Tumor necrosis factor p55 receptor (TNF-RI) mediates the in vitro inhibition of hepatic erythropoietin production.
Tumor necrosis factor alpha (TNFalpha) is thought to contribute to the blunted erythropoietin (Epo) production in inflammatory diseases. The present study was carried out to find out as to whether the 55 kD (TNF-RI) or the 75 kD (TNF-RII) receptor is responsible for the TNFalpha-induced inhibition of hepatic Epo synthesis. When the effects of two receptor-specific mutants were compared, only the TNF-RI-specific isoform proved to suppress the formation of immunoreactive Epo in the human hepatoma cell lines HepG2 and Hep3B, similar to the effect of wild-type TNFalpha. Anti-TNFalpha antibody restored Epo production in TNFalpha- or TNF-RI mutant-treated cultures. By gel shift assay NF-kappaB binding to DNA was demonstrated following the addition of TNFalpha or TNF-RI-specific mutant to HepG2 cells, while the TNF-RII-specific mutant was ineffective. Finally, immunoreactive TNF-RI, but not TNF-RII, fragments were measurable in cell culture supernatants. Taken together, these results suggest that the inhibition of hepatic Epo production by TNFalpha is mediated by TNF-RI signaling.
Jelkmann
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W
Institute of Physiology, Medical University of Luebeck, Germany. jelkmann@physiol.mu-luebeck.de
Hellwig-Buergel
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T
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004921:Erythropoietin / Q000096:biosynthesis*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D015703:Antigens, CD; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin