Expression of the NF-kappaB inhibitor ABIN-3 in response to TNF and toll-like receptor 4 stimulation is itself regulated by NF-kappaB.
Although the nuclear factor-kappaB (NF-kappaB)-dependent gene expression is critical to the induction of an efficient immune response to infection or tissue injury, excessive or prolonged NF-kappaB signalling can contribute to the development of several inflammatory diseases. Therefore, the NF-kappaB signal transduction pathway is tightly regulated by several intracellular proteins. We have previously identified A20-binding inhibitor of NF-kappaB activation (ABIN)-3 as an lipopolysaccharide (LPS)-inducible protein in monocytes that negatively regulates NF-B activation in response to tumour necrosis factor (TNF) and LPS. Here we report that ABIN-3 expression is also up-regulated upon TNF treatment of monocytes and other non-myeloid cell types. We also found a significantly enhanced expression of ABIN-3 in monocytes of sepsis patients, which is restored to control levels by corticotherapy. To further understand the transcriptional regulation of ABIN-3 expression, we isolated the human ABIN-3 promoter and investigated its activation in response to TNF and LPS. This revealed that the LPS- and TNF-inducible expression of ABIN-3 is dependent on the binding of NF-kappaB to a specific B site in the ABIN-3 promoter. Altogether, these data indicate an important role for NF-kappaB-dependent gene expression of ABIN-3 in the negative feedback regulation of TNF receptor and toll-like receptor 4 induced NF-kappaB activation.
Verstrepen
Lynn
L
Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, Ghent, Belgium.
Adib-Conquy
Minou
M
Kreike
Marja
M
Carpentier
Isabelle
I
Adrie
Christophe
C
Cavaillon
Jean-Marc
JM
Beyaert
Rudi
R
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D000305:Adrenal Cortex Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; C495345:TLR4 protein, human; C426747:TNIP3 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha