%0 Journal Article %1 Hu.2008 %A Hu, X. %A Chung, A. Y. %A Wu, I. %A Foldi, J. %A Chen, J. %A Ji, J. D. %A Tateya, T. %A Kang, Y. J. %A Han, J. %A Gessler, M. %A Kageyama, R. %A Ivashkiv, L. B. %D 2008 %J Immunity %K *Gene *Signal Animals Basic Expression Factor-alpha/immunology/metabolism Factors/metabolism Gene Helix-Loop-Helix Homeodomain Humans Immunoglobulin Interferon-gamma/*immunology/metabolism Interleukin-12/immunology/metabolism Interleukin-6/immunology/metabolism J Knockdown Lipopolysaccharides/immunology Macrophages/immunology/metabolism Mice Necrosis Protein/immunology/*metabolism Proteins/metabolism Receptors/immunology/*metabolism Receptors;Notch/*metabolism Recombination Regulation Repressor Sequence-Binding Signal Techniques Toll-Like Transcription Transduction Tumor %N 5 %P 691--703 %T Integrated regulation of Toll-like receptor responses by Notch and interferon-gamma pathways %V 29 %X 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-gamma (IFN-gamma), 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-gamma signals are integrated to modulate specific effector functions in macrophages.

@article{Hu.2008, 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-gamma (IFN-gamma), 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-gamma signals are integrated to modulate specific effector functions in macrophages.}, added-at = {2013-01-29T13:47:26.000+0100}, author = {Hu, X. and Chung, A. Y. and Wu, I. and Foldi, J. and Chen, J. and Ji, J. D. and Tateya, T. and Kang, Y. J. and Han, J. and Gessler, M. and Kageyama, R. and Ivashkiv, L. B.}, biburl = {https://www.bibsonomy.org/bibtex/2979703ffcc1043d01cecde7897c61b3c/ebch}, interhash = {f625fcf4307105baffae9de9bc504629}, intrahash = {979703ffcc1043d01cecde7897c61b3c}, journal = {Immunity}, keywords = {*Gene *Signal Animals Basic Expression Factor-alpha/immunology/metabolism Factors/metabolism Gene Helix-Loop-Helix Homeodomain Humans Immunoglobulin Interferon-gamma/*immunology/metabolism Interleukin-12/immunology/metabolism Interleukin-6/immunology/metabolism J Knockdown Lipopolysaccharides/immunology Macrophages/immunology/metabolism Mice Necrosis Protein/immunology/*metabolism Proteins/metabolism Receptors/immunology/*metabolism Receptors;Notch/*metabolism Recombination Regulation Repressor Sequence-Binding Signal Techniques Toll-Like Transcription Transduction Tumor}, number = 5, pages = {691--703}, timestamp = {2013-01-29T13:47:41.000+0100}, title = {Integrated regulation of Toll-like receptor responses by Notch and interferon-gamma pathways}, volume = 29, year = 2008 }