Enhanced Toll-like receptor (TLR) responses of TNFR-associated factor 3 (TRAF3)-deficient B lymphocytes

Department of Microbiology, The University of Iowa, Iowa City, Iowa, USA.
Journal of leukocyte biology (Impact Factor: 4.99). 12/2011; 90(6):1149-57. DOI: 10.1189/jlb.0111044
Source: PubMed

ABSTRACT The key role of TRAF6 in TLR signaling pathways is well known. More recent evidence has implicated TRAF3 as another TRAF family member important to certain TLR responses of myeloid cells. Previous studies demonstrate that TRAF3 functions are highly context-dependent, displaying receptor and cell-type specificity. We thus examined the TLR responses of TRAF3(-/-)mouse B lymphocytes to test the hypothesis that TRAF3 plays distinct roles in such responses, depending on cell type. TRAF3(-/-) DC are known to have a defect in type 1 IFN production and here, showed diminished production of TNF and IL-10 and unaltered IL-6. In marked contrast, TRAF3(-/-) B cells made elevated amounts of TNF and IL-6 protein, as well as IL-10 and IP-10 mRNA, in response to TLR ligands. Also, in contrast to TRAF3(-/-) DC, the type 1 IFN pathway was elevated in TRAF3(-/-) B cells. Increased early responses of TRAF3(-/-) B cells to TLR signals were independent of cell survival or proliferation but associated with elevated canonical NF-κB activation. Additionally, TRAF3(-/-) B cells displayed enhanced TLR-mediated expression of AID and Ig isotype switching. Thus, TRAF3 plays varied and cell type-specific, biological roles in TLR responses.

Download full-text


Available from: Ping Xie, Aug 10, 2015
  • Source
    • "TRAFs are composed of an N-terminal cysteine/ histidine-rich region containing a zinc RING and/or zinc finger motifs, a coiled-coil (leucine zipper) motif, and a C-terminal homology region that defines the TRAF family (Bradley and Pober 2001). TRAFs serve as adapter proteins for the TNF receptor superfamily and the IL-1R/TLR superfamily and participate in multiple biological functions, such as adaptive and innate immunity, tumorigenesis, embryonic development, and the stress response (Au and Yeh 2007; Zhou and Geahlen 2009; Clark et al. 2011; Xie et al. 2011). Recent studies have shown that TRAF proteins are markedly up-regulated in atherosclerotic plaques of human carotid arteries. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Tumor necrosis factor receptor-associated factor 5 (TRAF5) is an adaptor protein of the tumor necrosis factor (TNF) receptor superfamily and the interleukin-1 receptor/Toll-like receptor superfamily and plays important roles in regulating multiple signaling pathways. The role of TRAF5 in the context of brain ischemia/reperfusion (I/R) injury has not yet been examined. METHODS AND RESULTS: Transient occlusion of the middle cerebral artery was performed on TRAF5 knockout mice (KO), neuron-specific TRAF5 transgene (TG) and the appropriate controls. Compared with the WT mice, the TRAF5 KO mice showed lower infarct volumes and better outcomes in the neurological tests. A low neuronal apoptosis level, an attenuated blood brain barrier (BBB) disruption and an inhibited inflammatory response were exhibited in TRAF5 KO mice. TRAF5 TG mice exhibited an opposite phenotype. Moreover, the Akt/FoxO1 signaling pathway was enhanced in the ischemic brains of the TRAF5 KO mice. CONCLUSIONS: TRAF5 KO mice exhibited minor infarctions, low levels of neuronal apoptosis, an attenuated BBB disruption and an inhibited inflammatory response following cerebral I/R injury. These data demonstrate that TRAF5 is a critical mediator of I/R injury in an experimental stroke model. The Akt /FoxO1 signaling pathway probably plays an important role in the biological function of TRAF5 in this model. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12207.
    Journal of Neurochemistry 02/2013; 126(3). DOI:10.1111/jnc.12207 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptor 7 (TLR7) signals to B cells are critically involved in the innate immune response to microbes, as well as pathogenesis of autoimmune diseases, but the molecular mechanisms that normally regulate these responses are incompletely understood. We previously reported that repeated stimulation through TLR7 induces a state of hyporesponsiveness (TLR tolerance) in both human and mouse B cells, characterized by marked inhibition of particular signaling pathways. BCR signals prevent and overcome TLR7 tolerance. Because optimal responses to TLR7 in B cells require type I IFN, we investigated whether BCR-mediated effects on TLR7 tolerance are mediated by type I IFN receptor (IFNAR) signals. Surprisingly, although BCR-mediated reversal of TLR7 tolerance was IFNAR independent, IFNAR signals alone also blocked TLR7 tolerance, despite enhancing TLR7 expression. Both BCR and IFNAR signals restored the phosphorylation of the transcriptional regulator c-Jun, but only BCR signals blocked the tolerance-mediated inhibition of JNK. Both BCR and IFNAR-mediated regulation was dependent on activation of the PI3K/Akt/mammalian target of rapamycin signaling pathway, indicating a central role for this axis in integrating TLR7, BCR, and IFNAR signals in B cells. These new findings reveal distinct and overlapping signaling mechanisms used by BCR and IFNAR in the regulation of TLR7 tolerance and activation.
    The Journal of Immunology 07/2012; 189(4):1757-64. DOI:10.4049/jimmunol.1200624 · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Epstein-Barr virus (EBV)-encoded protein latent membrane protein 1 (LMP1) is essential for EBV-mediated B cell transformation and plays a critical role in the development of post-transplant B cell lymphomas. LMP1 also contributes to the exacerbation of autoimmune diseases such as systemic lupus erythematosus (SLE). LMP1 is a functional mimic of the tumor necrosis factor receptor (TNFR) superfamily member CD40, and relies on TNFR-associated factor (TRAF) adaptor proteins to mediate signaling. However, LMP1 activation signals to the B cell are amplified and sustained compared to CD40 signals. We previously demonstrated that LMP1 and CD40 use TRAF molecules differently. Although associating with CD40 and LMP1 via separate mechanisms, TRAF6 plays a significant role in signal transduction by both. It is unknown whether TRAF6 mediates CD40 versus LMP1 functions via distinct or shared pathways. In this study, we tested the hypothesis that TRAF6 uses the kinase TAK1 to trigger important signaling pathways following both CD40 and LMP1 stimulation. We determined that TAK1 was required for JNK activation and interleukin-6 (IL-6) production mediated by CD40 and LMP1, in both mouse and human B cells. Additionally, TRAF3 negatively regulated TRAF6-dependent, CD40-mediated TAK1 activation by limiting TRAF6 recruitment. This mode of regulation was not observed for LMP1 and may contribute to the dysregulation of LMP1 compared to CD40 signals.
    PLoS ONE 07/2012; 7(7):e42478. DOI:10.1371/journal.pone.0042478 · 3.53 Impact Factor
Show more