Rheumatology Advance Access published online on February 3, 2005
Rheumatology, doi:10.1093/rheumatology/keh462
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1 Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan; Department of Rheumatology, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan; Department of Hepatology, Nagasaki University School of Biomedical Science, Sakamoto 1-7-1, Nagasaki 852-8501, Japan
* To whom correspondence should be addressed. 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-1 Results. IL-1 Conclusion. These results indicate that MAPK signalling pathways are critical in IL-1
Received August 10, 2004
Accepted October 5, 2004
Original Papers
An active metabolite of leflunomide, A77 1726, inhibits the production of serum amyloid A protein in human hepatocytes
2 Department of Rheumatology, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan
3 Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan
4 Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan; Department of Hepatology, Nagasaki University School of Biomedical Science, Sakamoto 1-7-1, Nagasaki 852-8501, Japan
5 First Department of Internal Medicine, Nagasaki University School of Medicine, Sakamoto 1-7-1, Nagasaki 852-8501, Japan
K. Migita, E-mail: migita{at}nmc.hosp.go.jp
Abstract 
, 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-1 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. is a most potent inducer of SAA in normal hepatocytes. A77 1726 suppressed the production of SAA in human hepatocytes activated by IL-1 in a dose-dependent manner (0-50 µM). A77 1726 inhibited IL-1-induced p38 and c-Jun N-terminal kinase 1/2 (JNK1/2) activation, whereas A77 1726 did not affect IL-1-induced NF-B activation in hepatocytes.-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.
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