Toll-like receptor signaling stimulates cell cycle entry and progression in fibroblasts.
Toll-like receptors (TLRs) are proteins involved in recognition of foreign pathogen-associated molecular patterns and activation of processes leading to innate immune recognition. We show that stimulation of fibroblasts with a TLR5 ligand, flagellin, can induce proliferation of serum-starved cells or prevent cell cycle exit upon serum withdrawal independently of autologous growth factor secretion. Other TLR ligands, such as poly(I:C) and lipopolysaccharide, can have a similar effect only if the action of type I interferons is blocked. Flagellin stimulation can prevent cell cycle arrest induced by overexpression of exogenous cyclin-dependent kinase inhibitor p27. Stimulation of TLR5 and overexpression of MyD88, but not TRIF, TIRAP, or TRAM, result in p27 degradation, which can be suppressed by dominant negative Akt and mutation of the p27 C-terminal Thr(187) site. These data provide evidence for a nonimmune and cell autonomous role of TLR signaling, whereby TLR stimulation provides a positive signal for cell division.
Hasan
Uzma A
UA
Schering-Plough, Laboratory for Immunological Research, 27 Chemin des Peupliers, B.P.11, 69571 Dardilly Cedex, France. Hasan@iarc.fr
Trinchieri
Giorgio
G
Vlach
Jaromir
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016895:Culture Media, Serum-Free; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005347:Fibroblasts / Q000166:cytology*; D005408:Flagellin / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007370:Interferon Type I / Q000502:physiology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D016296:Mutagenesis; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D007370:Interferon Type I; D008024:Ligands; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D025521:Tumor Suppressor Proteins; D005408:Flagellin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D011070:Poly I-C