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

Research output: Contribution to journalArticlepeer-review

173 Citations (Scopus)


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 languageEnglish
Pages (from-to)691-703
Number of pages13
Issue number5
Publication statusPublished - 2008 Nov 14
Externally publishedYes



ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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