Toll-like receptors (TLRs) are involved in the recognition of microbial pathogens. A subset of TLRs, TLR7, TLR8 and TLR9, induces antiviral responses by producing interferon-alpha (IFN-alpha). Production of IFN-alpha is dependent on the Toll-interleukin-1 receptor domain-containing adaptor MyD88. Here we show that MyD88 formed a complex with the transcription factor IRF7 but not with IRF3. The death domain of MyD88 interacted with an inhibitory domain of IRF7, and this interaction resulted in activation of the IFN-alpha-dependent promoters. Furthermore, the adaptor molecule TRAF6 also bound and activated IRF7. Ubiquitin ligase activity of TRAF6 was required for IRF7 activation. These results indicate that TLR-mediated IFN-alpha induction requires the formation of a complex consisting of MyD88, TRAF6 and IRF7 as well as TRAF6-dependent ubiquitination.
"TLR9, a type I transmembrane protein with an extracellular domain composed of leucine-rich repeat motifs and a cytoplasmic TIR signaling domain  , is localized in the endoplasmic reticulum (ER) of antigenpresenting cells and B cells  . The interaction between CpG ODNs and TLR9 occurs within the acidified endosome/lysosome , which leads to induction of cytokines, including interleukin-6 (IL-6) and interferon-a (IFN-a)  . Synthetic CpG ODNs, used in clinical applications, can be divided into at least 4 classes on the basis of the potential of cytokine induction, depending on their sequence properties. "
[Show abstract][Hide abstract] ABSTRACT: Toll-like receptor 9 recognizes CpG oligodeoxynucleotides (ODNs) and induces immune-mediator cytokines. Natural phosphodiester class B CpG ODNs induce interleukin-6 (IL-6), but not interferon-α (IFN-α). We prepared silicon nanoparticles (Si NPs) with different positive surface charge density and bound negatively charged class B CpG ODN molecules electrostatically. No significant differences in the amount of class B CpG ODN molecules or negative surface charge after binding of the molecules onto naked NPs was observed. However, the profile of cytokine induction from peripheral blood mononuclear cells was correlated with a positive surface charge density of naked NPs prior to binding of CpG ODN molecules. The level of IL-6 induction slightly decreased as the positive surface charge density was increased, while the IFN-α induction significantly increased as the positive surface charge density was increased. This observation demonstrates that the bifurcated cytokine induction can be regulated by the surface charge of naked NPs.
Journal of Drug Delivery Science and Technology 09/2015; 29:251-260. DOI:10.1016/j.jddst.2015.08.008 · 0.48 Impact Factor
"MyD88 transfection alone resulted in the formation of very large condensed aggregates in the cytoplasm of both human and bat cells. Human MyD88 and human IRF7 colocalised in a manner similar to previous studies (Figure 6B) ,. Similarly, bat MyD88 and IRF7 proteins also demonstrated clear co-localisation. As shown in Figure 6B, bat IRF7 appeared to be surrounded by MyD88 in an aggregated form, which is the typical MyD88 structure ,. "
[Show abstract][Hide abstract] ABSTRACT: As the only flying mammal, bats harbor a number of emerging and re-emerging viruses, many of which cause severe diseases in humans and other mammals yet result in no clinical symptoms in bats. As the master regulator of the interferon (IFN)-dependent immune response, IFN regulatory factor 7 (IRF7) plays a central role in innate antiviral immunity. To explore the role of bat IRF7 in the regulation of the IFN response, we performed sequence and functional analysis of IRF7 from the pteropid bat, Pteropus alecto. Our results demonstrate that bat IRF7 retains the ability to bind to MyD88 and activate the IFN response despite unique changes in the MyD88 binding domain. We also demonstrate that bat IRF7 has a unique expression pattern across both immune and non-immune related tissues and is inducible by double-strand RNA. The broad tissue distribution of IRF7 may provide bats with an enhanced ability to rapidly activate the IFN response in a wider range of tissues compared to other mammals. The importance of IRF7 in antiviral activity against the bat reovirus, Pulau virus was confirmed by siRNA knockdown of IRF7 in bat cells resulting in enhanced viral replication. Our results highlight the importance of IRF7 in innate antiviral immunity in bats.
PLoS ONE 08/2014; 9(8):e103875. DOI:10.1371/journal.pone.0103875 · 3.23 Impact Factor
"During TLR 7 and 9 activation, MYD88 also recruits TRAF3 to activate TBK1 and IKKε, which phosphorylates the transcription factor interferon-regulatory factor 7 (IRF7) and leads to IFN-α production (40, 41). IFN-α production, as with production of other IFNs, is particularly important for anti-viral responses (42) (Figure 1). "
[Show abstract][Hide abstract] ABSTRACT: Pattern recognition receptors (PRRs) expressed on immune cells are crucial for the early detection of invading pathogens, in initiating early innate immune response and in orchestrating the adaptive immune response. PRRs are activated by specific pathogen-associated molecular patterns that are present in pathogenic microbes or nucleic acids of viruses or bacteria. However, inappropriate activation of these PRRs, such as the Toll-like receptors (TLRs), due to genetic lesions or chronic inflammation has been demonstrated to be a major cause of many hematological malignancies. Gain-of-function mutations in the TLR adaptor protein MYD88 found in 39% of the activated B cell type of diffuse large B cell lymphomas and almost 100% of Waldenström's macroglobulinemia further highlight the involvement of TLRs in these malignancies. MYD88 mutations result in the chronic activation of TLR signaling pathways, thus the constitutive activation of the transcription factor NFκB to promote cell survival and proliferation. These recent insights into TLR pathway driven malignancies warrant the need for a better understanding of TLRs in cancers and the development of novel anti-cancer therapies targeting TLRs. This review focuses on TLR function and signaling in normal or inflammatory conditions, and how mutations can hijack the TLR signaling pathways to give rise to cancer. Finally, we discuss how potential therapeutic agents could be used to restore normal responses to TLRs and have long lasting anti-tumor effects.
Frontiers in Immunology 07/2014; 5:367. DOI:10.3389/fimmu.2014.00367
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