TLR7 and CD40 cooperate in IL‐6 production <i>via </i>enhanced JNK and AP‐1 activation

Bush, Tony J. Vanden; Bishop, Gail A.

doi:10.1002/eji.200737602

Cited by 56 publications

(55 citation statements)

References 52 publications

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“…IFNAR-mediated effects on c-Jun phosphorylation were greatly reduced in the presence of rapamycin and LY294002, indicating that an important mechanism by which the PI3K/Akt/mTOR pathway mediates downstream restoration of IL-6 production in TLR-tolerant B cells is through activation of c-Jun. These results are consistent with our previous findings that IL-6 production in B cells is dependent on AP-1 activation (10,33), and indicate that in contrast with BCR-mediated effects, the IFNAR contributes to c-Jun phosphorylation in a JNK-independent manner.…”

Section: Relationship Between Mapk and Pi3k Pathways In Ifnar-mediatesupporting

confidence: 93%

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Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Poovassery

Bishop

2012

The Journal of Immunology

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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.

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Section: Relationship Between Mapk and Pi3k Pathways In Ifnar-mediatesupporting

confidence: 93%

“…TLR7 signals synergize with BCR and CD40 signals to promote B cell Ag presentation, via upregulation of costimulatory molecules and cytokine production (10). Recent studies reveal a critical role for type I IFN receptor (IFNAR) signals in regulating TLR-mediated B cell responses (11).…”

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confidence: 99%

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Poovassery

Bishop

2012

The Journal of Immunology

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“…These pathways induce similar cytokine secretion patterns (IL-6 and IL-10) and up-regulation of activation markers (ie, CD80, CD86, MHC II) in both cell types. 19 Notably, TLR3 and TLR4, which both signal via TRIF, an adapter molecule that promotes MyD88-independent signaling, are not expressed in human B cells. To date, it is unclear whether TRIF plays a role in TLR-mediated B-cell activation.…”

Section: Tlr Expression In Normal and Neoplastic B Cells Normal B-celmentioning

confidence: 99%

Toll-like receptors: lessons to learn from normal and malignant human B cells

Chiron

Bekeredjian‐Ding

Pellat‐Deceunynck

et al. 2008

Blood

102

103

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IntroductionThe human immune system is continuously challenged by commensal microflora as well as invasive infectious agents. The decision to mount a rapid and protective immune response to a pathogen is a consequence of the activation of the innate immune system via pattern recognition receptors, such as Toll-like receptors (TLRs), that sense microbial products. 1 TLR polymorphisms have been implicated in increased severity and predisposition to infection and septic shock 2 in both mice and humans. TLRs recognize highly conserved structures of viral (TLR3,7,8,and 9) and bacterial (TLR1,2,4,5,6,7,8,and 9) origin, known as pathogen-associated molecular patterns (PAMPs; Figure 1). TLR2 heterodimerization with TLR1 or TLR6 is triggered by bacterial lipopeptides, whereas TLR3 is activated by double-stranded RNA, TLR4 is activated by lipopolysaccharide (LPS), TLR5 is activated by flagellin, TLR7 and TLR8 are activated by single-stranded RNA (ssRNA), and TLR9 is activated by unmethylated CpG DNA motifs. Moreover, endogenous ligands released during cellular stress or matrix degradation (eg, heat-shock proteins, fibronectin, heparan sulfates) are thought to activate TLRs. 3 Numerous reports have described how TLRs orchestrate the immune response to pathogens in dendritic cells (DCs) and macrophages. 4 Much less is known about the effects of TLR-mediated B-cell activation, although the design of vaccines could benefit from a more detailed understanding of this process.Leukemic B cells often retain the expression of markers specific for their cellular origin (eg, CD5, CD10, CD138). Furthermore, several reports have demonstrated TLR expression and function in neoplastic B cells. Because DCs can be activated and matured upon triggering of TLRs, immunotherapeutic protocols in leukemia have recently included TLR agonists to improve tumor antigen presentation and subsequent T-cell activation. 5 However, recent reports have indicated that leukemic cells could hijack the TLR machinery to their own benefit. A better understanding of the effects of TLR ligands on normal B cells and their leukemic counterparts could therefore help avoid adverse vaccination effects. In this review, we will discuss the role of TLRs in generating the humoral immune response and their dual effects on different leukemic cell types. TLR expression in normal and neoplastic B cells Normal B-cell subsets and modulation of expressionThe TLR expression pattern is specific for each cell type and is summarized in Figure 2 for human B cells. TLRs expression in human B cells is characterized by high expression of TLR1, 6, 7, 9, and 10. 6-8 Low expression of TLR2 allows for the formation of the functional heterodimers TLR1/2 and TLR2/6, which are required to respond to diacylated and triacylated lipoproteins. The inability to be activated by LPS is a hallmark of human B cells because they lack TLR4, in contrast to mouse B cells. However, human B cells are well equipped to recognize nucleic acids given their expression of TLR7 and TLR9. This profile allows them to ...

