Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs

doi:10.1073/pnas.0700664104

Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs

*Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC–WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France;
^‡Centre Léon Berard, 28 Rue Laennec, 69373 Lyon Cedex 08, France;
^§Innate Pharma, 27 Chemin des Peupliers, BP78, 69573 Dardilly Cedex, France;
^¶Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Building 560/Room 31-93, Frederick, MD 21702-1201; and
^‖Schering–Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033

Edited by Ralph M. Steinman, The Rockefeller University, New York, NY, and approved March 12, 2007 (received for review January 25, 2007)

Abstract

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.

Footnotes

^†To whom correspondence should be addressed. E-mail: hasan{at}iarc.fr
Author contributions: U.A.H., G.T., and J.V. designed research; U.A.H., I.P., and A.-C.D. performed research; U.A.H., C.C., and M.T. contributed new reagents/analytic tools; U.A.H., C.C., and C.M.-C. analyzed data; and U.A.H., G.T., M.T., and J.V. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0700664104/DC1.
Abbreviations:

DC,

dendritic cell;

IFNARab,

antibodies against the type I IFN receptor;

LPS,

lipopolysaccharide;

MonoDC,

monocyte-derived DC;

TLR,

Toll-like receptor.