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(Journal of Leukocyte Biology. 2005;77:626-633.)
© 2005 by Society for Leukocyte Biology

Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver

Anja Uhrig^*, Ramin Banafsche, Michael Kremer, Silke Hegenbarth, Alf Hamann, Markus Neurath^#, Guido Gerken^¶, Andreas Limmer and Percy A. Knolle^,1

^* Department of Transplant Surgery, University Mainz, Germany;
Department of Surgery, University Heidelberg, Germany;
Institute of Molecular Medicine and Experimental Immunology, University Bonn, Germany;
Deutsches Rheumaforschungszentrum, Berlin, Germany;
^¶ Department of Gastroenterology and Hepatology, University Essen, Germany;
^# 1st Medical Department, University Hospital, Mainz, Germany

¹ Correspondence: Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. E-mail: Percy.Knolle{at}ukb.uni-bonn.de

Kupffer cells and liver sinusoidal endothelial cells (LSEC) clear portal venous blood from gut-derived bacterial degradation products such as lipopolysaccharide (LPS) without inducing a local inflammatory reaction. LPS tolerance was reported for Kupffer cells, but little is known whether sensitivity of LSEC toward LPS is dynamically regulated. Here, we demonstrate that LSEC react to LPS directly as a function of constitutive Toll-like receptor 4 (TLR4)/CD14 expression but gain a LPS-refractory state upon repetitive stimulation without loss of scavenger activity. LPS tolerance in LSEC is characterized by reduced nuclear localization of nuclear factor-B upon LPS rechallenge. In contrast to monocytes, however, TLR4 surface expression of LSEC is not altered by LPS stimulation and thus does not account for LPS tolerance. Mechanistically, LPS tolerance in LSEC is linked to prostanoid production and may account for cross-tolerance of LPS-treated LSEC to interferon- stimulation. Functionally, LPS tolerance in LSEC results in reduced leukocyte adhesion following LPS rechallenge as a consequence of decreased CD54 surface expression. Furthermore, LPS tolerance is operative in vivo, as we observed by intravital microscopy-reduced leukocyte adhesion to LSEC and improved sinusoidal microcirculation in the liver after repetitive LPS challenges. Our results support the notion that LPS tolerance in organ-resident scavenger LSEC contributes to local hepatic control of inflammation.

Key Words: liver • TLR-4 • lipopolysaccharide • cell adhesion

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