Basic Research
Copyright ©The Author(s) 2004. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 1, 2004; 10(11): 1608-1611
Published online Jun 1, 2004. doi: 10.3748/wjg.v10.i11.1608
Leflunomide attenuates hepatocyte injury by inhibiting Kupffer cells
Hong-Wei Yao, Jun Li, Ji-Qiang Chen, Shu-Yun Xu
Hong-Wei Yao, Ji-Qiang Chen, Zhejiang Respiratory Drugs Research Laboratory of State Drugs Administration of China, School of Medicine, Zhejiang University, Hangzhou 310031, Zhejiang Province, China
Jun Li, Shu-Yun Xu, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui Province, China
Author contributions: All authors contributed equally to the work.
Supported by Natural Science Foundation of Anhui Province, No. 98446733
Correspondence to: Professor Jun Li, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui Province, China.
Telephone: +86-551-5161040 Fax: +86-551-5161040
Received: November 13, 2003
Revised: December 4, 2003
Accepted: December 29, 2003
Published online: June 1, 2004

AIM: To investigate the importance of direct contact between Kupffer cells (KCs) and hepatocytes (HCs) during hepatic inflammatory responses, and the effect of leflunomide’s active metabolite, A771726, on cytokines in KCs, HCs and KC cocultures (DC cocultures).

METHODS: KCs and HCs in liver were isolated by digestion with pronase and collagenase. Lipopolysaccharide (LPS) -induced inflammatory response in monocultures of rat HCs and KCs was compared with that in DC cocultures. Tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) concentrations in different culture supernatants were measured with ELISA. TNF-α mRNA in KCs of inflammatory liver injury was analyzed with reverse transcriptase polymerase chain reaction (RT-PCR).

RESULTS: DC cocultures strongly exhibited the production of TNF-α and IL-1 compared with other cultures, and these cytokines were mainly produced by KCs, especially by activated KCs. Time course studies revealed an increased production of TNF-α preceding the IL-1 production, suggesting that increased TNF-α levels could be involved in the increase of IL-1 production. Leflunomide’s active metabolite, A771726, had significantly inhibitory effect on TNF-α and IL-1 at protein and transcription levels, and the reduced production of IL-1 by A771726 was associated with the inhibitory action of A771726 on TNF-α.

CONCLUSION: Leflunomide can inhibit hepatocyte damage by inhibiting proinflammatory cytokine release from KCs.

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