Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs.
TRIF is an adaptor protein associated with the signaling by Toll-like receptor (TLR)3 and TLR4 for the induction of type I IFNs. Here, we demonstrate a mechanism by which TLR signaling controls cell proliferation and survival. We show that TLR3 and TLR4 can induce cell cycle entry via TRIF, which targets the cell cycle inhibitor p27(kip1) for relocalization, phosphorylation by cyclin/cdk complexes, and proteasome degradation. These events are antagonized by type I IFN induced by the TRIF pathway. Furthermore, in human dendritic cells treated with TLR3, TLR4, or TLR5 ligands, we demonstrate that IFN signaling modulates p27(kip1) degradation and apoptosis, identifying an immunoregulatory "switching" function of type I IFNs. These findings reveal a previously uncharacterized function of TLR signaling in cell proliferation and survival.
Hasan
Uzma A
UA
Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC-WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France. hasan@iarc.fr
Caux
Christophe
C
Perrot
Ivan
I
Doffin
Anne-Claire
AC
Menetrier-Caux
Christine
C
Trinchieri
Giorgio
G
Tommasino
Massimo
M
Vlach
Jaromir
J
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D007370:Interferon Type I; D008070:Lipopolysaccharides; D016328:NF-kappa B; C470409:TICAM1 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D046988:Proteasome Endopeptidase Complex