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Toll-like receptor signaling pathways--therapeutic opportunities.

Zhu J, Mohan C - Mediators Inflamm. (2010)

Bottom Line: Triggering TLRs results in increased expression of multiple inflammatory genes, which then play a protective role against infection.However, aberrant activation of TLR signaling has a significant impact on the onset of cancer, allergy, sepsis and autoimmunity.Various adaptor proteins, including MyD88, IRAKs, TIRAP, TRIF, and TRAM, are involved in specific TLR signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: The Department of Internal Medicine (Rheumatology), University of Texas Southwestern Medical School, Dallas, TX 75390, USA.

ABSTRACT
Toll-like receptors (TLRs) are transmembrane proteins acting mainly as sensors of microbial components. Triggering TLRs results in increased expression of multiple inflammatory genes, which then play a protective role against infection. However, aberrant activation of TLR signaling has a significant impact on the onset of cancer, allergy, sepsis and autoimmunity. Various adaptor proteins, including MyD88, IRAKs, TIRAP, TRIF, and TRAM, are involved in specific TLR signaling pathways. This article reviews the role of these molecules in TLR signaling, and discusses the impact of this pathway on various disease scenarios. Given their important role in infectious and non-infectious disease settings, TLRs and their signaling pathways emerge as attractive targets for therapeutics.

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Related in: MedlinePlus

The TLR signaling pathway and downstream effector molecules. Depicted are key TLR molecules, their signaling adaptors and downstream mediators that are essential for TLR signaling and function. The specific molecules in this network that are presently being interrogated as potential therapeutic targets include TLR7/9, MyD88 and IRAK1/4, as discussed in the text.
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fig1: The TLR signaling pathway and downstream effector molecules. Depicted are key TLR molecules, their signaling adaptors and downstream mediators that are essential for TLR signaling and function. The specific molecules in this network that are presently being interrogated as potential therapeutic targets include TLR7/9, MyD88 and IRAK1/4, as discussed in the text.

Mentions: TLRs are type I transmembrane glycoproteins which are structurally characterized by extracellular leucine-rich repeats (LPRs) and Toll/IL-1 receptor (TIR) signaling domains. The first TLR to be characterized was TLR4 and the family has now been expanded to include 10 members in humans and 12 members in mice [2, 3]. Apart from the highly conserved pathogenic components of bacteria, viruses, fungi, and parasites, TLRs can also be activated by endogenous ligands such as chromatin-IgG complexes [4]. Various TIR domain-containing adaptors such as MyD88, TIRAP, TRIF, and TRAM become engaged or activated upon ligation of TLRs, as diagrammed in Figure 1. TLR1, TLR2, TLR4, and TLR6 recruit TIRAP, which serves as an adaptor between the TIR domain of TLRs and MyD88, while TLR5, TLR7, TLR9, and TLR11 can recruit MyD88 directly. Binding of TLR3 and TLR4 ligands results in the recruitment of TRIF. However, the recruitment of TRIF by TLR4 needs the participation of TRAM (Figure 1). The recruitment of these adaptors triggers a cascade of signaling molecules and ultimately activates the transcription factors, NF-κB and IRFs (Figure 1). These transcription factors induce the expression of various inflammatory cytokines, type I interferons, and chemokines. NF-κB is a central regulator of immune responses involved in cell proliferation and survival and induces the expression of many cytokine and chemokine genes including IL-2, IL-6, IL-12, MCP-1, and TNF-α [1].


Toll-like receptor signaling pathways--therapeutic opportunities.

Zhu J, Mohan C - Mediators Inflamm. (2010)

The TLR signaling pathway and downstream effector molecules. Depicted are key TLR molecules, their signaling adaptors and downstream mediators that are essential for TLR signaling and function. The specific molecules in this network that are presently being interrogated as potential therapeutic targets include TLR7/9, MyD88 and IRAK1/4, as discussed in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2963142&req=5

fig1: The TLR signaling pathway and downstream effector molecules. Depicted are key TLR molecules, their signaling adaptors and downstream mediators that are essential for TLR signaling and function. The specific molecules in this network that are presently being interrogated as potential therapeutic targets include TLR7/9, MyD88 and IRAK1/4, as discussed in the text.
Mentions: TLRs are type I transmembrane glycoproteins which are structurally characterized by extracellular leucine-rich repeats (LPRs) and Toll/IL-1 receptor (TIR) signaling domains. The first TLR to be characterized was TLR4 and the family has now been expanded to include 10 members in humans and 12 members in mice [2, 3]. Apart from the highly conserved pathogenic components of bacteria, viruses, fungi, and parasites, TLRs can also be activated by endogenous ligands such as chromatin-IgG complexes [4]. Various TIR domain-containing adaptors such as MyD88, TIRAP, TRIF, and TRAM become engaged or activated upon ligation of TLRs, as diagrammed in Figure 1. TLR1, TLR2, TLR4, and TLR6 recruit TIRAP, which serves as an adaptor between the TIR domain of TLRs and MyD88, while TLR5, TLR7, TLR9, and TLR11 can recruit MyD88 directly. Binding of TLR3 and TLR4 ligands results in the recruitment of TRIF. However, the recruitment of TRIF by TLR4 needs the participation of TRAM (Figure 1). The recruitment of these adaptors triggers a cascade of signaling molecules and ultimately activates the transcription factors, NF-κB and IRFs (Figure 1). These transcription factors induce the expression of various inflammatory cytokines, type I interferons, and chemokines. NF-κB is a central regulator of immune responses involved in cell proliferation and survival and induces the expression of many cytokine and chemokine genes including IL-2, IL-6, IL-12, MCP-1, and TNF-α [1].

Bottom Line: Triggering TLRs results in increased expression of multiple inflammatory genes, which then play a protective role against infection.However, aberrant activation of TLR signaling has a significant impact on the onset of cancer, allergy, sepsis and autoimmunity.Various adaptor proteins, including MyD88, IRAKs, TIRAP, TRIF, and TRAM, are involved in specific TLR signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: The Department of Internal Medicine (Rheumatology), University of Texas Southwestern Medical School, Dallas, TX 75390, USA.

ABSTRACT
Toll-like receptors (TLRs) are transmembrane proteins acting mainly as sensors of microbial components. Triggering TLRs results in increased expression of multiple inflammatory genes, which then play a protective role against infection. However, aberrant activation of TLR signaling has a significant impact on the onset of cancer, allergy, sepsis and autoimmunity. Various adaptor proteins, including MyD88, IRAKs, TIRAP, TRIF, and TRAM, are involved in specific TLR signaling pathways. This article reviews the role of these molecules in TLR signaling, and discusses the impact of this pathway on various disease scenarios. Given their important role in infectious and non-infectious disease settings, TLRs and their signaling pathways emerge as attractive targets for therapeutics.

Show MeSH
Related in: MedlinePlus