The Ataxia Telangiectasia Mutated Kinase Pathway Regulates IL-23 Expression by Human Dendritic Cells

Qunwei Wang; Hester Franks; Stephanie Joyce Lax; Mohamed  El Refaee; Anna Malecka; Sabaria Shah; Ian Spendlove; Michael Gough; Claire Seedhouse; Srinivasan Madhusudan; Poulam Patel; Andrew Jackson

doi:10.4049/jimmunol.1201484

The Ataxia Telangiectasia Mutated Kinase Pathway Regulates IL-23 Expression by Human Dendritic Cells

Qunwei Wang, Hester Franks, Stephanie Joyce Lax, Mohamed El Refaee, Anna Malecka, Sabaria Shah, Ian Spendlove, Michael Gough, Claire Seedhouse, Srinivasan Madhusudan, Poulam Patel, Andrew Jackson

Health Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	3246-3255
Journal	Journal of Immunology
Volume	190
Issue number	7
DOIs	https://doi.org/10.4049/jimmunol.1201484
Publication status	Published - 22 Mar 2013

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10.4049/jimmunol.1201484

http://www.jimmunol.org/content/190/7/3246

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@article{010c852a032d49d08cce2e75236f656e,

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.",

author = "Qunwei Wang and Hester Franks and Lax, {Stephanie Joyce} and {El Refaee}, Mohamed and Anna Malecka and Sabaria Shah and Ian Spendlove and Michael Gough and Claire Seedhouse and Srinivasan Madhusudan and Poulam Patel and Andrew Jackson",

note = "{\textcopyright} 2013 by The American Association of Immunologists, Inc. Self-archiving of publisher's PDF not supported by the publisher. ",

year = "2013",

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doi = "10.4049/jimmunol.1201484",

language = "English",

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T1 - The Ataxia Telangiectasia Mutated Kinase Pathway Regulates IL-23 Expression by Human Dendritic Cells

AU - Wang, Qunwei

AU - Franks, Hester

AU - Lax, Stephanie Joyce

AU - El Refaee, Mohamed

AU - Malecka, Anna

AU - Shah, Sabaria

AU - Spendlove, Ian

AU - Gough, Michael

AU - Seedhouse, Claire

AU - Madhusudan, Srinivasan

AU - Patel, Poulam

AU - Jackson, Andrew

PY - 2013/3/22

Y1 - 2013/3/22

N2 - 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.

AB - 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.

U2 - 10.4049/jimmunol.1201484

DO - 10.4049/jimmunol.1201484

M3 - Article

SN - 0022-1767

VL - 190

SP - 3246

EP - 3255

JO - Journal of Immunology

JF - Journal of Immunology

IS - 7

ER -