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Toll-like receptor downstream signaling.

Kawai T, Akira S - Arthritis Res. Ther. (2004)

Bottom Line: Almost all TLRs use a TIR-containing adapter MyD88 to activate a common signaling pathway that results in the activation of NF-kappaB to express cytokine genes relevant to inflammation.In particular, activation of the TRIF-dependent pathway confers antiviral responses by inducing anti-viral genes including that encoding interferon-beta.Taken together, these results indicate that the interaction between individual TLRs and the different combinations of adapters directs appropriate responses against distinct pathogens.

View Article: PubMed Central - PubMed

Affiliation: ERATO, Japan Science and Technology Agency, Osaka, Japan.

ABSTRACT
The family of Toll-like receptors (TLRs) senses conserved structures found in a broad range of pathogens, causing innate immune responses that include the production of inflammatory cytokines, chemokines and interferons. The signal transduction is initiated from the Toll/interleukin-1 receptor (TIR) domain of TLRs after pathogen recognition. Almost all TLRs use a TIR-containing adapter MyD88 to activate a common signaling pathway that results in the activation of NF-kappaB to express cytokine genes relevant to inflammation. Recently, three further TIR-containing adapters have been identified and shown to selectively interact with several TLRs. In particular, activation of the TRIF-dependent pathway confers antiviral responses by inducing anti-viral genes including that encoding interferon-beta. Taken together, these results indicate that the interaction between individual TLRs and the different combinations of adapters directs appropriate responses against distinct pathogens.

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Schematic representation of Toll-like receptor (TLR) signaling pathways. All TLRs except for TLR3 are thought to share the MyD88-dependent pathway that activates NF-κB and mitogen-activated protein (MAP) kinases, leading to the induction of inflammatory cytokine genes. Interleukin-1 receptor-associated kinases (IRAKs) and TRAF6 are located downstream of MyD88. TIRAP is involved in the MyD88-dependent pathway downstream of TLR2 and TLR4. TRIF is utilized in the TLR3-mediated and TLR4-mediated activation of interferon regulatory factor (IRF)3 and the subsequent induction of IRF3-dependent gene expression such as interferon-β (IFN-β). TRAM is specifically involved in the activation of IRF3 in TLR4 signaling. The complex of TBK1/IκB kinase-i (IKK-i) is responsible for the activation of IRF3 downstream of TRIF in TLR3 and TLR4 signaling. TRAF6 is also involved in the TRIF-dependent activation of NF-κB and MAP kinases. Receptor-interacting protein (RIP) mediates TRIF-dependent NF-κB activation. DD, death domain.
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Figure 3: Schematic representation of Toll-like receptor (TLR) signaling pathways. All TLRs except for TLR3 are thought to share the MyD88-dependent pathway that activates NF-κB and mitogen-activated protein (MAP) kinases, leading to the induction of inflammatory cytokine genes. Interleukin-1 receptor-associated kinases (IRAKs) and TRAF6 are located downstream of MyD88. TIRAP is involved in the MyD88-dependent pathway downstream of TLR2 and TLR4. TRIF is utilized in the TLR3-mediated and TLR4-mediated activation of interferon regulatory factor (IRF)3 and the subsequent induction of IRF3-dependent gene expression such as interferon-β (IFN-β). TRAM is specifically involved in the activation of IRF3 in TLR4 signaling. The complex of TBK1/IκB kinase-i (IKK-i) is responsible for the activation of IRF3 downstream of TRIF in TLR3 and TLR4 signaling. TRAF6 is also involved in the TRIF-dependent activation of NF-κB and MAP kinases. Receptor-interacting protein (RIP) mediates TRIF-dependent NF-κB activation. DD, death domain.

Mentions: MyD88 was originally identified as one of the myeloid differentiation primary response genes rapidly induced by IL-6 in M1 myeloleukemic cells. MyD88 contains two domains characterized by a death domain and a TIR domain, but lacks a putative transmembrane region, suggesting that MyD88 might function as an adapter protein in cytoplasm (Fig. 2). Consequently, MyD88 was shown to be recruited to the IL-1R after IL-1 ligation and to associate with IRAK1, resulting in the activation of transcription factors NF-κB and AP-1 [22-24]. Studies on MyD88-deficient mice clearly demonstrated that MyD88 is an essential component in the responses to IL-1 and the IL-1-related cytokine IL-18 [25]. All of the responses to IL-1 and IL-18 and the activation of NF-κB and MAP kinases were completely defective in cells from MyD88-deficient mice. Subsequent investigation confirmed that MyD88 is also used in TLR signaling. In MyD88-deficient mice, the production of inflammatory cytokines such as tumor necrosis factor-α, IL-1β and IL-6, the proliferation of B cells, and the induction of endotoxin shock in response to LPS (TLR4 ligand) are also completely abolished, demonstrating that MyD88 is indispensable for the responses to LPS in vivo [26]. In addition, cells from MyD88-deficient mice are totally unresponsive to peptidoglycan, lipoprotein, CpG DNA, and imidazoquinolines in terms of cytokine production [12,27,28] (Fig. 3).


Toll-like receptor downstream signaling.

Kawai T, Akira S - Arthritis Res. Ther. (2004)

Schematic representation of Toll-like receptor (TLR) signaling pathways. All TLRs except for TLR3 are thought to share the MyD88-dependent pathway that activates NF-κB and mitogen-activated protein (MAP) kinases, leading to the induction of inflammatory cytokine genes. Interleukin-1 receptor-associated kinases (IRAKs) and TRAF6 are located downstream of MyD88. TIRAP is involved in the MyD88-dependent pathway downstream of TLR2 and TLR4. TRIF is utilized in the TLR3-mediated and TLR4-mediated activation of interferon regulatory factor (IRF)3 and the subsequent induction of IRF3-dependent gene expression such as interferon-β (IFN-β). TRAM is specifically involved in the activation of IRF3 in TLR4 signaling. The complex of TBK1/IκB kinase-i (IKK-i) is responsible for the activation of IRF3 downstream of TRIF in TLR3 and TLR4 signaling. TRAF6 is also involved in the TRIF-dependent activation of NF-κB and MAP kinases. Receptor-interacting protein (RIP) mediates TRIF-dependent NF-κB activation. DD, death domain.
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Related In: Results  -  Collection

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Figure 3: Schematic representation of Toll-like receptor (TLR) signaling pathways. All TLRs except for TLR3 are thought to share the MyD88-dependent pathway that activates NF-κB and mitogen-activated protein (MAP) kinases, leading to the induction of inflammatory cytokine genes. Interleukin-1 receptor-associated kinases (IRAKs) and TRAF6 are located downstream of MyD88. TIRAP is involved in the MyD88-dependent pathway downstream of TLR2 and TLR4. TRIF is utilized in the TLR3-mediated and TLR4-mediated activation of interferon regulatory factor (IRF)3 and the subsequent induction of IRF3-dependent gene expression such as interferon-β (IFN-β). TRAM is specifically involved in the activation of IRF3 in TLR4 signaling. The complex of TBK1/IκB kinase-i (IKK-i) is responsible for the activation of IRF3 downstream of TRIF in TLR3 and TLR4 signaling. TRAF6 is also involved in the TRIF-dependent activation of NF-κB and MAP kinases. Receptor-interacting protein (RIP) mediates TRIF-dependent NF-κB activation. DD, death domain.
Mentions: MyD88 was originally identified as one of the myeloid differentiation primary response genes rapidly induced by IL-6 in M1 myeloleukemic cells. MyD88 contains two domains characterized by a death domain and a TIR domain, but lacks a putative transmembrane region, suggesting that MyD88 might function as an adapter protein in cytoplasm (Fig. 2). Consequently, MyD88 was shown to be recruited to the IL-1R after IL-1 ligation and to associate with IRAK1, resulting in the activation of transcription factors NF-κB and AP-1 [22-24]. Studies on MyD88-deficient mice clearly demonstrated that MyD88 is an essential component in the responses to IL-1 and the IL-1-related cytokine IL-18 [25]. All of the responses to IL-1 and IL-18 and the activation of NF-κB and MAP kinases were completely defective in cells from MyD88-deficient mice. Subsequent investigation confirmed that MyD88 is also used in TLR signaling. In MyD88-deficient mice, the production of inflammatory cytokines such as tumor necrosis factor-α, IL-1β and IL-6, the proliferation of B cells, and the induction of endotoxin shock in response to LPS (TLR4 ligand) are also completely abolished, demonstrating that MyD88 is indispensable for the responses to LPS in vivo [26]. In addition, cells from MyD88-deficient mice are totally unresponsive to peptidoglycan, lipoprotein, CpG DNA, and imidazoquinolines in terms of cytokine production [12,27,28] (Fig. 3).

Bottom Line: Almost all TLRs use a TIR-containing adapter MyD88 to activate a common signaling pathway that results in the activation of NF-kappaB to express cytokine genes relevant to inflammation.In particular, activation of the TRIF-dependent pathway confers antiviral responses by inducing anti-viral genes including that encoding interferon-beta.Taken together, these results indicate that the interaction between individual TLRs and the different combinations of adapters directs appropriate responses against distinct pathogens.

View Article: PubMed Central - PubMed

Affiliation: ERATO, Japan Science and Technology Agency, Osaka, Japan.

ABSTRACT
The family of Toll-like receptors (TLRs) senses conserved structures found in a broad range of pathogens, causing innate immune responses that include the production of inflammatory cytokines, chemokines and interferons. The signal transduction is initiated from the Toll/interleukin-1 receptor (TIR) domain of TLRs after pathogen recognition. Almost all TLRs use a TIR-containing adapter MyD88 to activate a common signaling pathway that results in the activation of NF-kappaB to express cytokine genes relevant to inflammation. Recently, three further TIR-containing adapters have been identified and shown to selectively interact with several TLRs. In particular, activation of the TRIF-dependent pathway confers antiviral responses by inducing anti-viral genes including that encoding interferon-beta. Taken together, these results indicate that the interaction between individual TLRs and the different combinations of adapters directs appropriate responses against distinct pathogens.

Show MeSH
Related in: MedlinePlus