{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:45:53Z","timestamp":1791276353961,"version":"4.1.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1095,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>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-\u03baB (NF-\u03baB) system is activated in response to several of these stresses, we hypothesized that NF-\u03baB activation in hepatocytes may contribute to fibrosis development. To activate the NF-\u03baB 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<\/jats:bold>\n                                 <jats:bold>\n                                    Ikbkb\n                                 <\/jats:bold>\n                                 <jats:bold>gene (IKK2 protein [CAIKK2]). Double-transgenic mice displayed doxycycline-regulated CAIKK2 expression in hepatocytes. Removal of doxycycline at birth led to activation of NF-\u03baB 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-\u03baB-induced liver fibrosis in a liver-injury-independent manner.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion\n                                 <\/jats:bold>: <jats:bold>Our results revealed that hepatic activation of IKK\/NF-\u03baB is sufficient to induce liver fibrosis by way of macrophage-mediated chronic inflammation. Therefore, agents controlling the hepatic NF-\u03baB system represent attractive therapeutic tools to prevent fibrosis development in multiple chronic liver diseases.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.25711","type":"journal-article","created":{"date-parts":[[2012,3,12]],"date-time":"2012-03-12T10:58:35Z","timestamp":1331549915000},"page":"1117-1128","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":128,"title":["Hepatic activation of IKK\/NF\u03baB signaling induces liver fibrosis via macrophage-mediated chronic 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