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65-396: 4G8A , 2Z62 , 2Z63 , 2Z65 , 2Z66 , 3FXI , 3UL7 , 3UL8 , 3UL9 , 3ULA 7099 21898 ENSG00000136869 ENSMUSG00000039005 O00206 Q9QUK6 NM_138557 NM_003266 NM_138554 NM_138556 NM_021297 NP_003257 NP_612564 NP_612567 NP_067272 Toll-like receptor 4 (TLR4), also designated as CD284 ( cluster of differentiation 284), is

130-410: A chemokine receptor on the surface of a T helper cell to gain entry. The number of CD4 and CD8 T cells in blood is often used to monitor the progression of HIV infection . While CD molecules are very useful in defining leukocytes, they are not merely markers on the cell surface . Though only a fraction of known CD molecules have been thoroughly characterised, most of them have important functions. In

195-578: A stem cell , as opposed to a fully differentiated endothelial cell . Some cell populations can also be defined as , , or (alternatively, , , or ), indicating an overall variability in CD expression , particularly when compared to other cells being studied. A review of the development of T cells in the thymus uses this nomenclature to identify cells transitioning from CD4 /CD8 double-positive cells to CD4 /CD8 . Since 1982 there have been nine Human Leukocyte Differentiation Antigen Workshops culminating in

260-535: A PAMP by a PRR triggers rapid activation of the innate immunity essential to fight infectious diseases. TLR4 is expressed in immune cells mainly of myeloid origin, including monocytes, macrophages and dendritic cells (DC). It is also expressed at a lower level on some non-immune cells, including epithelium, endothelium, placental cells and beta cells in Langerhans islets. Most myeloid cells express also high amounts of plasma membrane-anchored CD14 , which facilitates

325-426: A conference. The CD system is commonly used as cell markers in immunophenotyping , allowing cells to be defined based on what molecules are present on their surface. These markers are often used to associate cells with certain immune functions . While using one CD molecule to define populations is uncommon (though a few examples exist), combining markers has allowed for cell types with very specific definitions within

390-492: A glycolipid, lipopolysaccharide (LPS), on their outer cell wall. Together with bactericidal permeability-increasing protein (BPI), the encoded protein binds LPS and interacts with the CD14 receptor, probably playing a role in regulating LPS-dependent monocyte responses. Studies in mice suggest that the encoded protein is necessary for the rapid acute-phase response to LPS but not for the clearance of LPS from circulation. This protein

455-594: A key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene . TLR4 belongs to the toll-like receptor family which is representative of the pattern recognition receptors (PRR), so named for their ability to recognize evolutionarily conserved components of microorganisms (bacteria, viruses, fungi and parasites) called pathogen-associated molecular patterns (PAMPs). The recognition of

520-606: A more severe course of sepsis in critically ill patients was reported.However, they are very rare, and their frequency varies according to ethnic origin. The 2 predominant SNPs are Asp299Gly and Thr399Ile, with a frequency of <10% in the Caucasian population and even lower in the Asian population. These two SNPs are missense mutations, thus associated with a loss of function, which may explain their negative impact on infection control. Studies have indeed shown that TLR4 D299G SNP limits

585-775: A positive association between baseline TLR4 expression in tumors and the increase of overall response rates has been reported. The potential impact of TLR4 on the progression of some cancers was associated with the excessive production of pro-inflammatory cytokines via activation of the TLR4-MyD88/NF-kB signaling pathway. Several studies showed that this is mediated by the misuse of DAMP signaling by tumor cells. Many DAMPs are released by dying or necrotic tumor cells and present during cancer progression. DAMPs released from tumor cells can directly activate tumor-expressed TLR4 that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in

650-573: A potent phagocytic response by microglia while triggering a moderate inflammatory reaction. However, adverse effects can be caused by TLR 4 agonists inducing secretion of inflammatory mediators. Studies therefore suggested that TLR4 agonists that selectively activate the TRIF signaling pathway could be highly beneficial in the treatment of neurodegenerative disorders by increasing glial cell phagocytic activity without significantly increasing glial cytokines and cytotoxins. TLR4 has been shown to be important for

