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Bench-to-bedside review: Toll-like receptors and their role in septic shock.

Opal SM, Huber CE - Crit Care (2002)

Bottom Line: The Toll-like receptors (TLRs) are essential transmembrane signaling receptors of the innate immune system that alert the host to the presence of a microbial invader.The recent discovery of the TLRs has rapidly expanded our knowledge of molecular events that initiate host-pathogen interactions.The potential clinical implications of therapeutic modulation of these recently characterized receptors of innate immunity are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Professor of Medicine, Infectious Disease Division, Brown University Medical School, Providence, Rhode Island, USA. Steven_Opal@brown.edu

ABSTRACT
The Toll-like receptors (TLRs) are essential transmembrane signaling receptors of the innate immune system that alert the host to the presence of a microbial invader. The recent discovery of the TLRs has rapidly expanded our knowledge of molecular events that initiate host-pathogen interactions. These functional attributes of the cellular receptors provide insights into the nature of pattern recognition receptors that activate the human antimicrobial defense systems. The fundamental significance of the TLRs in the generation of systemic inflammation and the pathogenesis of septic shock is reviewed. The potential clinical implications of therapeutic modulation of these recently characterized receptors of innate immunity are also discussed.

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Related in: MedlinePlus

The intracellular signaling pathways of the Toll-like receptor 2 (TLR2) complex. Akt, intracellular protein kinase; IKB, inhibitory subunit κB; IKK, I-κB kinase; IRAK, IL-1 receptor-associated kinase; MyD88, myeloid differentiation factor; NF-κB, nuclear factor-κB; NIK, nuclear factor-κB inducing kinase; PG, peptidoglycan; PI3K, phosphatidyl inositol-3'-kinase; Rac, Rho-type GTPase; TIR, Toll IL-1 receptor; Tollip, Toll interactive protein; TRAF6, tumor necrosis factor receptor-associated factor 6.
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Figure 4: The intracellular signaling pathways of the Toll-like receptor 2 (TLR2) complex. Akt, intracellular protein kinase; IKB, inhibitory subunit κB; IKK, I-κB kinase; IRAK, IL-1 receptor-associated kinase; MyD88, myeloid differentiation factor; NF-κB, nuclear factor-κB; NIK, nuclear factor-κB inducing kinase; PG, peptidoglycan; PI3K, phosphatidyl inositol-3'-kinase; Rac, Rho-type GTPase; TIR, Toll IL-1 receptor; Tollip, Toll interactive protein; TRAF6, tumor necrosis factor receptor-associated factor 6.

Mentions: TLR2 signaling shares many similarities with IL-1R/TLR4 signaling. TLR2-dependent NF-κB activation requires the TIR domain, which is the epitope for the TIR–MyD88–IRAK complex that induces TRAF6 [23]. Nonetheless, there are severe unique features involved in TLR2 signaling. TLR2 forms heterodimeric structures with other TLR members such as TLR1 and TLR6. A recent report demonstrated that the p85 regulatory subunit of phosphatidylinositol-3'-kinase can directly associate with the intracellular domain of TLR2 [38]. The Rho-type GTPase Rac1 also appears to be associated with TLR2-mediated signaling. This alternative signaling pathway activates a number of phosphorylated lipids and results in the generation of the intracellular protein kinase Akt. This pathway directly activates NF-κB, independent of the phosphorylation and degradation of I-κB [38] (see Fig. 4).


Bench-to-bedside review: Toll-like receptors and their role in septic shock.

Opal SM, Huber CE - Crit Care (2002)

The intracellular signaling pathways of the Toll-like receptor 2 (TLR2) complex. Akt, intracellular protein kinase; IKB, inhibitory subunit κB; IKK, I-κB kinase; IRAK, IL-1 receptor-associated kinase; MyD88, myeloid differentiation factor; NF-κB, nuclear factor-κB; NIK, nuclear factor-κB inducing kinase; PG, peptidoglycan; PI3K, phosphatidyl inositol-3'-kinase; Rac, Rho-type GTPase; TIR, Toll IL-1 receptor; Tollip, Toll interactive protein; TRAF6, tumor necrosis factor receptor-associated factor 6.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC137294&req=5

Figure 4: The intracellular signaling pathways of the Toll-like receptor 2 (TLR2) complex. Akt, intracellular protein kinase; IKB, inhibitory subunit κB; IKK, I-κB kinase; IRAK, IL-1 receptor-associated kinase; MyD88, myeloid differentiation factor; NF-κB, nuclear factor-κB; NIK, nuclear factor-κB inducing kinase; PG, peptidoglycan; PI3K, phosphatidyl inositol-3'-kinase; Rac, Rho-type GTPase; TIR, Toll IL-1 receptor; Tollip, Toll interactive protein; TRAF6, tumor necrosis factor receptor-associated factor 6.
Mentions: TLR2 signaling shares many similarities with IL-1R/TLR4 signaling. TLR2-dependent NF-κB activation requires the TIR domain, which is the epitope for the TIR–MyD88–IRAK complex that induces TRAF6 [23]. Nonetheless, there are severe unique features involved in TLR2 signaling. TLR2 forms heterodimeric structures with other TLR members such as TLR1 and TLR6. A recent report demonstrated that the p85 regulatory subunit of phosphatidylinositol-3'-kinase can directly associate with the intracellular domain of TLR2 [38]. The Rho-type GTPase Rac1 also appears to be associated with TLR2-mediated signaling. This alternative signaling pathway activates a number of phosphorylated lipids and results in the generation of the intracellular protein kinase Akt. This pathway directly activates NF-κB, independent of the phosphorylation and degradation of I-κB [38] (see Fig. 4).

Bottom Line: The Toll-like receptors (TLRs) are essential transmembrane signaling receptors of the innate immune system that alert the host to the presence of a microbial invader.The recent discovery of the TLRs has rapidly expanded our knowledge of molecular events that initiate host-pathogen interactions.The potential clinical implications of therapeutic modulation of these recently characterized receptors of innate immunity are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Professor of Medicine, Infectious Disease Division, Brown University Medical School, Providence, Rhode Island, USA. Steven_Opal@brown.edu

ABSTRACT
The Toll-like receptors (TLRs) are essential transmembrane signaling receptors of the innate immune system that alert the host to the presence of a microbial invader. The recent discovery of the TLRs has rapidly expanded our knowledge of molecular events that initiate host-pathogen interactions. These functional attributes of the cellular receptors provide insights into the nature of pattern recognition receptors that activate the human antimicrobial defense systems. The fundamental significance of the TLRs in the generation of systemic inflammation and the pathogenesis of septic shock is reviewed. The potential clinical implications of therapeutic modulation of these recently characterized receptors of innate immunity are also discussed.

Show MeSH
Related in: MedlinePlus