Limits...
Toll-like receptor and its roles in myocardial ischemic/reperfusion injury.

Fang Y, Hu J - Med. Sci. Monit. (2011)

Bottom Line: TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs).TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses.In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.<br />

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular and Thoracic Surgery, 2nd Xiangya Hospital, Central South University, Changsha, China.

ABSTRACT
The innate immune system, mediated via toll-like receptors (TLRs), represents the first line of defensive mechanisms that protects hosts from invading microbial pathogens. TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses. TLR4 is a paramount type of TLRs, located in the heart, and plays an important role in mediating myocardial ischemic reperfusion (I/R) injury. Loss-of-function experiments and animal models using genetic techniques have found that the MyD88-independent and the MyD88-dependent pathways together participate in the pathological process of myocardial I/R injury. Some other distinctive signaling pathways, such as the PI3K/AKt and AMPK/ERK pathways, interacting with the TLR4 signaling pathway, were also found to be causes of myocardial I/R injury. These different pathways activate a series of downstream transcriptional factors, produced a great quantity of inflammatory cytokines, such as IL, TNF, and initiate inflammatory response. This results in cardiac injury and dysfunction, such as myocardial stunning, no reflow phenomenon, reperfusion arrhythmias and lethal reperfusion injury, and other related complication such as ventricular remodeling. In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.

Show MeSH

Related in: MedlinePlus

TLR4 signaling pathway: TLR4 is localized on cell surface for ligand recognition and activates both MyD88-dependent pathway and TRIF-dependent pathway. In MyD88-dependent pathway, TLR4 recruits MAL to link TIR domain of TLR4 with MyD88. MyD88 recruits the IRAK family of proteins and TRAF6. TRAF6 activates TAK1. The activated TAK1 not only activates the IKK complex activating NF-κB, also activates the MAPKs. In TRIF-dependent pathway, TLR4 recruits. TRAM to link TIR domain of TLR4 with TRIF. TRIF interacts with RIP1 and TRAF6, which could activate NF-κB and MAPKs; TRIF interacts with TRAF3 and activates TRAF3/IKKɛ which activates IRF3 and IRF7.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3539509&req=5

f2-medscimonit-17-4-ra100: TLR4 signaling pathway: TLR4 is localized on cell surface for ligand recognition and activates both MyD88-dependent pathway and TRIF-dependent pathway. In MyD88-dependent pathway, TLR4 recruits MAL to link TIR domain of TLR4 with MyD88. MyD88 recruits the IRAK family of proteins and TRAF6. TRAF6 activates TAK1. The activated TAK1 not only activates the IKK complex activating NF-κB, also activates the MAPKs. In TRIF-dependent pathway, TLR4 recruits. TRAM to link TIR domain of TLR4 with TRIF. TRIF interacts with RIP1 and TRAF6, which could activate NF-κB and MAPKs; TRIF interacts with TRAF3 and activates TRAF3/IKKɛ which activates IRF3 and IRF7.

Mentions: TLR4, which is recognized by the bacterial LPS, LTA and endogenous molecules, signals via both MyD88-dependent and -independent pathways (Figure 2). TLR4 could directly bind to LTA through cluster of differentiation 14 (CD14) and LPS through CD14 and LPS-Binding Protein (LBP). Upon formation and activation of TLR4/MD2/CD14 complex following TLR4-ligand interaction, the cytoplasm TIR domain recruits distinct adaptor proteins, activates the signaling cascade, and consequently produces diverse inflammatory mediators. In MyD88-dependent pathway, TLR4 recruits downstream IRAKs through adaptors Mal and MyD88, which both contain an N-terminal death domain (DD) and a C-terminal TIR domain. MyD88 binds to TLR4 through TIR-TIR interaction and binds to IRAKs via DD-DD interaction. MyD88 first recruits IRAK4, which is a multidomain protein consisting of a conserved N-terminal DD and a central kinase domain, permitting engagement of IRAK1 [57]. IRAK1 is phosphorylated by IRAK4 and further recruits Tumor Necrosis Factor-Receptor-Associated Factor-6 (TRAF6) [58]. Phosphorylated IRAK1 and TRAF6 together dissociate from cytoplasmic domain protein complex, and constitute a new complex with GTF-beta-Activated kinase 1 (TAK1), TAK1-Binding Protein-1 (TAB1) and TAK1-Binding Protein-2 (TAB2). TRAF6, TAK1, TAB1 and TAB2, binding to ubiquitin-conjugating enzyme, lead to ubiquitylation of TRAF6 and activation of TAK1. Activated TAK1 phophorylates MAPKs, p38 and JNKs via Mitogen-Activated Protein Kinase Kinase-3, 6, and 7 (MMKs3, 6 and 7). P38 and JNKs enter the cell nucleus and promote target genes expression. TAK1 also phophorylates the inhibitor of κ Light Polypeptide Gene Enhancer in B-Cell Kinase (IKK complex). The IKK complex degrades I-κB, resulting in NF-κB activation, transferring NF-κB into the nucleus and inducing expression of target genes [59,60]. In TRIF-dependent pathway, TLR4 signals via TRAM and TRIF, and activates NF-κB via direct and indirect mechanisms via interacting domains of TRIF with RIP1 and TRAF, respectively. This pathway also induces phophorylation of IRF3 and IFN-regulatory factor 7 (IRF7), which play key roles in initiating expression of type 1 IFN while translocation into nucleus occurs [61]. All the TLRs are listed in Table 1.