715-625: A study of 158 humans worldwide, 0.6% had a nonsense mutation. This suggests that there are weaker evolutionary pressures on the human TLR4 than on our primate relatives. The distribution of human TLR4 polymorphisms matches the out-of-Africa migration, and it is likely that the polymorphisms were generated in Africa before migration to other continents. Various single nucleotide polymorphisms (SNPs) of TLR4 have been identified in humans . For some of them, an association with increased susceptibility to Gram-negative bacterial infections or faster progression and

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780-532: A variety of human diseases, such as bacterial infections and cancers. This dual role of TLR4 depends on the intensity, duration and site (surface or endosome) of its activation, its polymorphism and the balance of activation of signaling pathways (MyD88 vs . TRIF). TLR4 play a central role in the control of bacterial infections through the recognition of LPS molecules from gram-negative, and some gram-positive, bacteria. During infections, TLR4s on innate immunity cells are activated by LPS molecules present in tissues and

845-486: Is TLR4 (as well as TLR2) dependent. There are also reports on the treatment of oral squamous cell carcinoma , gastric , Head-and-neck and cervical cancers with lyophilized streptococcal preparation OK-432 (Picibanil). The mechanism of action of OK-432 involves TLR4 activation, since OKA-432 does not inhibit tumor growth on TLR4 knockouts as it does on wild-type mice. Purified LPS also showed potent anti-tumor efficacy as systemic therapeutic agents in several tumor models. In

910-546: Is a protein that in humans is encoded by the LBP gene . LBP is a soluble acute-phase protein that binds to bacterial lipopolysaccharide (or LPS) to elicit immune responses by presenting the LPS to important cell surface pattern recognition receptors called CD14 and TLR4 . The protein encoded by this gene is involved in the acute-phase immunologic response to gram-negative bacterial infections. Gram-negative bacteria contain

975-412: Is accompanied by the release of DAMPs into the extracellular space, which can then further activate TLR4, aggravating neuroinflammation. In patients with Alzheimer's disease (AD), the levels of circulating DAMPs like HMGB1 and soluble RAGE, are significantly elevated, which was correlated with the levels of amyloid beta. In AD patients, the serum levels of S100B are also intimately related to the severity of

1040-449: Is also known to stimulate the generation of effective adaptive immune responses and to induce their recruitment, polarization and maintenance via the panel of cytokines and chemokines produced. The TRIF and MyD88 signaling pathways have a different but complementary impact on immune cell activation. Macrophages stimulation has been shown to be strictly dependent on TRIF pathway activation whereas DC activation and maturation depend on both

1105-409: Is however important for effective cytotoxic T-cell differentiation by facilitating fusion of MHC I-bearing recycling endosomes with phagosomes allowing cross-presentation of antigens. In contrast, robust activation of MYD88 pathway induces excessive production of pro-inflammatory cytokines leading to life-threatening pathological consequences such as cytokine storms. The impact of TLR4 activation on

1170-456: Is initiated by an LPS binding to an LBP protein . This LPS-LBP complex transfers the LPS to CD14 which is a glycosylphosphatidylinositol-anchored membrane protein that binds the LPS-LBP complex and facilitates the transfer of LPS to MD-2 protein , which is associated with the extracellular domain of TLR4. LPS binding promotes the dimerization of TLR4/MD-2 complex. The conformational changes of

1235-431: Is linked to the ability of LPS to stimulate innate immunity via TLR4, resulting in the production of pro-inflammatory cytokines and type 1 interferons, and the indirect generation of adaptive anti-tumor responses. The first clues about the efficacy of TLR4 agonists like LPS in cancer immunotherapy was found in the 19th centuries, when bacterial infections were found to induce tumor regressions. Later, Dr William Coley showed

1300-535: Is part of a family of structurally and functionally related proteins, including BPI, plasma cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP). Finally, this gene is found on chromosome 20, immediately downstream of the BPI gene. LPS exposure induces LBP production. LBP is synthesized by the liver, adipose tissue, and intestinal cells. Dietary glucose and saturated fats acutely increase plasma LBP. The proinflammatory activity of plasma LPS

1365-411: Is thought to reduce the efficacy of opioid drug treatment with time, and be involved in both the development of tolerance to opioid analgesic drugs, and in the emergence of side-effects such as hyperalgesia and allodynia that can become a problem following extended use of opioid drugs. Drugs that block the action of TNF-α or IL-1β have been shown to increase the analgesic effects of opioids and reduce

