Goh Felicia, Irvine Katharine M, Lovelace Erica, Donnelly Sheila, Jones Malcolm K, Brion Kristian, Hume David A, Kotze Andrew C, Dalton John P, Ingham Aaron, Sweet Matthew J
Institute for Molecular Bioscience, University of Queensland, Qld, Australia.
Immunology. 2009 Jul;127(3):326-37. doi: 10.1111/j.1365-2567.2008.02979.x. Epub 2008 Nov 14.
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.
曼氏血吸虫的可溶性虫卵抗原（SEA）通过调节抗原呈递细胞功能促进2型辅助性T细胞（Th2）应答。Jagged/Notch信号通路最近被认为与Th2细胞的发育有关。我们在此表明，SEA能迅速上调小鼠骨髓来源巨噬细胞（BMM）和人单核细胞来源巨噬细胞（HMDM）中Notch配体Jagged-1的mRNA和蛋白表达。另一种潜在的Th2促进因子白细胞介素（IL）-33，在BMM中未被SEA转录诱导。SEA对Jagged-1 mRNA的上调在常规树突状细胞（DC）中也很明显，尽管其效果不如在BMM中显著。相反，SEA脉冲处理的DC，而不是BMM，在T细胞激活后促进IL-4的产生，这表明仅Jagged-1的诱导不足以指导Th2细胞的发育。对SEA和细菌内毒素脂多糖（LPS）在BMM中引发的反应进行比较，发现细胞外信号调节激酶-1/2（ERK-1/2）和p38磷酸化以及Jagged-1 mRNA的诱导存在共同激活。然而，只有LPS能触发IκB降解、c-Jun氨基末端激酶（Jnk）和信号转导及转录激活因子1（Stat1）Tyr701的磷酸化，以及IL-33和IL-12p40 mRNA的上调。巨噬细胞生长因子集落刺激因子（CSF）-1的存在改变了诱导型基因表达，它抑制SEA和LPS诱导的Jagged-1表达，但增强LPS诱导的IL-12p40表达。与LPS不同，SEA能强烈激活表达Toll样受体2（TLR2）或TLR4/MD2的HEK293细胞中的信号传导。ERK-1/2信号通路的药理抑制削弱了SEA和LPS诱导的BMM中Jagged-1的表达。综上所述，我们的数据表明Jagged-1是TLR信号传导的ERK依赖性靶点，在对SEA的应答中具有巨噬细胞特异性功能。
