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Hepatic activation of IKK/NFκB signaling induces liver fibrosis via macrophage‐mediated chronic inflammation
Author(s) -
Sunami Yoshiaki,
Leithäuser Frank,
Gul Sarah,
Fiedler Katja,
Güldiken Nurdan,
Espenlaub Sigrid,
Holzmann KarlHeinz,
Hipp Nora,
Sindrilaru Anca,
Luedde Tom,
Baumann Bernd,
Wissel Sebastian,
Kreppel Florian,
Schneider Marion,
ScharffetterKochanek Karin,
Kochanek Stefan,
Strnad Pavel,
Wirth Thomas
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25711
Subject(s) - hepatic stellate cell , fibrosis , chemokine , inflammation , hepatic fibrosis , hepatocyte , cxcl1 , cancer research , liver injury , biology , transactivation , immunology , medicine , endocrinology , gene expression , biochemistry , gene , in vitro
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. Conclusion : 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. (H EPATOLOGY 2012;56:1117–1128)