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Erythropoietin production: Molecular mechanisms of the antagonistic actions of cyclic adenosine monophosphate and interleukin‐1
Author(s) -
Batmunkh Chimedtseren,
Krajewski Jochen,
Jelkmann Wolfgang,
Hellwig-Bürgel Thomas
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.04.069
Subject(s) - erythropoietin , transcription factor , messenger rna , microbiology and biotechnology , northern blot , cyclic adenosine monophosphate , transcription (linguistics) , adenosine , biology , gene expression , western blot , promoter , blot , medicine , endocrinology , gene , chemistry , biochemistry , receptor , linguistics , philosophy
Erythropoietin (Epo) mRNA expression is suppressed by interleukin 1 (IL‐1). Cyclic adenosine monophosphate (cAMP) can increase Epo mRNA and Epo protein levels in IL‐1 treated HepG2 cells to some extent. To identify molecular mechanisms of this reaction we investigated three transcription factors (NF‐κB, GATA‐2 and HIF‐1) that control the Epo gene. Western blot analyses and electrophoretic mobility shift assays (EMSAs) revealed that IL‐1 strongly activated NF‐κB, which is a likely suppressor of the Epo promoter. Treatment of the cells with dibutyryl‐cAMP (Bt 2 ‐cAMP) inhibited the activation of NF‐κB by IL‐1. Bt 2 ‐cAMP increased GATA‐2 DNA binding. Since GATA‐2 is a suppressor of the Epo promoter, GATA‐2 activation was unlikely to cause the increase of Epo mRNA expression in IL‐1 treated cells. Furthermore, Western blots, EMSAs and reporter gene studies showed that Bt 2 ‐cAMP was without effect on the hypoxia‐inducible transcription factor HIF‐1. Thus, NF‐κB is probably the primary transcription factor by which cAMP counteracts the inhibition of Epo gene expression by IL‐1.