Distinct Signaling Pathways Mediate Phorbol‐Ester‐Induced and Cytokine‐Induced Inhibition of Erythropoietin Gene Expression

Joachim Fandrey*, Andrea Huwiler, Stilla Frede, Josef Pfeilschifter, Wolfgang Jelkmann

*Corresponding author for this work
36 Citations (Scopus)


Hypoxia‐induced erythropoietin (Epo) production in vitro is suppressed by interleukin 1β (IL‐ 1β), tumor necrosis factor α (TNF) and phorbol esters. Herein, the Epo‐synthesizing human hepatoma cell line HepG2 was used to investigate whether protein kinase C (PKC) is involved in the inhibitory action of the cytokines. Within 1 h after the onset of hypoxia, Epo mRNA levels were markedly increased in untreated HepG2 cells as quantitated by competitive reverse transcription PCR. The cytokines IL‐1β and TNF prevented this hypoxia‐induced increase in Epo mRNA levels. In phorbol‐ester‐treated cells first inhibitory effects on Epo mRNA levels were observed only after 3 h. Western blot analyses revealed the presence of four isoenzymes of PKC in HepG2 cells. None of these isoenzymes was translocated in response to TNF or IL‐1β, suggesting that the cytokines do not activate PKC in HepG2 cells. In contrast, phorbol esters translocated and, upon prolonged exposure, down‐regulated PKC isoenzymes α and ɛ. Activation of protein kinase A by dibutyryl‐cAMP partially antagonized the cytokine‐dependent inhibition of Epo production but did not influence the inhibitory effect of phorbol esters. Endogenous cAMP levels in HepG2 cells were unchanged by cytokine treatment. Obviously, at least two signaling pathways exist that can confer inhibition of Epo production in HepG2 cells. One of these may be mediated by down‐regulation of the PKC α or ɛ isoenzyme. The other pathway, however, which is triggered by IL‐1β and TNF, is independent of PKC.

Original languageEnglish
JournalEuropean Journal of Biochemistry
Issue number2
Pages (from-to)335-340
Number of pages6
Publication statusPublished - 12.1994

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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