Integrated regulation of Toll-like receptor responses by Notch and interferon-gamma pathways.
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.
Hu
Xiaoyu
X
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
Chung
Allen Y
AY
Wu
Indira
I
Foldi
Julia
J
Chen
Janice
J
Ji
Jong Dae
JD
Tateya
Tomoko
T
Kang
Young Jun
YJ
Han
Jiahuai
J
Gessler
Manfred
M
Kageyama
Ryoichiro
R
Ivashkiv
Lionel B
LB
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007371:Interferon-gamma; D018664:Interleukin-12; D015850:Interleukin-6; D008070:Lipopolysaccharides; D051880:Receptors, Notch; D012097:Repressor Proteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C405694:Hairy, HRT1 protein