title: Hepatic activation of IKK/NFκB signaling induces liver fibrosis via macrophage-mediated chronic inflammation.
abstract: Liver damage in humans is induced by various insults including alcohol abuse, hepatitis B/C virus infection, autoimmune or metabolic disorders and, when persistent, leads to development of liver fibrosis. Because the nuclear factor-κB (NF-κB) system is activated in response to several of these stresses, we hypothesized that NF-κB activation in hepatocytes may contribute to fibrosis development. To activate the NF-κB signaling pathway in a time- and cell-type-specific manner in the liver, we crossed transgenic mice carrying the tetracycline-responsive transactivator under the control of the liver activator protein promotor with transgenic mice carrying a constitutively active form of the Ikbkb gene (IKK2 protein [CAIKK2]). Double-transgenic mice displayed doxycycline-regulated CAIKK2 expression in hepatocytes. Removal of doxycycline at birth led to activation of NF-κB signaling, moderate liver damage, recruitment of inflammatory cells, hepatocyte proliferation, and ultimately to spontaneous liver fibrosis development. Microarray analysis revealed prominent up-regulation of chemokines and chemokine receptors and this induction was rapidly reversed after switching off the CAIKK2 expression. Turning off the transgene expression for 3 weeks reversed stellate cell activation but did not diminish liver fibrosis. The elimination of macrophages by clodronate-liposomes attenuated NF-κB-induced liver fibrosis in a liver-injury-independent manner.
  
  
  CONCLUSIONS
  Our results revealed that hepatic activation of IKK/NF-κB is sufficient to induce liver fibrosis by way of macrophage-mediated chronic inflammation. Therefore, agents controlling the hepatic NF-κB system represent attractive therapeutic tools to prevent fibrosis development in multiple chronic liver diseases.
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sunami
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.forename: Sarah
authors.initials: S
authors.lastname: Gul
authors.forename: Katja
authors.initials: K
authors.lastname: Fiedler
authors.forename: Nurdan
authors.initials: N
authors.lastname: Güldiken
authors.forename: Sigrid
authors.initials: S
authors.lastname: Espenlaub
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Holzmann
authors.forename: Nora
authors.initials: N
authors.lastname: Hipp
authors.forename: Anca
authors.initials: A
authors.lastname: Sindrilaru
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wissel
authors.forename: Florian
authors.initials: F
authors.lastname: Kreppel
authors.forename: Marion
authors.initials: M
authors.lastname: Schneider
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
mesh_terms: D000818:Animals; D002908:Chronic Disease; D051550:I-kappa B Kinase / Q000502:physiology*; D007249:Inflammation / Q000276:immunology*; D008103:Liver Cirrhosis / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse