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Title: Role of Bruton's tyrosine kinase (Btk) in BCR and TLR signalling
Keywords: Bruton's tyrosine kinase, B cell receptor, Toll-like receptor, Lipopolysaccharide, Interleukin
Issue Date: 28-Jul-2010
Source: LEE KOON GUAN (2010-07-28). Role of Bruton's tyrosine kinase (Btk) in BCR and TLR signalling. ScholarBank@NUS Repository.
Abstract: Toll-like receptors (TLR) are responsible for activating host defense against various pathogen and microorganisms. Recognition of pathogen-associated molecular patterns (PAMPs) by various TLRs activates the innate immune system. We aimed to investigate if Bruton?s tyrosine kinase (Btk) is involved in TLR signaling. B lymphocytes express both B-cell receptor (BCR) and TLR. We showed here that Btk, a critical component in BCR signaling, is also involved in TLR9 signaling in B cells. Stimulation of B cells with TLR9 ligand CpG ODN leads to transient phosphorylation of Btk and in the absence of Btk, TLR9-induced proliferation of B cells is impaired. Interestingly, Btk-/- B cells secreted significantly more IL-12 but much less IL-10 compared with wildtype B cells upon TLR9 stimulation. Immunization of Btk-/- mice with CpG ODN also leads to elevated level of IL-12 in-vivo and consequently, a greater fold increment in the production of Th1-type IgG2b and IgG3 antibodies in these mice compared with wildtype controls. The addition of exogenous recombinant IL-10 could suppress IL-12 production by TLR9-activated Btk-/- B cells, suggesting that in B cells, Btk negatively regulates IL-12 through the induction of autocrine IL-10 production. TLR9 signaling also leads to the activation of NF?B including the p65RelA subunit in wildtype B cells. The lack of Btk signaling affects the activation of NF?B, and impairs the translocation of the p65RelA subunit to the nucleus of B cells upon TLR9 stimulation. However, p65RelA-/- B cells could respond similarly as wildtype B cells in terms of IL-10 and IL-12 secretion when stimulated with CpG ODN suggesting that the defect in NF?B p65RelA activation is additional to the impairment in cytokine production in TLR9-activated Btk-/- B cells. Thus Btk plays an important role in TLR9 signaling and acts separately to regulate NF?B RelA activation as well as IL-10 and IL-12 production in B cells. Toll-like receptor 3 (TLR3) mediates innate immune response to pathogens by recognizing double-stranded RNA and initiating signaling via the adaptor TRIF. We demonstrated here that Btk also participates in TRIF-dependent signaling and acts at a nodal point before the bifurcating of the NF?B and IRF3 pathways. In the absence of Btk, TLR3-stimulated macrophages failed to secrete inflammatory cytokines and IFN? and mutant mice were less susceptible to poly(I:C)-induced septic shock and death. Btk signaling is required for TLR3-induced RIP1 ubiquitination necessary for NF?B activation as well as for TBK1 induction that is important for IRF3 phosphorylation. Mechanistically, Btk signals the recruitment of RIP1 to TRIF and induces the formation of a Btk/TRAF3/TBK1 complex. In addition, Btk itself binds TRIF upon TLR3 stimulation and is required for the phosphorylation of TLR3 at Tyr759 residue. Thus, Btk is an essential component of the TRIF signalosome critical for host anti-viral response. In summary, we have identified Btk as an integral protein tyrosine kinase critical for mediating signal transduction pathways downstream of both TLR9 and TLR3 which are important nucleic acids pattern recognition receptors (PRRs) in innate immunity.
Appears in Collections:Ph.D Theses (Open)

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