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1430-618: Is triggered by TLR4 localized to the plasma membrane, while the TRIF-dependent one by the TLR4 internalized in endosomes. These signaling pathways lead to the production of two sets of cytokines. The MyD88-dependent pathway induces the production of pro-inflammatory cytokines while TRIF-dependent pathway induces the production of type I interferons and chemokines. The molecular structure of TLR4 ligands (in particular LPS), as well as their complexation with proteins or lipids, greatly influence

1495-425: The 90’s, clinical trials evaluating the intravenous administration of LPS to patients with cancer provided positive results including several cases of disease stabilization and partial responses. However, limiting toxicities at doses in the ng/kg range has been reported which are too low to obtain significant antitumor effects. Subsequently, detoxified TLR4 agonists (LPS derivatives) have been produced and evaluated in

1560-459: The MD-2 protein stably associated with the extracellular fragment of the receptor. TLR4 signaling responds to signals by forming a complex using an extracellular leucine-rich repeat domain (LRR) and an intracellular toll/interleukin-1 receptor (TIR) domain. LPS stimulation induces a series of interactions with several accessory proteins which form the TLR4 complex on the cell surface. LPS recognition

1625-499: The MyD88 and TRIF pathways. The increased expression of costimulatory and MHC molecules is a hallmark of DC maturation required for antigen presentation by these cells. However, significant differences were found in the signaling pathways leading to this phenomenon. In macrophages, the upregulation of costimulatory molecules depends strictly on the TRIF-dependent pathway, whereas in DC both

1690-481: The MyD88- and TRIF-dependent ones are involved. The increased cell surface presence of the costimulatory molecules and also of MHC II is a hallmark of DC maturation required for antigen presentation by these cells. The activation of MyD88 and TRIF signaling pathways were also found to induce Th1 polarization of the T cells responses through DC maturation and the panel of cytokines produced. Low activation of MYD88 pathway

1755-522: The TLR4 induce the recruitment of intracellular adaptor proteins containing the TIR domain which is necessary to activate the downstream signaling pathway. The binding of an LPS molecule to the TLR4/MD-2 complex involves acyl chains and phosphate groups of lipid A, the conserved part of LPS and the main inducer of pro-inflammatory responses to LPS. TLR4 activation and response to LPS is greatly influenced by

1820-446: The action of these TLR4-related signaling pathways, leading to different cytokine balances. The MyD88-dependent pathway is regulated by two adaptor-associated proteins: Myeloid Differentiation Primary Response Gene 88 ( MyD88 ) and TIR Domain-Containing Adaptor Protein ( TIRAP ). It also involves the activation of IL-1 Receptor-Associated Kinases ( IRAKs ) and the adaptor molecules TNF Receptor-Associated Factor 6 ( TRAF6 ). TRAF6 induces

1885-534: The activation of TAK1 (Transforming growth factor-β-Activated Kinase 1) that leads to the activation of MAPK cascades (Mitogen-Activated Protein Kinase) and the IκB Kinases ( IKK ), called IKKα and IKKβ. IKKs' signaling pathway leads to the induction of the transcription factor NF-κB , while activation of MAPK cascades lead to the activation of another transcription factor AP-1 . These two transcription factorsnduces

1950-702: The activation of TLR4 by LPS and controls the subsequent internalization of the LPS-activated TLR4 important for receptor signaling and degradation. The main ligands for TLR4 are lipopolysaccharides (LPS), the major components of the outer membrane of Gram-negative bacteria and some Gram-positive bacteria . TLR4 can also be activated by endogenous compounds called damage-associated molecular patterns ( DAMPs ), including high mobility group box protein 1 ( HMGB1 ), S100 proteins, or histones . These compounds are released during tissue injury and by dying or necrotic cells. The first function described for TLR4

2015-454: The beginning of vertebrate evolution. Sequence alignments of human and great ape TLR4 exons have demonstrated that not much evolution has occurred in human TLR4 since our divergence from our last common ancestor with chimpanzees; human and chimp TLR4 exons only differ by three substitutions while humans and baboons are 93.5% similar in the extracellular domain. Notably, humans possess a greater number of early stop codons in TLR4 than great apes; in

