title: Synergism between curdlan and GM-CSF confers a strong inflammatory signature to dendritic cells.
abstract: A simultaneous engagement of different pathogen recognition receptors provides a tailor-made adaptive immunity for an efficient defense against distinct pathogens. For example, cross-talk of TLR and C-type lectin signaling effectively shapes distinct gene expression patterns by integrating the signals at the level of NF-κB. In this study, we extend this principle to a strong synergism between the dectin-1 agonist curdlan and an inflammatory growth factor, GM-CSF. Both together act in synergy in inducing a strong inflammatory signature that converts immature dendritic cells (DCs) to potent effector DCs. A variety of cytokines (IL-1β, IL-6, TNF-α, IL-2, and IL-12p70), costimulatory molecules (CD80, CD86, CD40, and CD70), chemokines (CXCL1, CXCL2, CXCL3, CCL12, CCL17), as well as receptors and molecules involved in fugal recognition and immunity such as Mincle, dectin-1, dectin-2, and pentraxin 3 are strongly upregulated in DC treated simultaneously with curdlan and GM-CSF. The synergistic effect of both stimuli resulted in strong IκBα phosphorylation, its rapid degradation, and enhanced nuclear translocation of all NF-κB subunits. We further identified MAPK ERK as one possible integration site of both signals, because its phosphorylation was clearly augmented when curdlan was coapplied with GM-CSF. Our data demonstrate that the immunomodulatory activity of curdlan requires an additional signal provided by GM-CSF to successfully initiate a robust β-glucan-specific cytokine and chemokine response. The integration of both signals clearly prime and tailor a more effective innate and adaptive response against invading microbes and fungi.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Lin
authors.initials: L
authors.lastname: Min
authors.forename: Siti Aminah Bte Mohammad
authors.initials: SA
authors.lastname: Isa
authors.forename: Wee Nih
authors.initials: WN
authors.lastname: Fam
authors.forename: Siu Kwan
authors.initials: SK
authors.lastname: Sze
authors.forename: Ottavio
authors.initials: O
authors.lastname: Beretta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mortellaro
authors.forename: Christiane
authors.initials: C
authors.lastname: Ruedl
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D002454:Cell Differentiation; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D007155:Immunologic Factors; D037181:Lectins, C-Type / Q000819:agonists / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011135:Polysaccharides, Bacterial / Q000276:immunology; D015398:Signal Transduction; D047071:beta-Glucans / Q000276:immunology* / Q000494:pharmacology; D000099181:Dectin-1
chemical_list: D015703:Antigens, CD; D018925:Chemokines; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020672:I-kappa B Proteins; D007155:Immunologic Factors; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D011135:Polysaccharides, Bacterial; D047071:beta-Glucans; D000099181:Dectin-1; C000606205:Nfkbia protein, mouse; C038459:curdlan