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“…B cell responses to stimulation by TLRs include proliferation, differentiation, cytokine secretion, up-regulation of adhesion and co-stimulatory molecules, antibody production, and Ig isotype switching [65,66]. Furthermore, TLRs can synergize with BCR or CD40 to promote B cell activation, thus providing powerful protection against various microbial pathogens [65,67,68] However, in the case of co-ligation of TLRs and BCR by autoantigens (DNA or RNA containing complexes), autoantibody production and autoimmunity may develop [65].…”

Section: Toll-like Receptors (Tlrs)mentioning

confidence: 99%

Roles of TRAF molecules in B lymphocyte function

Xie

Kraus

Stunz

et al. 2008

Cytokine & Growth Factor Reviews

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Tumor necrosis factor receptor associated factors (TRAFs) play a variety of interesting and important roles in the regulation of B lymphocyte function. They act both as cytoplasmic regulatory molecules, and as signal transducers for receptors involved in both innate and adaptive humoral immune responses. In this brief review, we highlight the current state of knowledge of the diverse roles of TRAF molecules in the functions of B lymphocytes. CD40CD40 is the most well-studied member of the TNFR superfamily expressed by B lymphocytes, so its interactions with TRAF molecules have also been intensively investigated. B cell CD40 is important in the induction of B cell survival and expansion, immunoglobulin (Ig) production and isotype switching, upregulation of surface molecules involved in B cell antigen presentation, differentiation to B memory cells, and the production of various cytokines (reviewed in [1]. The TRAF molecules have been shown to contribute to each of these functions (reviewed in [2].In 1994, TRAF3 became the first cytoplasmic molecule demonstrated to associate with CD40 (reviewed in [2]). However, for many years, its roles in CD40 signaling were largely unknown, and are still not completely understood. TRAF3 -/-mice die shortly after birth, but adoptive transfer of fetal liver cells from these mice suggested that their B cells were capable of reconstituting the humoral response [3], implying that TRAF3 is not required to promote CD40-mediated antibody responses. This conclusion was supported by experiments in B cell lines demonstrating that inducible overexpression of TRAF3 inhibits both CD40 responses [4], and cooperation between CD40 and the BCR [5]. Subsequently, B cell lines made completely TRAF3-deficient via gene targeting by homologous recombination show no defects in CD40 signaling overall, and display enhanced CD40-mediated c-jun kinase (JNK) activation and IgM production [6]. Recently, mice made conditionally deficient in TRAF3 only in CD19+ B cells show no deficiencies in CD40 signaling in vitro and have enhanced antibody responses [7]. TRAF2 was initially demonstrated to bind CD40 by exogenous overexpression studies in adenocarcinoma cell lines, in which it promotes JNK activation and the activity of NF-κB reporter genes (reviewed in [2]. Because TRAF2 -/-mice have an early lethal phenotype [8],Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

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TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Cited by 56 publications

References 52 publications

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Toll-like receptors: lessons to learn from normal and malignant human B cells

Roles of TRAF molecules in B lymphocyte function

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