title: Novel approach for interleukin-23 up-regulation in human dendritic cells and the impact on T helper type 17 generation.
abstract: Interleukin-23 (IL-23) is important for T helper type 17 (Th17) responses and strategies to regulate IL-23 in human dendritic cells (DC) are limited. This study describes a novel means to control IL-23 secretion by conditioning DC with a phosphatidyl inositol 3-kinase inhibitor Wortmannin (WM). Treatment of monocyte-derived DC with WM increased Toll-like receptor (TLR) -dependent IL-23 secretion 10-fold and IL-12p70 twofold, but IL-27 was unaffected. The effect of WM was restricted to TLR3/4 pathways, did not occur through TLR2, TLR7/8 or Dectin-1, and was characterized by increased p19, p35 and p40 transcription. These responses were not solely dependent on phosphatidyl inositol 3-kinase as the alternative inhibitor LY294002 did not modulate IL-23 production. The normal patterns of activation of mitogen-activated protein kinase pathways were unaffected by WM-conditioning but IL-23 secretion required p38, ERK and JNK pathways. Importantly, this effect was manifest in populations of blood DC. Conditioning freshly isolated myeloid DC with WM before TLR3 or TLR4 triggering resulted in high levels of IL-23 secretion and an absence of IL-12p70. These WM-conditioned myeloid DC were highly effective at priming Th17 responses from naive CD4(+) T cells. Our findings provide a novel means to generate IL-23-rich environments and Th17 responses and suggest as yet unidentified regulatory factors, identification of which will provide new approaches to control IL-23-dependent immunity in infectious disease, autoimmunity and malignancy.
authors: Academic Unit of Clinical Oncology, University of Nottingham, Nottingham, UK.
authors: Qunwei
authors: Q
authors: Wang
authors: Hester A
authors: HA
authors: Franks
authors: Joanne
authors: J
authors: Porte
authors: Mohamed
authors: M
authors: El Refaee
authors: Suharsh
authors: S
authors: Shah
authors: James
authors: J
authors: Crooks
authors: Poulam M
authors: PM
authors: Patel
authors: Andrew M
authors: AM
authors: Jackson
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; C508717:IL17A protein, human; C508600:IL6 protein, human; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6; D007378:Interleukins; D008070:Lipopolysaccharides; C464565:MYDGF protein, human; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin