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
UR - http://www.scopus.com/inward/record.url?scp=55349128861&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2008.08.016
DO - 10.1016/j.immuni.2008.08.016
M3 - Article
C2 - 18976936
AN - SCOPUS:55349128861
SN - 1074-7613
VL - 29
SP - 691
EP - 703
JO - Immunity
JF - Immunity
IS - 5
ER -
