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.

ACKNOWLEDGMENTS

We thank Hui-Kuan Lin for providing TRAF6 expression vectors, Charlène Blanchet, Anne Leroux, Martine Fanton d'Andon, Catherine Fitting, and Mathieu Medina for technical help, and Monique Fabre, Jean-Marc Cavaillon, Marie-Louise Michel, and Christine Neuveut for insightful discussion.

This work was funded in part by the French Ligue Contre le Cancer, Comité d'Ile-de-France, the Association pour la Recherche sur le Cancer, and Institut National du Cancer. J.D. was supported by the French Ministère de l'Enseignement Supérieur et de la Recherche, and Y.N. was supported by the Cancéropôle Ile-de-France.