Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats . Rai, R. M., S. Q. Yang, C. McClain, C. L. Karp, A. S. Klein, and A. M. Diehl. Departments of Medicine, and Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Medicine, University of Kentucky, Lexington, KY 40506
APStracts 2:0252G, 1995.
Tumor necrosis factor [alpha] (TNF) helps initiate the regenerative response after 70% partial hepatectomy (PH), as demonstrated by evidence that neutralizing antibodies to TNF inhibit PH-induction of a growth-related kinase (Jun Nuclear Kinase), several growth-related genes (c-jun, C/EBP [beta] and C/EBP [delta]) and hepatocyte proliferation. Since TNF has not been detected in serum after PH, it is probably produced within the liver. However, the cellular source of TNF following PH is uncertain. Kupffer cells synthesize TNF during many types of toxic liver injury and, thus, may release TNF after PH. If true, then Kupffer cell depletion should mimic the growth -inhibitory effects of anti-TNF antibodies. To test this hypothesis, rats were pretreated with gadolinium chloride (GdCl) to deplete the liver of Kupffer cells. Then, cytokine expression and TNF-sensitive regenerative events were compared in GdCl treated and control rats. Functional assays and Northern blot analysis of a Kupffer cell -specific mRNA demonstrated that GdCl depleted the liver of Kupffer cells. Despite this, semiquantitative RT-PCR analysis of total hepatic RNA isolated from both groups at the time of PH showed 6- to 8-fold higher levels of TNF transcripts in the GdCl-treated group. In GdCl-treated rats, PH caused 12-16 fold greater induction of IL-6, a TNF-inducible cytokine, and 2-3 fold greater induction of c-Jun, C/EBP [beta] and C/EBP [delta] than in controls. GdCl pre-treatment also amplified regeneration-associated increases in the DNA binding activity of AP-1, a growth regulatory transcription factor. Furthermore, after PH, the incorporation of [H3]-thymidine into liver DNA, expression of the S phase antigen, PCNA, and the hepatocyte mitotic index were each significantly greater in GdCl-treated rats. Thus, although GdCl causes Kupffer cell depletion, it neither decreases liver TNF nor inhibits liver regeneration. Therefore, Kupffer cell depletion by gadolinium chloride does not mimic the growth inhibitory actions of anti-TNF antibodies. Instead, it actually enhances liver regeneration after PH. 

Received 19 June 1995; accepted in final form 15 November 1995.
APS Manuscript Number G262-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 8 December 95