LPS-mediated NFjB activation varies between activated human hepatic stellate cells from different donors Marcus Mu ¨ hlbauer a , Thomas S. Weiss b,c , Wolfgang E. Thasler c,d , Cornelia M. Gelbmann a , Bernd Schnabl a , Ju ¨ rgen Scho ¨ lmerich a , Claus Hellerbrand a,c, * a Department of Internal Medicine I, University of Regensburg, Germany b Department of Surgery, University of Regensburg, Germany c Center for Liver Cell Research, University of Regensburg, Germany d Department of Surgery, LTM University Munich, Hospital Grosshadern, Germany Received 4 October 2004 Abstract The activation of hepatic stellate cells (HSC) is recognized as the key event of hepatic fibrosis [Virchows Arch. 430 (1997) 195; Semin. Liver Dis. 21 (2001) 437; Front. Biosci. 7 (2002) d808]. NFjB has been associated with the development of the activated phenotype, the expression of proinflammatory genes, and with promoting survival of activated HSC. High levels of circulating endo- toxin are observed in liver fibrosis and several lines of evidence indicate that LPS plays an important role in chronic liver disease. Here, we investigated the LPS-induced NFjB activation in activated HSC from different human donors. HSC were isolated from liver specimens obtained during surgical liver resection and were activated by culturing on plastic. LPS-induced NFjB activity and IL-8 expression revealed a significant correlation but differed significantly comparing HSC from individual donors. These variations seen in LPS mediated NFjB activation and chemokine secretion between HSC from different donors in vitro may contribute to differences seen in vivo between patients in the progression of fibrosis and the degree of inflammation during chronic liver disease. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Heptic stellate cells; Endotoxin; LPS; NFjB; Chemokines; IL-8 Hepatic fibrosis represents the common end point of the majority of chronic liver injuries [2,3]. Well-charac- terized causal agents include chronic hepatitis C (HCV) infection and alcohol abuse. However, a broad spectrum of response to the same etiologic agent is seen in different individuals. For example, large-scale studies have allowed the identification of HCV-patients with ra- pid fibrosis progression and those with slow fibrosis pro- gression per unit time [4]. Fibrosis can be viewed as a disease in which multiple genes and gene products interact with environmental factors [2]. Furthermore, genetic variability in factors influencing fibrogenesis and inflammation may be responsible for some of the variation in disease progres- sion as seen in patients with chronic HCV infection [5,6] and alcoholic liver disease (ALD) [7]. More and more research is directed towards identify- ing and characterizing the interfaces of the cross-interac- tions between primary intrinsic factors and secondary risk factors to help understand individual predisposition to liver disease. Cell type-specific research helps to eluci- date specific contributions not only of hepatocytes, but also of non-parenchymal cells to sensitizing and priming mechanisms. There is a wealth of evidence indicating that hepa- tic stellate cells (HSC) represent the pivot in hepatic fibrosis. Following hepatic injury, HSC undergo an activation process and transform to an activated, 0006-291X/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2004.10.020 * Corresponding author. Fax: +49 941 944 7002. E-mail address: claus.hellerbrand@klinik.uni-regensburg.de (C. Hellerbrand). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 325 (2004) 191–197 BBRC