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Toll-like receptor downstream signaling.

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

Bottom Line: 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.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.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: 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.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.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