title: DC-SIGN ligation greatly affects dendritic cell differentiation from monocytes compromising their normal function.
abstract: DC-SIGN is a C-type lectin selectively expressed by certain types of DCs, including monocyte-derived DCs. Many reports have described the impact of DC-SIGN engagement with concomitant TLR signaling in tailoring of the DC maturation process, but so far, none has addressed the importance of DC-SIGN engagement during their differentiation from blood progenitors. We therefore examined the role of DC-SIGN engagement limited to the stage of IL-4-guided differentiation of DCs from human peripheral blood monocytes but not during maturation. We used two different anti-DC-SIGN antibodies with reported DC-SIGN-engaging activities. In cultures with DC-SIGN ligands, the resulting iDCs displayed abrogated expression of differentiation markers CD1a and DC-SIGN. Without further DC-SIGN activation, such DCs matured with low CD80/CD86 and high ILT3 expression, along with the appearance of macrophage marker CD14. Additionally, treated DCs indicated a tolerogenic potential by possessing a low, allostimulatory capacity and inducing naïve, allogeneic CD4(+) T cells to produce low levels of IFN-γ. Upon activation, IL-10 production was greatly increased by such DCs; however, the use of IL-10-blocking antibodies could not completely reverse alternative DC activation. This suggests an alternative activation response that is a result of a different elementary state of DCs generated with concomitant ligation of DC-SIGN. During differentiation, IL-4-induced pSTAT6 was reduced by DC-SIGN ligands. Furthermore, during LPS-induced maturation, treated DCs displayed lowered activation levels of p38 MAPK, STAT1, as well as STAT6, compared with controls. Collectively, evidence is presented confirming a crucial role for DC-SIGN signaling in DC generation from monocytes.
authors: Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia. svajgerurban@yahoo.com
authors: Urban
authors: U
authors: Svajger
authors: Natasa
authors: N
authors: Obermajer
authors: Marko
authors: M
authors: Anderluh
authors: Janko
authors: J
authors: Kos
authors: Matjaz
authors: M
authors: Jeras
mesh_terms: D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D004705:Endocytosis; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D009000:Monocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D015847:Interleukin-4; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C494101:STAT6 protein, human