title: Selective induction of the Notch ligand Jagged-1 in macrophages by soluble egg antigen from Schistosoma mansoni involves ERK signalling.
abstract: Soluble egg antigen (SEA) from the helminth Schistosoma mansoni promotes T helper type 2 (Th2) responses by modulating antigen-presenting cell function. The Jagged/Notch pathway has recently been implicated in driving Th2 development. We show here that SEA rapidly up-regulated mRNA and protein expression of the Notch ligand Jagged-1 in both murine bone marrow-derived macrophages (BMMs) and human monocyte-derived macrophages (HMDMs). Another potential Th2-promoting factor, interleukin (IL)-33, was not transcriptionally induced by SEA in BMMs. Up-regulation of Jagged-1 mRNA by SEA was also apparent in conventional dendritic cells (DCs), although the effect was less striking than in BMMs. Conversely, SEA-pulsed DCs, but not BMMs, promoted IL-4 production upon T-cell activation, suggesting that Jagged-1 induction alone is insufficient for instructing Th2 development. A comparison of the responses initiated in BMMs by SEA and the bacterial endotoxin lipopolysaccharide (LPS) revealed common activation of extracellular signal-regulated kinase-1/2 (ERK-1/2) and p38 phosphorylation, as well as induction of Jagged-1 mRNA. However, only LPS triggered IkappaB degradation, phosphorylation of c-Jun N-terminal kinase (Jnk) and signal transducer and activator of transcription 1 (Stat1) Tyr701, and IL-33 and IL-12p40 mRNA up-regulation. Inducible gene expression was modified by the presence of the macrophage growth factor colony-stimulating factor (CSF)-1, which inhibited Jagged-1 induction by SEA and LPS, but enhanced LPS-induced IL-12p40 expression. Unlike LPS, SEA robustly activated signalling in HEK293 cells expressing either Toll-like receptor 2 (TLR2) or TLR4/MD2. Pharmacological inhibition of the ERK-1/2 pathway impaired SEA- and LPS-inducible Jagged-1 expression in BMMs. Taken together, our data suggest that Jagged-1 is an ERK-dependent target of TLR signalling that has a macrophage-specific function in the response to SEA.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Qld, Australia.
authors.forename: Felicia
authors.initials: F
authors.lastname: Goh
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Irvine
authors.forename: Erica
authors.initials: E
authors.lastname: Lovelace
authors.forename: Sheila
authors.initials: S
authors.lastname: Donnelly
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Jones
authors.forename: Kristian
authors.initials: K
authors.lastname: Brion
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kotze
authors.forename: John P
authors.initials: JP
authors.lastname: Dalton
authors.forename: Aaron
authors.initials: A
authors.lastname: Ingham
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000947:Antigens, Helminth / Q000276:immunology*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D012550:Schistosoma mansoni / Q000276:immunology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D000947:Antigens, Helminth; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3