Toll-like receptor 4 - Misplaced Pages Continue

2080-630: The bloodstream. This activates innate immunity, the first line of defense against invading microorganisms, and triggers pro-inflammatory responses that facilitate the eradication of invading bacteria. Generally, inflammation has a protective role. It is a complex and coordinated process followed by the induction of resolution pathways that restore tissue integrity and function. However, in some cases, exaggerated and uncontrolled inflammation triggered by TLR4 during infection can lead to sepsis and septic shock . Infections with Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa are

2145-418: The brain, TLR4 can be activated by various endogenous DAMPs in addition to pathology-associated proteins such as aggregates of amyloid-βpeptides (Aβ) or α-synuclein. All these structures bind TLR4 and activate downstream signaling pathways in glia, inducing secretion of reactive oxygen species (ROS) and proinflammatory cytokines such as IL-1β and TNF-α, which can lead to damage and death of neurons. Neuronal death

2210-492: The brain, TLR4 is expressed by neurons as well as the non-neuronal glial cells, which include microglia, astrocytes, and oligodendrocytes. TLR4 is expressed primarily by microglia, and to a lesser extent by astrocytes, oligodendrocytes, and neurons. Microglia are representatives of the mononuclear phagocyte system in the brain, and TLR4 activation regulates some of their functions, such as phagocytic activity. Activation of microglial TLR4 has been suggested to protect against or slow

2275-465: The chemokine CCL5/ RANTES and interferon-regulated genes as that encoding the chemokine CXCL10/IP-10. TRIF-dependent signaling pathway of TLR4 is known to play a central role in the stimulation of innate immune cells such as macrophages, the maturation of DCs and the induction and recruitment of Th1 adaptive immune responses. TLR4 activation by LPS enables a rapid stimulation of a whide range of innate immune cells such as macrophages and DCs. This leads to

2340-444: The classification of the many monoclonal antibodies (mAbs) generated by different laboratories around the world against epitopes on the surface molecules of leukocytes (white blood cells). Since then, its use has expanded to many other cell types, and more than 370 CD unique clusters and subclusters have been identified. The proposed surface molecule is assigned a CD number once two specific monoclonal antibodies are shown to bind to

2405-654: The clinic. This includes the MPL, a chemically modified LPS which was the first TLR4 agonist to be approved and commercialized by GSK in 5 human vaccines (HPV, Zoster, Hepatitis B, Malaria, RSV). MPL was investigated as an adjuvant for curative anti-tumor vaccines, with the approval of Melacine in Canada for the treatment of patients with malignant melanoma. Synthetic LPS derivatives based on dephosphorylated lipid A moiety structures were also developed and confirmed potent adjuvant and antitumor activities as therapeutic agents. In particular,

2470-426: The designation (e.g., CD2 molecule). Currently, "CD2" is generally used to designate the molecule, and "CD2 antibody " is used to designate the antibody. Cell populations are usually defined using a '+' or a '−' symbol to indicate whether a certain cell fraction expresses or lacks a CD molecule. For example, a " CD34 +, CD31 −" cell is one that expresses CD34 but not CD31. This CD combination typically corresponds to

2535-448: The development of neurodegenerative diseases, notably by enhancing the clearance of neurotoxic proteins such as Aβ and its aggregates, thanks to increased phagocytic and autophagic activity. However, chronic TLR4 activation is believed to be associated with glia-mediated neuronal death due to excessive secretion of pro-inflammatory cytotoxins leading to neuroinflammation, a key factor in the development of many neurodegenerative diseases. In

2600-441: The development of some cancers, (prostate, liver, breast and lung cancers) and may contribute to resistance to paclitaxel chemotherapy in breast cancer. Some clinical studies also suggested a potential correlation between TLR4 expression on tumor cells and tumor progression. However, no such effect was reported in the numerous clinical studies conducted with natural LPS or LPS derivatives. On the contrary, in phase 2 studies with GLA,

2665-418: The development of tolerance and other side-effects, and this has also been demonstrated with drugs that block TLR4 itself. The response of TLR4 to opioid drugs has been found to be enantiomer -independent, so the "unnatural" enantiomers of opioid drugs such as morphine and naloxone , which lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers. This means that

