title: The ataxia telangiectasia mutated kinase pathway regulates IL-23 expression by human dendritic cells.
abstract: Little is known of the regulation of IL-23 secretion in dendritic cells (DC) despite its importance for human Th17 responses. In this study, we show for first time, to our knowledge, that the ataxia telangiectasia mutated (ATM) pathway, involved in DNA damage sensing, acts as an IL-23 repressor. Inhibition of ATM with the highly selective antagonist KU55933 markedly increased IL-23 secretion in human monocyte-derived DC and freshly isolated myeloid DC. In contrast, inhibiting the closely related mammalian target of rapamycin had no effect on IL-23. Priming naive CD4(+) T cells with ATM-inhibited DC increased Th17 responses over and above those obtained with mature DC. Although ATM blockade increased the abundance of p19, p35, and p40 mRNA, IL-12p70 secretion was unaffected. To further examine a role for ATM in IL-23 regulation, we exposed DC to low doses of ionizing radiation. Exposure of DC to x-rays resulted in ATM phosphorylation and a corresponding depression of IL-23. Importantly, ATM inhibition with KU55933 prevented radiation-induced ATM phosphorylation and abrogated the capacity of x-rays to suppress IL-23. To explore how ATM repressed IL-23, we examined a role for endoplasmic reticulum stress responses by measuring generation of the spliced form of X-box protein-1, a key endoplasmic reticulum stress transcription factor. Inhibition of ATM increased the abundance of X-box protein-1 mRNA, and this was followed 3 h later by increased peak p19 transcription and IL-23 release. In summary, ATM activation or inhibition, respectively, inhibited or augmented IL-23 release. This novel role of the ATM pathway represents a new therapeutic target in autoimmunity and vaccine development.
authors: Host:Tumour Interactions Group, Academic Unit of Clinical Oncology, University of Nottingham, Nottingham NG5 1PB, United Kingdom.
authors: Qunwei
authors: Q
authors: Wang
authors: Hester A
authors: HA
authors: Franks
authors: Stephanie J
authors: SJ
authors: Lax
authors: Mohamed
authors: M
authors: El Refaee
authors: Anna
authors: A
authors: Malecka
authors: Sabaria
authors: S
authors: Shah
authors: Ian
authors: I
authors: Spendlove
authors: Michael J
authors: MJ
authors: Gough
authors: Claire
authors: C
authors: Seedhouse
authors: Srinivasan
authors: S
authors: Madhusudan
authors: Poulam M
authors: PM
authors: Patel
authors: Andrew M
authors: AM
authors: Jackson
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D053759:Interleukin-23 / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000528:radiation effects; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D053759:Interleukin-23; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases