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Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NF?B2 signaling that contributes to autoimmunity.

ABSTRACT: TNF receptor-associated factor 2 (TRAF2) is a key intracellular signaling mediator that acts downstream of not only TNF? but also various members of the TNF? superfamily. Here, we report that, despite their lack of TNF? signaling, TRAF2(-/-)TNF?(-/-) mice develop an inflammatory disorder characterized by autoantibody accumulation and organ infiltration by T cells with the phenotypes of activated, effector, and memory cells. RAG1(-/-) mice reconstituted with TRAF2(-/-)TNF?(-/-) bone marrow cells showed increased numbers of hyperactive T cells and rapidly developed progressive and eventually lethal inflammation. No inflammation was observed in RAG1(-/-) mice reconstituted with TRAF2(-/-)TNF?(-/-)T-cell receptor ?(-/-) or TRAF2(-/-)TNF?(-/-)NF?B-induced kinase(+/-) bone marrow cells. The pathogenic TRAF2(-/-)TNF?(-/-) T cells showed constitutive NF?B2p52 activation and produced elevated levels of T-helper 1 and T-helper 17 cytokines. Our results suggest that a regulatory circuit consisting of TRAF2-NF?B-induced kinase-NF?B2p52 is essential for the proper control of effector T-cell polarization and that loss of T-cell TRAF2 function induces constitutive NF?B2p52 activity that drives fatal autoimmune inflammation independently of TNF? signaling. The involvement of this regulatory circuit in controlling autoimmune responses highlights the delicate balance required to avoid paradoxical adverse events when implementing new targeted anti-inflammatory therapies.

SUBMITTER: Lin WJ

PROVIDER: S-EPMC3215017 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFκB2 signaling that contributes to autoimmunity.

Lin Wen-Jye WJ Su Yu-Wen YW Lu Yong-Chen YC Hao Zhenyue Z Chio Iok In Christine II Chen Nien-Jung NJ Brüstle Anne A Li Wanda Y WY Mak Tak Wah TW

Proceedings of the National Academy of Sciences of the United States of America 20111031 45

TNF receptor-associated factor 2 (TRAF2) is a key intracellular signaling mediator that acts downstream of not only TNFα but also various members of the TNFα superfamily. Here, we report that, despite their lack of TNFα signaling, TRAF2(-/-)TNFα(-/-) mice develop an inflammatory disorder characterized by autoantibody accumulation and organ infiltration by T cells with the phenotypes of activated, effector, and memory cells. RAG1(-/-) mice reconstituted with TRAF2(-/-)TNFα(-/-) bone marrow cells ...[more]

PMID: 22042853

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Project description:Alzheimer's disease (AD) is the most common type of dementia and is a serious social and medical problem threatening human health. The present study investigated the effect and underlying action mechanism of triptolide (Tri) on AD progression. Reverse transcription-quantitative PCR and western blotting analysis were used to determine the changes in RNA expression and levels of NF-κB signaling pathway proteins before and after lipopolysaccharide (LPS) induction. Nucleocytoplasmic separation experiments determined the intracellular localization of long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1). A dual-luciferase assay was used to analyze the binding between NEAT1 and microRNA (miRNA/miR)-361 or tumor necrosis factor receptor-associated factor 2 (TRAF2) and miR-361-3p and RNA pull-down was used to analyze the binding between NEAT1 and miR-361-3p. Cell Counting Kit-8, flow cytometry and ELISA were used to detect the effects of interaction between Tri and NEAT1/miR-361-3p/TRAF2 on cell viability, apoptosis and inflammatory factor levels, respectively. The results showed that LPS-mediated human microglial clone 3 cell line (HMC3) viability decreased and apoptosis and inflammatory factors (IL-1β, IL-6, IL-18 and TNF-α) increased. Tri inhibited LPS-mediated effects in a dose-dependent manner by downregulating NEAT1 expression. NEAT1 is highly expressed in the cytoplasm and reduces the transcription and translation of downstream TRAF2 by acting as a competitive endogenous RNA that adsorbs miR-361-3p. LPS-mediated HMC3 cell injury, inflammation and activation of NF-κB signaling were partially reversed in presence of Tri. The miR-361-3p mimic promoted the Tri effect and overexpression of (ov)-NEAT1 partially reversed the Tri-miR-361-3p combined effect. The effects of ov-NEAT1 were partially attenuated by small interfering (si)-TRAF2. Overall, Tri inhibited the LPS-induced decrease in viability, increase in apoptosis and inflammation and activation of NF-κB signaling in HMC3 cells. Tri regulation affected the NEAT1/miR-361-3p/TRAF2 axis. These findings suggested a potential therapeutic role for Tri in the clinical management of AD by modulating this molecular axis.

Dataset Information

Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NF?B2 signaling that contributes to autoimmunity.

Publications

Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFκB2 signaling that contributes to autoimmunity.

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