A 771726, the active metabolite of leflunomide, inhibits TNF-alpha and IL-1 from Kupffer cells.

Inflammation
Hong Wei YaoShu Yun Xu

Abstract

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 p...Continue Reading

Citations

Mar 18, 2006·The Journal of Investigative Dermatology·Benno WeigmannAngelika B Reske-Kunz
Nov 3, 2005·Expert Opinion on Emerging Drugs·Rachel FarrellGavin Giovannoni
Oct 26, 2016·Chemical Biology & Drug Design·Angelika DryndaMarcin Mączyński
May 23, 2008·Journal of Clinical Gastroenterology·Steffen LamparterHeinz H Koehler
Oct 27, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Michał ZimeckiMarcin Mączyński
Nov 8, 2007·American Journal of Physiology. Endocrinology and Metabolism·Miriam GranadoM Angeles Villanúa

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