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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Franks, Hester A. Seedhouse, Claire El Refaee, Mohamed Jackson, Andrew M. Malecka, Anna Lax, Stephanie J. Shah, Sabaria Gough, Michael J. Patel, Poulam M. Wang, Qunwei Spendlove, Ian Madhusudan, Srinivasan |
| Description | Country affiliation: United kingdom Author Affiliation: Wang Q ( Host:Tumour Interactions Group, Academic Unit of Clinical Oncology, University of Nottingham, Nottingham NG5 1PB, United Kingdom.) |
| 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. |
| ISSN | 00221767 |
| e-ISSN | 15506606 |
| DOI | 10.4049/jimmunol.1201484 |
| Journal | The Journal of Immunology |
| Issue Number | 7 |
| Volume Number | 190 |
| Language | English |
| Publisher | The American Association of Immunologists |
| Publisher Date | 2013-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Cycle Proteins Metabolism Dna-binding Proteins Dendritic Cells Gene Expression Regulation Interleukin-23 Genetics Protein-serine-threonine Kinases Signal Transduction Tumor Suppressor Proteins Ataxia Telangiectasia Mutated Proteins Cells, Cultured Cytokines Immunology Endoplasmic Reticulum Stress Enzyme Activation Radiation Effects Lymphocyte Activation Th17 Cells Transcription Factors Transcription, Genetic Research Support, Non-u.s. Gov't Discipline Immunology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
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