When Signaling Pathways Collide: Positive and Negative Regulation of Toll-like Receptor Signal Transduction

School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
Immunity (Impact Factor: 21.56). 07/2008; 29(1):12-20. DOI: 10.1016/j.immuni.2008.06.004
Source: PubMed


Toll-like receptor (TLR) signaling is subjected to crosstalk from other signals, with a resulting positive or negative effect. There is complex crosstalk between the NLR family of immune-regulatory molecules and TLRs, and C-type lectin receptors such as Dectin-1 synergize with TLR2 via the tyrosine kinase Syk. Bruton's tyrosine kinase plays an important positive role in TLR signaling, whereas the TAM family of receptor tyrosine kinases is inhibitory. The tyrosine phosphatase SHP1 has been shown to positively regulate induction of interferon-beta, whereas SHP2 inhibits the kinase TBK1, limiting this response. K63-linked polyubiquination has also been shown to be critical for the initiation of TLR signaling. Finally, glucocorticoids affect TLR signaling by inducing the phosphatase MKP1 and inhibiting TBK1 activation. These recent findings emphasize the importance of considering TLR signaling in the context of other signaling pathways, as is likely to occur in vivo during infection and inflammation.

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    • "C.-Y. Lai et al. / Vaccine xxx (2014) xxx–xxx such as imiquimod, loxoribine, and CL264, selectively activate TLR7 but not TLR8 [7] [8] [9] [10] [11]. Activation of TLR7/8 triggers a MyD88- dependent signaling pathway to elicit production of inflammatory cytokines and type I interferons (IFNs) via activation of NF-␬B and IRF7, respectively [12] [13] [14]. Because of their efficiency in activating immune responses, the TLR7/8 agonists are being investigated for a broad variety of applications, including antiviral and antitumor therapies, and use as a vaccine adjuvant [7] [8] [9] [10] [11]. "
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    ABSTRACT: Toll-like receptors 7 (TLR7) and 8 (TLR8) recognize viral single-stranded RNA and small molecular weight agonists to activate anti-viral immune responses. TLR8s from different species have distinct ligand recognitions. For example, human TLR8 is responsive to ligand stimulation, but mouse and rat TLR8 are activated by small molecular weight agonists only in the presence of polyT-oligodeoxynucleotides. TLR7 and TLR8 have been reported to be absent and pseudogenized, respectively, in rabbit (Oryctolagus cuniculus). In this study, we detected the expression of rabbit (rab)TLR8 in immune-cell-associated tissues. Cell proliferation and cytokine expressions in rabbit splenocytes were induced by the TLR7/8 ligand but not by the TLR7 ligands, suggesting that rabTLR8 is functional but rabTLR7 is not. In rabbits, CL075, a TLR7/8 ligand, activated an antigen-specific antibody response, although one not as potent as aluminum salt or Freund's adjuvant. Nevertheless, CL075, alone or in combination with aluminum salt, generates fewer adverse effects than Freund's adjuvant at the injection sites. To further investigate the activation of rabTLR8, we cloned its cDNA. In cell-based assay, this rabTLR8 is activated by TLR7/8 ligand but not activated by TLR7 ligand. Upon stimulation the rabTLR8 had a lower activation compared to the activation of TLR8 from other species, except the mouse and rat TLR8s. Using different deletion and human-rabbit chimeric TLR8 expressing constructs, we showed that an extra peptide in the undefined region results in reduced activity of rabTLR8. These results provide a molecular basis for the mild activities of TLR7/8 ligands in rabbits, and suggest TLR7/8 agonists may provide safer immune stimuli in rabbits than in other non-rodent species.
    Full-text · Article · Aug 2014 · Vaccine
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    • "In this sense, there must be some intrinsic or adaptive mechanisms to protect against dysfunctional inflammation during infection. An increasing number of reports have indicated that the hosts have developed sophisticated negative mechanism to regulate the multiple layers of inflammatory response [20], [22], [23]. Indeed, some cell wall components of bacteria, such as lipoteichoic acids and lipopolysaccharides, were reported to activate the basic leucine zipper transcription factor NF-E2-related factor 2 (Nrf2), a key factor involved in antioxidant protein expression in human tracheal smooth muscle cells and monocytes [24]. "
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    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Several mechanisms have been described which are involved in ET of NFκB -dependent readouts. These include the up-regulation of endogenous suppressors of NFκB activation such as SIGIRR, ST2, A20, Myd88 s and IRAK-M [9], [38]. NFκB is also important with respect to MΦ subset polarisation; IκBα over-expression resulted in M2 polarisation [19], whereas IKKβ deletion favoured M1 MΦs [20]. "
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    Full-text · Article · Jul 2013 · PLoS ONE
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