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

ABSTRACT: 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.

SUBMITTER: Verstrepen L

PROVIDER: S-EPMC3823492 | biostudies-literature | 2008 Jan-Feb

REPOSITORIES: biostudies-literature

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

Verstrepen Lynn L Adib-Conquy Minou M Kreike Marja M Carpentier Isabelle I Adrie Christophe C Cavaillon Jean-Marc JM Beyaert Rudi R

Journal of cellular and molecular medicine 20071210 1

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 ...[more]

PMID: 18081698

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Project description:BACKGROUND: The role of alveolar type II cells in the regulation of innate and adaptive immunity is unclear. Toll-like receptors (TLRs) have been implicated in host defense. The purpose of the present study was to investigate whether Chlamydophila pneumoniae (I) alters the expression of TLR2 and/orTLR4 in type II cells in a (II) Rho-GTPase- and (III) NF-kappaB-dependent pathway, subsequently (IV) leading to the production of (IV) pro-inflammatory TNF-alpha and MIP-2. METHODS: Isolated rat type II pneumocytes were incubated with C. pneumoniae after pre-treatment with calcium chelator BAPTA-AM, inhibitors of NF-kappaB (parthenolide, SN50) or with a specific inhibitor of the Rho-GTPase (mevastatin). TLR2 and TLR4 mRNA expressions were analyzed by PCR. Activation of TLR4, Rac1, RhoA protein and NF-kappaB was determined by Western blotting and confocal laser scan microscopy (CLSM) and TNF-alpha and MIP-2 release by ELISA. RESULTS: Type II cells constitutively expressed TLR4 and TLR2 mRNA. A prominent induction of TLR4 but not TLR2 mRNA was detected after 2 hours of incubation with C. pneumoniae. The TLR4 protein expression reached a peak at 30 min, began to decrease within 1-2 hours and peaked again at 3 hours. Incubation of cells with heat-inactivated bacteria (56 degrees C for 30 min) significantly reduced the TLR4 expression. Treated bacteria with polymyxin B (2 mug/ml) did not alter TLR4 expression. C. pneumoniae-induced NF-kappaB activity was blocked by TLR4 blocking antibodies. TLR4 mRNA and protein expression were inhibited in the presence of BAPTA-AM, SN50 or parthenolide. TNF-alpha and MIP-2 release was increased in type II cells in response to C. pneumoniae, whereas BAPTA-AM, SN50 or parthenolide decreased the C. pneumoniae-induced TNF-alpha and MIP-2 release. Mevastatin inhibited C. pneumoniae-mediated Rac1, RhoA and TLR4 expression. CONCLUSION: The TLR4 protein expression in rat type II cells is likely to be mediated by a heat-sensitive C. pneumoniae protein that induces a fast Ca2+-mediated NF-kappaB activity, necessary for maintenance of TLR4 expression and TNF-alpha and MIP-2 release through possibly Rac and Rho protein-dependent mechanism. These results indicate that type II pneumocytes play an important role in the innate pulmonary immune system and in inflammatory response mechanism of the alveolus.

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

Publications

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

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