Expression of the NF-κB inhibitor ABIN-3 in response to TNF and toll-like receptor 4 stimulation is itself regulated by NF-κB

Abstract

Although the nuclear factor-κB (NF-κB)-dependent gene expression is critical to the induction of an efficient immune response to infection or tissue injury, excessive or prolonged NF-κB signalling can contribute to the development of several inflammatory diseases. Therefore, the NF-κB signal transduction pathway is tightly regulated by several intracellular proteins. We have previously identified A20-binding inhibitor of NF-κB 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-κB to a specific B site in the ABIN-3 promoter. Altogether, these data indicate an important role for NF-κB-dependent gene expression of ABIN-3 in the negative feedback regulation of TNF receptor and toll-like receptor 4 induced NF-κB activation. © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.