Elsevier

Surgery

Volume 133, Issue 1, January 2003, Pages 101-109
Surgery

Original Communications
Tumor necrosis factor-α and interleukin-6 reduce bile canalicular contractions of rat hepatocytes*,**,*

https://doi.org/10.1067/msy.2003.91Get rights and content

Abstract

Background. Surgeons sometimes encounter hyperbilirubinemia without mechanical obstruction of the biliary tree postoperatively. Many of these patients have bacterial infections and endotoxemia. Kupffer's cells stimulated by endotoxin secrete inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6. We hypothesized that TNF-α and IL-6 might be involved in the pathogenesis of hyperbilirubinemia. Methods. Effects of TNF-α and IL-6 on the contractions of bile canaliculi (BC) of rat hepatocyte couplets were examined and time-lapse images using phase-contrast microscopy were taken. Bile was collected from rats treated with or without the cytokines. The livers, perfused with lanthanum after the injection of cytokines, were examined ultrastructurally using electron microscopy. Results. The number of BC contractions decreased in the couplets treated with both cytokines. The rapid movement of a droplet from BC was observed at the intercellular space of the hepatocyte couplet treated with TNF-α. Systolic blood pressure and hepatic tissue blood flow of rats injected with TNF-α were not changed, whereas the hepatic tissue blood flow of rats treated with IL-6 decreased (Dunnett test, P <.05). Bile secretion was reduced in both groups of rats (Dunnett test, P <.05). In rats treated with TNF-α the total serum bile acid concentration increased and lanthanum temporarily accumulated in BC. Conclusions. These results suggest that TNF-α and IL-6 may reduce BC contractions and thereby decrease bile flow. (Surgery 2003;133:101-9).

Section snippets

Chemicals

Recombinant rat TNF-α (specific activity > 2 × 107 U/mg; endotoxin < 0.1 ng/μg) and recombinant rat IL-6 (specific activity > 1 × 108 U/μg; endotoxin < 0.1 ng/μg) were purchased from Pepro Tech EC, Ltd (London, United Kingdom). These cytokines were dissolved in phosphate-buffered saline containing 0.1% bovine serum albumin (Intergen Co, Purchase, NY). Other agents were purchased as follows: fetal bovine serum (ICN Biochemicals, Inc, Aurora, Ohio); L-15 medium and gentamicin (Gibco Laboratories,

Effects of TNF-α and IL-6 on BC contraction

Animated time-lapse images showed repeated BC contractions and enlargement between hepatocyte couplets several times within 2 hours (Fig 2).

. Digital images of a representative BC contraction. The maximum diastolic phase of the BC (A), and 10 (B), 20 (C), and 30 (D) seconds later. These images show the minimum BC space of the couplet. Bars are 10 μm.

Fig 2, A and D show the maximal BC enlargement and the closed BC, respectively. In most cases BC gradually expanded and suddenly contracted. The time

Discussion

In the current study we showed that administration of TNF-α or IL-6 to rats could result in a decrease of bile excretion and in an increase of total bile acid in serum. There are 3 possible reasons why the amount of the bile was reduced without mechanical obstruction of the biliary tree: (1) prehepatic, (2) intrahepatic, and (3) posthepatic impairment. The prehepatic cause of cholestasis is overabundance of bilirubin, which is induced by blood transfusion.3 Hemolysis of transfused red blood

Acknowledgements

We thank Mr H. Araake, Ms M. Kuwano, and Ms Y. Tanaka-Takahashi for technical assistance. We are also grateful to Dr Tomoko Sonoda (Department of Public Health, Sapporo Medical University) for her suggestions about statistics and to Mr K. Barrymore for help with the article.

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    *

    Supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture, Japan (09470256 and 12470265 for K. Hirata, 12670211 for T. Mitaka, and 1247243 for Y. Mochizuki) and by a Grant-in-Aid from the Sapporo Medical University Foundation for Promotion of Medical Science (for S. Ikeda).

    **

    Reprint requests: Toshihiro Mitaka, MD, PhD, Department of Pathology, Cancer Research Institute, Sapporo Medical University School of Medicine, Chuo-ku, S-1, W-17, Sapporo 060-8556, Japan.

    *

    0039-6060/2003/$30.00 + 0

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