Toll-like receptor and its roles in myocardial ischemic/reperfusion injury.

Fang Y, Hu J - Med. Sci. Monit. (2011)

TLR4 signaling pathway: TLR4 is localized on cell surface for ligand recognition and activates both MyD88-dependent pathway and TRIF-dependent pathway. In MyD88-dependent pathway, TLR4 recruits MAL to link TIR domain of TLR4 with MyD88. MyD88 recruits the IRAK family of proteins and TRAF6. TRAF6 activates TAK1. The activated TAK1 not only activates the IKK complex activating NF-κB, also activates the MAPKs. In TRIF-dependent pathway, TLR4 recruits. TRAM to link TIR domain of TLR4 with TRIF. TRIF interacts with RIP1 and TRAF6, which could activate NF-κB and MAPKs; TRIF interacts with TRAF3 and activates TRAF3/IKKɛ which activates IRF3 and IRF7.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3539509&req=5

f2-medscimonit-17-4-ra100: TLR4 signaling pathway: TLR4 is localized on cell surface for ligand recognition and activates both MyD88-dependent pathway and TRIF-dependent pathway. In MyD88-dependent pathway, TLR4 recruits MAL to link TIR domain of TLR4 with MyD88. MyD88 recruits the IRAK family of proteins and TRAF6. TRAF6 activates TAK1. The activated TAK1 not only activates the IKK complex activating NF-κB, also activates the MAPKs. In TRIF-dependent pathway, TLR4 recruits. TRAM to link TIR domain of TLR4 with TRIF. TRIF interacts with RIP1 and TRAF6, which could activate NF-κB and MAPKs; TRIF interacts with TRAF3 and activates TRAF3/IKKɛ which activates IRF3 and IRF7.
Mentions: TLR4, which is recognized by the bacterial LPS, LTA and endogenous molecules, signals via both MyD88-dependent and -independent pathways (Figure 2). TLR4 could directly bind to LTA through cluster of differentiation 14 (CD14) and LPS through CD14 and LPS-Binding Protein (LBP). Upon formation and activation of TLR4/MD2/CD14 complex following TLR4-ligand interaction, the cytoplasm TIR domain recruits distinct adaptor proteins, activates the signaling cascade, and consequently produces diverse inflammatory mediators. In MyD88-dependent pathway, TLR4 recruits downstream IRAKs through adaptors Mal and MyD88, which both contain an N-terminal death domain (DD) and a C-terminal TIR domain. MyD88 binds to TLR4 through TIR-TIR interaction and binds to IRAKs via DD-DD interaction. MyD88 first recruits IRAK4, which is a multidomain protein consisting of a conserved N-terminal DD and a central kinase domain, permitting engagement of IRAK1 [57]. IRAK1 is phosphorylated by IRAK4 and further recruits Tumor Necrosis Factor-Receptor-Associated Factor-6 (TRAF6) [58]. Phosphorylated IRAK1 and TRAF6 together dissociate from cytoplasmic domain protein complex, and constitute a new complex with GTF-beta-Activated kinase 1 (TAK1), TAK1-Binding Protein-1 (TAB1) and TAK1-Binding Protein-2 (TAB2). TRAF6, TAK1, TAB1 and TAB2, binding to ubiquitin-conjugating enzyme, lead to ubiquitylation of TRAF6 and activation of TAK1. Activated TAK1 phophorylates MAPKs, p38 and JNKs via Mitogen-Activated Protein Kinase Kinase-3, 6, and 7 (MMKs3, 6 and 7). P38 and JNKs enter the cell nucleus and promote target genes expression. TAK1 also phophorylates the inhibitor of κ Light Polypeptide Gene Enhancer in B-Cell Kinase (IKK complex). The IKK complex degrades I-κB, resulting in NF-κB activation, transferring NF-κB into the nucleus and inducing expression of target genes [59,60]. In TRIF-dependent pathway, TLR4 signals via TRAM and TRIF, and activates NF-κB via direct and indirect mechanisms via interacting domains of TRIF with RIP1 and TRAF, respectively. This pathway also induces phophorylation of IRF3 and IFN-regulatory factor 7 (IRF7), which play key roles in initiating expression of type 1 IFN while translocation into nucleus occurs [61]. All the TLRs are listed in Table 1.

Bottom Line: TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs).TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses.In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.<br />

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular and Thoracic Surgery, 2nd Xiangya Hospital, Central South University, Changsha, China.

ABSTRACT
The innate immune system, mediated via toll-like receptors (TLRs), represents the first line of defensive mechanisms that protects hosts from invading microbial pathogens. TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses. TLR4 is a paramount type of TLRs, located in the heart, and plays an important role in mediating myocardial ischemic reperfusion (I/R) injury. Loss-of-function experiments and animal models using genetic techniques have found that the MyD88-independent and the MyD88-dependent pathways together participate in the pathological process of myocardial I/R injury. Some other distinctive signaling pathways, such as the PI3K/AKt and AMPK/ERK pathways, interacting with the TLR4 signaling pathway, were also found to be causes of myocardial I/R injury. These different pathways activate a series of downstream transcriptional factors, produced a great quantity of inflammatory cytokines, such as IL, TNF, and initiate inflammatory response. This results in cardiac injury and dysfunction, such as myocardial stunning, no reflow phenomenon, reperfusion arrhythmias and lethal reperfusion injury, and other related complication such as ventricular remodeling. In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.

Show MeSH
Related in: MedlinePlus