Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-γ Pathways

Xiaoyu Hu; Allen Y. Chung; Indira Wu; Julia Foldi; Janice Chen; Jong Dae Ji; Tomoko Tateya; Young Jun Kang; Jiahuai Han; Manfred Gessler; Ryoichiro Kageyama; Lionel B. Ivashkiv

doi:10.1016/j.immuni.2008.08.016

Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-γ Pathways

Xiaoyu Hu
, Allen Y. Chung
, Indira Wu
, Julia Foldi
, Janice Chen
, Jong Dae Ji
, Tomoko Tateya
, Young Jun Kang
, Jiahuai Han
, Manfred Gessler
, Ryoichiro Kageyama
, Lionel B. Ivashkiv^*

^*Corresponding author for this work

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

227 Citations (Scopus)

Abstract

Toll-like receptor (TLR) responses are regulated to avoid toxicity and achieve coordinated responses appropriate for the cell environment. We found that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines TNF, IL-6, and IL-12. Cooperation by these pathways to increase target gene expression was mediated by the Notch-pathway component and transcription factor RBP-J, which also contributed to lethality after endotoxin injection. TLR- and Notch-induced Hes1 and Hey1 attenuated IL-6 and IL-12 production. This Hes1- and Hey1-mediated feedback inhibitory loop was abrogated by interferon-γ (IFN-γ), which blocked TLR-induced activation of canonical Notch target genes by inhibiting Notch2 signaling and downstream transcription. These findings identify new immune functions for RBP-J, Hes, and Hey proteins and provide insights into mechanisms by which Notch, TLR, and IFN-γ signals are integrated to modulate specific effector functions in macrophages.

Original language	English
Pages (from-to)	691-703
Number of pages	13
Journal	Immunity
Volume	29
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2008.08.016
Publication status	Published - 2008 Nov 14
Externally published	Yes

Bibliographical note

Funding Information:
We thank R. Kopan for the Hes1 reporter and NICD1 expression plasmids, A. Beg for the IL-6-reporter construct, T. Honjo for permission to use Rbpj floxed mice, and E. Fuchs for transfer of Rbpj floxed mice. We also thank C. Shi for some of the RBPJ RNAi experiments, K.-H. Park-Min for critical review of the manuscript and I. Rogatsky for helpful discussions. This work was supported by grants from the Arthritis Foundation (X.H.) and the National Institutes of Health (L.B.I.).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

Access to Document

10.1016/j.immuni.2008.08.016

Cite this

@article{84e1bae3c63f40858c3f1daa19958894,

title = "Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-γ Pathways",

abstract = "Toll-like receptor (TLR) responses are regulated to avoid toxicity and achieve coordinated responses appropriate for the cell environment. We found that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines TNF, IL-6, and IL-12. Cooperation by these pathways to increase target gene expression was mediated by the Notch-pathway component and transcription factor RBP-J, which also contributed to lethality after endotoxin injection. TLR- and Notch-induced Hes1 and Hey1 attenuated IL-6 and IL-12 production. This Hes1- and Hey1-mediated feedback inhibitory loop was abrogated by interferon-γ (IFN-γ), which blocked TLR-induced activation of canonical Notch target genes by inhibiting Notch2 signaling and downstream transcription. These findings identify new immune functions for RBP-J, Hes, and Hey proteins and provide insights into mechanisms by which Notch, TLR, and IFN-γ signals are integrated to modulate specific effector functions in macrophages.",

keywords = "MOLIMMUNO",

author = "Xiaoyu Hu and Chung, \{Allen Y.\} and Indira Wu and Julia Foldi and Janice Chen and Ji, \{Jong Dae\} and Tomoko Tateya and Kang, \{Young Jun\} and Jiahuai Han and Manfred Gessler and Ryoichiro Kageyama and Ivashkiv, \{Lionel B.\}",

note = "Funding Information: We thank R. Kopan for the Hes1 reporter and NICD1 expression plasmids, A. Beg for the IL-6-reporter construct, T. Honjo for permission to use Rbpj floxed mice, and E. Fuchs for transfer of Rbpj floxed mice. We also thank C. Shi for some of the RBPJ RNAi experiments, K.-H. Park-Min for critical review of the manuscript and I. Rogatsky for helpful discussions. This work was supported by grants from the Arthritis Foundation (X.H.) and the National Institutes of Health (L.B.I.). ",

year = "2008",

month = nov,

day = "14",

doi = "10.1016/j.immuni.2008.08.016",

language = "English",

volume = "29",

pages = "691--703",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-γ Pathways

AU - Hu, Xiaoyu

AU - Chung, Allen Y.

AU - Wu, Indira

AU - Foldi, Julia

AU - Chen, Janice

AU - Ji, Jong Dae

AU - Tateya, Tomoko

AU - Kang, Young Jun

AU - Han, Jiahuai

AU - Gessler, Manfred

AU - Kageyama, Ryoichiro

AU - Ivashkiv, Lionel B.

N1 - Funding Information: We thank R. Kopan for the Hes1 reporter and NICD1 expression plasmids, A. Beg for the IL-6-reporter construct, T. Honjo for permission to use Rbpj floxed mice, and E. Fuchs for transfer of Rbpj floxed mice. We also thank C. Shi for some of the RBPJ RNAi experiments, K.-H. Park-Min for critical review of the manuscript and I. Rogatsky for helpful discussions. This work was supported by grants from the Arthritis Foundation (X.H.) and the National Institutes of Health (L.B.I.).

PY - 2008/11/14

Y1 - 2008/11/14

N2 - Toll-like receptor (TLR) responses are regulated to avoid toxicity and achieve coordinated responses appropriate for the cell environment. We found that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines TNF, IL-6, and IL-12. Cooperation by these pathways to increase target gene expression was mediated by the Notch-pathway component and transcription factor RBP-J, which also contributed to lethality after endotoxin injection. TLR- and Notch-induced Hes1 and Hey1 attenuated IL-6 and IL-12 production. This Hes1- and Hey1-mediated feedback inhibitory loop was abrogated by interferon-γ (IFN-γ), which blocked TLR-induced activation of canonical Notch target genes by inhibiting Notch2 signaling and downstream transcription. These findings identify new immune functions for RBP-J, Hes, and Hey proteins and provide insights into mechanisms by which Notch, TLR, and IFN-γ signals are integrated to modulate specific effector functions in macrophages.

AB - Toll-like receptor (TLR) responses are regulated to avoid toxicity and achieve coordinated responses appropriate for the cell environment. We found that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines TNF, IL-6, and IL-12. Cooperation by these pathways to increase target gene expression was mediated by the Notch-pathway component and transcription factor RBP-J, which also contributed to lethality after endotoxin injection. TLR- and Notch-induced Hes1 and Hey1 attenuated IL-6 and IL-12 production. This Hes1- and Hey1-mediated feedback inhibitory loop was abrogated by interferon-γ (IFN-γ), which blocked TLR-induced activation of canonical Notch target genes by inhibiting Notch2 signaling and downstream transcription. These findings identify new immune functions for RBP-J, Hes, and Hey proteins and provide insights into mechanisms by which Notch, TLR, and IFN-γ signals are integrated to modulate specific effector functions in macrophages.

KW - MOLIMMUNO

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DO - 10.1016/j.immuni.2008.08.016

M3 - Article

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SN - 1074-7613

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ER -

Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-γ Pathways

Abstract

Bibliographical note

UN SDGs

Keywords

ASJC Scopus subject areas

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