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Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization.


ABSTRACT: Emerging concepts suggest that the functional phenotype of macrophages is regulated by transcription factors that define alternative activation states. We found that RBP-J, the main nuclear transducer of signaling via Notch receptors, augmented Toll-like receptor 4 (TLR4)-induced expression of key mediators of classically activated M1 macrophages and thus of innate immune responses to Listeria monocytogenes. Notch-RBP-J signaling controlled expression of the transcription factor IRF8 that induced downstream M1 macrophage-associated genes. RBP-J promoted the synthesis of IRF8 protein by selectively augmenting kinase IRAK2-dependent signaling via TLR4 to the kinase MNK1 and downstream translation-initiation control through eIF4E. Our results define a signaling network in which signaling via Notch-RBP-J and TLRs is integrated at the level of synthesis of IRF8 protein and identify a mechanism by which heterologous signaling pathways can regulate the TLR-induced inflammatory polarization of macrophages.

SUBMITTER: Xu H 

PROVIDER: S-EPMC3513378 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization.

Xu Haixia H   Zhu Jimmy J   Smith Sinead S   Foldi Julia J   Zhao Baohong B   Chung Allen Y AY   Outtz Hasina H   Kitajewski Jan J   Shi Chao C   Weber Silvio S   Saftig Paul P   Li Yueming Y   Ozato Keiko K   Blobel Carl P CP   Ivashkiv Lionel B LB   Hu Xiaoyu X  

Nature immunology 20120520 7


Emerging concepts suggest that the functional phenotype of macrophages is regulated by transcription factors that define alternative activation states. We found that RBP-J, the main nuclear transducer of signaling via Notch receptors, augmented Toll-like receptor 4 (TLR4)-induced expression of key mediators of classically activated M1 macrophages and thus of innate immune responses to Listeria monocytogenes. Notch-RBP-J signaling controlled expression of the transcription factor IRF8 that induce  ...[more]

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