receptor, Cholecystokinin A / Q000235:genetics / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D012844:Sincalide / Q000235:genetics* / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D018124:Receptors, Tumor Necrosis Factor; C495371:TLR9 protein, human; D048029:TNF Receptor-Associated Factor 6; D051217:Toll-Like Receptor 9; D012844:Sincalide
keywords: CCK8; IFN-α; IRF7; Plasmacytoid dendritic cells; TRAF6