PMID- 15379215
OWN - NLM
STAT- MEDLINE
DCOM- 20050208
LR  - 20211203
IS  - 0360-3997 (Print)
IS  - 0360-3997 (Linking)
VI  - 28
IP  - 2
DP  - 2004 Apr
TI  - A 771726, the active metabolite of leflunomide, inhibits TNF-alpha and IL-1 from 
      Kupffer cells.
PG  - 97-103
AB  - This study was conducted to investigate the importance of direct contact between 
      Kupffer cells (KCs) and hepatocytes (HCs) during the hepatic inflammatory 
      responses, and the effect of leflunomide's active metabolite, A771726, on 
      cytokines in KCs and HCs (DC cocultures) and KC cultures using an in vitro 
      approach. Lipopolysaccharide (LPS)-induced inflammatory response in monocultures 
      of rats HCs and KCs were compared with DC cocultures. Tumor necrosis factor-alpha 
      (TNF-alpha) and interleukin-1 (IL-1) concentrations of different culture 
      supernatants were measured with ELISA. TNF-alpha and IL-1 mRNA in KCs of 
      inflammatory liver injury was analyzed with reverse transcription polymerase 
      chain reaction (RT-PCR). Our data showed that DC cocultures exhibited the highest 
      production of TNF-alpha and IL-1 compared with other cultures, and these 
      cytokines were mainly produced by KCs, in particular activated KCs. Time course 
      studies revealed an increased production of TNF-a preceding the IL-1 production, 
      suggesting that increased TNF-alpha levels could be involved in the increased 
      IL-1 production. Leflunomide's active metabolite, A771726, has significantly 
      inhibitory effect on TNF-a and IL-1 at protein and transcription levels, and 
      reduced production of IL-1 by A771726 was associated with inhibitory action of 
      A771726 on TNF-alpha. These results provided evidence that leflunomide 
      significantly inhibited TNF-alpha and IL-1 from KCs.
FAU - Yao, Hong Wei
AU  - Yao HW
AD  - School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.
FAU - Li, Jun
AU  - Li J
FAU - Chen, Ji Qiang
AU  - Chen JQ
FAU - Xu, Shu Yun
AU  - Xu SY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Inflammation
JT  - Inflammation
JID - 7600105
RN  - 0 (Aniline Compounds)
RN  - 0 (Crotonates)
RN  - 0 (Hydroxybutyrates)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-1)
RN  - 0 (Isoxazoles)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Nitriles)
RN  - 0 (RNA, Messenger)
RN  - 0 (Toluidines)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 1C058IKG3B (teriflunomide)
RN  - G162GK9U4W (Leflunomide)
SB  - IM
MH  - Aniline Compounds/metabolism/*pharmacology
MH  - Animals
MH  - Cell Communication/drug effects/immunology
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Crotonates
MH  - Hepatitis/*drug therapy/immunology/metabolism
MH  - Hepatocytes/cytology/immunology
MH  - Hydroxybutyrates/metabolism/*pharmacology
MH  - Immunosuppressive Agents/metabolism/*pharmacology
MH  - Interleukin-1/*antagonists & inhibitors/genetics
MH  - Isoxazoles/metabolism
MH  - Kupffer Cells/cytology/drug effects/*immunology
MH  - Leflunomide
MH  - Lipopolysaccharides/pharmacology
MH  - Male
MH  - Nitriles
MH  - RNA, Messenger/analysis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Toluidines
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/genetics
EDAT- 2004/09/24 05:00
MHDA- 2005/02/09 09:00
CRDT- 2004/09/24 05:00
PHST- 2004/09/24 05:00 [pubmed]
PHST- 2005/02/09 09:00 [medline]
PHST- 2004/09/24 05:00 [entrez]
AID - 10.1023/b:ifla.0000033025.73363.d3 [doi]
PST - ppublish
SO  - Inflammation. 2004 Apr;28(2):97-103. doi: 10.1023/b:ifla.0000033025.73363.d3.