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Am J Physiol Gastrointest Liver Physiol 280: G720-G728, 2001;
0193-1857/01 $5.00
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Vol. 280, Issue 4, G720-G728, April 2001

Direct cell-to-cell contact between Kupffer cells and hepatocytes augments endotoxin-induced hepatic injury

Kasper H. N. Hoebe1, Renger F. Witkamp1,2, Johanna Fink-Gremmels1, Adelbert S. J. P. A. M. Van Miert1, and Mario Monshouwer3

1 Department of Veterinary Pharmacy, Pharmacology, and Toxicology, Utrecht University, 3584 CM Utrecht; 2 Department of Pharmacology, TNO Pharma, 3704 HE Zeist, The Netherlands; and 3 Pharmacia and Upjohn, Drug Metabolism Research, 20014 Nerviano, Italy

This study focuses on the importance of direct contact between Kupffer cells (KCs) and hepatocytes (HCs) during the hepatic inflammatory response using an in vitro approach. The lipopolysaccharide (LPS)-induced inflammatory response in monocultures of porcine HCs and KCs were compared with cocultures prepared either with direct contact between KCs and HCs (DC cocultures) or without direct contact using cell culture membrane inserts. Our data show that DC cocultures exhibited the highest production of tumor necrosis factor (TNF)-alpha , interleukin-6, and nitric oxide (NO) compared with the other cultures. Immunohistochemical studies revealed that TNF-alpha was exclusively produced by KCs, whereas HCs were responsible for NO production after LPS stimulation. Biotransformation capacity, as determined by cytochrome P-450 and UDP glucuronosyl transferase enzyme activities, was most significantly decreased in DC cocultures. These results provide evidence that direct contact between KCs and HCs favors the extensive TNF-alpha production by KCs but in turn affects HC functionality and viability. These findings suggest that direct contact between KCs and HCs plays a key role in the development of a fulminating hepatic inflammatory response.

lipopolysaccharide; cytokines; biotransformation; nitric oxide


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