title: Protein kinase Cδ is a critical component of Dectin-1 signaling in primary human monocytes.
abstract: Zymosan, a mimic of fungal pathogens, and its opsonized form (ZOP) are potent stimulators of monocyte NADPH oxidase, resulting in the production of O(2)(.-), which is critical for host defense against fungal and bacterial pathogens and efficient immune responses; however, uncontrolled O(2)(.-) production may contribute to chronic inflammation and tissue injury. Our laboratory has focused on characterizing the signal transduction pathways that regulate NADPH oxidase activity in primary human monocytes. In this study, we examined the involvement of various pattern recognition receptors and found that Dectin-1 is the primary receptor for zymosan stimulation of O(2)(.-) via NADPH oxidase in human monocytes, whereas Dectin-1 and CR3 mediate the activation by ZOP. Further studies identified Syk and Src as important signaling components downstream of Dectin-1 and additionally identified PKCδ as a novel downstream signaling component for zymosan-induced O(2)(.-) as well as phagocytosis. Our results show that Syk and Src association with Dectin-1 is dependent on PKCδ activity and expression and demonstrate direct binding between Dectin-1 and PKCδ. Finally, our data show that PKCδ and Syk but not Src are required for Dectin-1-mediated phagocytosis. Taken together, our data identify Dectin-1 as the major PRR for zymosan in primary human monocytes and identify PKCδ as a novel downstream signaling kinase for Dectin-1-mediated regulation of monocyte NADPH oxidase and zymosan phagocytosis.
authors.affiliation: Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Deena H
authors.initials: DH
authors.lastname: Elsori
authors.forename: Valentin P
authors.initials: VP
authors.lastname: Yakubenko
authors.forename: Talat
authors.initials: T
authors.lastname: Roome
authors.forename: Praveena S
authors.initials: PS
authors.lastname: Thiagarajan
authors.forename: Ashish
authors.initials: A
authors.lastname: Bhattacharjee
authors.forename: Satya P
authors.initials: SP
authors.lastname: Yadav
authors.forename: Martha K
authors.initials: MK
authors.lastname: Cathcart
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D037181:Lectins, C-Type; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010587:Phagocytosis; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D020349:Surface Plasmon Resonance; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015054:Zymosan / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D016177:Macrophage-1 Antigen; D008565:Membrane Proteins; D019255:NADPH Oxidases; D009419:Nerve Tissue Proteins; D051745:Protein Kinase C-delta; D011505:Protein-Tyrosine Kinases; D013481:Superoxides; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014443:Tyrosine; D015054:Zymosan; D019061:src-Family Kinases; D000099181:Dectin-1; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C000606896:SYK protein, human