title: LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis.
abstract: Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor κB (NF-κB) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-κB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-κB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-κB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-κB signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-κB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-κB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells.
authors.affiliation: Unité d'Oncogenèse et Virologie Moléculaire, Institut Pasteur, Paris, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dahan
authors.forename: Yann
authors.initials: Y
authors.lastname: Nouët
authors.forename: Grégory
authors.initials: G
authors.lastname: Jouvion
authors.forename: Florence
authors.initials: F
authors.lastname: Levillayer
authors.forename: Minou
authors.initials: M
authors.lastname: Adib-Conquy
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cassard-Doulcier
authors.forename: Ali
authors.initials: A
authors.lastname: Tebbi
authors.forename: Fany
authors.initials: F
authors.lastname: Blanc
authors.forename: Lauriane
authors.initials: L
authors.lastname: Remy
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Stefano
authors.initials: S
authors.lastname: Cairo
authors.forename: Catherine
authors.initials: C
authors.lastname: Werts
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.forename: Thierry
authors.initials: T
authors.lastname: Tordjmann
authors.forename: Marie-Annick
authors.initials: MA
authors.lastname: Buendia
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D004052:Diethylnitrosamine / Q000009:adverse effects*; D017353:Gene Deletion; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000473:pathology* / Q000502:physiology* / Q000648:ultrastructure; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D008115:Liver Regeneration; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; C491382:Fhl2 protein, mouse; D060850:LIM-Homeodomain Proteins; D008070:Lipopolysaccharides; D009124:Muscle Proteins; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; D004052:Diethylnitrosamine