Rheumatology Advance Access originally published online on February 3, 2005
Rheumatology 2005 44(4):443-448; doi:10.1093/rheumatology/keh462
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Rheumatology Vol. 44 No. 4 © British Society for Rheumatology 2005; all rights reserved
An active metabolite of leflunomide, A77 1726, inhibits the production of serum amyloid A protein in human hepatocytes
1 Clinical Research Center and 2 Department of Rheumatology, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan, 3 Department of Hepatology, Nagasaki University School of Biomedical Science and 4 First Department of Internal Medicine, Nagasaki University School of Medicine, Sakamoto 1-7-1, Nagasaki 852-8501, Japan.
Correspondence to: K. Migita, Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan. E-mail: migita{at}nmc.hosp.go.jp
Objective. Cytokine-induced hepatic serum amyloid A (SAA) synthesis is the critical step in the pathogenesis of AA amyloidosis secondary to rheumatoid arthritis (RA). This study was conducted to provide more insight into the mechanism of SAA production in hepatocytes and its regulation.
Methods. Primary cultured normal human hepatocytes were stimulated with cytokines (IL-1ß, TNF-
and IL-6) and the culture supernatants were analysed for the production of SAA. Human hepatocytes, treated or not treated with A77 1726, were stimulated with IL-1ß and the cellular lysates were analysed by immunoblot using anti-phospho-specific mitogen-activated protein kinase (MAPK) and I
B-. Acute phase-SAA (SAA1) mRNA expression was analysed by reverse transcription–polymerase chain reaction.
Results. IL-1ß is a most potent inducer of SAA in normal hepatocytes. A77 1726 suppressed the production of SAA in human hepatocytes activated by IL-1ß in a dose-dependent manner (0–50 µM). A77 1726 inhibited IL-1ß-induced p38 and c-Jun N-terminal kinase 1/2 (JNK1/2) activation, whereas A77 1726 did not affect IL-1ß-induced NF-B activation in hepatocytes.
Conclusion. These results indicate that MAPK signalling pathways are critical in IL-1ß-induced hepatic SAA synthesis. Leflunomide may suppress SAA synthesis by affecting these pathways and may therefore have some beneficial effect on AA amyloidosis secondary to RA.
KEY WORDS: Amyloidosis, Hepatocytes, Rheumatoid arthritis, Serum amyloid A protein, Leflunomide, Mitogen-activated protein kinase
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