Toll-like receptor 4 - Misplaced Pages Continue

2730-881: The disease. The role of the HMGB1-TLR4 axis is very important in the pathogenesis of Parkinson's disease (PD). The serum HMGB1 and TLR4 protein levels were significantly elevated in PD patients and correlated with the PD stages. Targeting TLR4 with agonists or antagonists, or modulating its downstream signaling pathways, may have a therapeutic potential in treating neurodegenerative diseases. TLR4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators and cytotoxins by glia. However, TLR4 antagonists could have adverse CNS effects by inhibiting phagocytosis by glia, reducing protein clearance, and interfering with myelination. Some studies showed that selective TLR4 agonists could be beneficial by upregulating

2795-633: The example of CD4 and CD8, these molecules are critical in antigen recognition. Others (e.g., CD135 ) act as cell surface receptors for growth factors . Recently, the marker CD47 was found to have anti- phagocytic signals to macrophages and inhibit natural killer (NK) cells. This enabled researchers to apply CD47 as a potential target to attenuate immune rejection . Lipopolysaccharide binding protein 4M4D 3929 16803 ENSG00000129988 ENSMUSG00000016024 P18428 Q61805 NM_004139 NM_008489 NP_004130 NP_032515 Lipopolysaccharide binding protein ( LBP )

2860-410: The expression of genes encoding pro-inflammatory mediators, such as tumor necrosis factor α (TNF-α), interleukin (IL)-6, and type III interferons (IFNλ1/2). The TRIF-dependent pathway involves the internalization of TLR4 in endosomes and the recruitment of the adaptor proteins TIR-domain-containing adaptor inducing interferon-β ( TRIF ) and TRIF-related Adaptor Molecule (TRAM). TRAM-TRIF signals activate

2925-509: The immune system. CD molecules are utilized in cell sorting using various methods, including flow cytometry . Two commonly used CD molecules are CD4 and CD8 , which are, in general, used as markers for helper and cytotoxic T cells, respectively. These molecules are defined in combination with CD3+, as some other leukocytes also express these CD molecules (some macrophages express low levels of CD4; dendritic cells express high levels of CD8). Human immunodeficiency virus binds CD4 and

2990-457: The induction of resolution pathways that restore tissue integrity and function. However, in some cases, an excessive and/or poorly regulated inflammatory response to DAMPs can be detrimental to the organism, accelerating the development or progression of pathologies such as a number of cancers and neurodegenerative diseases (as discussed below). TLR4 binds LPS with the help of LPS-binding protein (LBP) and CD14, and an indispensable contribution of

3055-425: The innate and adaptive immune system explains why TLR4 agonists, such as LPS derivatives, have been developed as vaccine adjuvants. Among them is GSK's Monophosphorylated Lipid A (MPL), a detoxified Lipid A derived from Salmonella LPS, which is the first and only natural immunostimulant to have been approved as adjuvant in five human vaccines. TLR4 originated when TLR2 and TLR4 diverged about 500 million years ago near

3120-494: The intratumoral administration of Glucopyranosyl Lipid Adjuvant (GLA-SE/G100), a synthetic detoxified analog of lipid A formulated in a stable emulsion, showed anti-tumor immune responses and tumor regression in patients with Merkel cell carcinoma, and potent adjuvant activity in phase 2 trials in combination with pembrolizumab in patients with follicular lymphoma. Besides the recognized anti-tumor efficacy of TLR4 activation by LPS, some studies suggest that TLR4 may also contribute to

3185-419: The invading bacteria. TLR4 is also involved in the recognition of endogenous DAMP molecules leading to different signaling outcomes than PAMPs, both quantitatively and qualitatively. DAMPs can activate TLR4 in non-infectious conditions to induce tissue repair and the activation of mainly proinflammatory responses. Generally, inflammation has a protective role. It is a complex and coordinated process followed by

3250-548: The lipid A domain, the polysaccharide moiety plays an important role in the binding and activation of the LPS molecules as the lipid A moiety alone was demonstrated to be significantly less active than the full LPS molecule. Unlike all the other TLRs, TLR4 stimulation triggers two signaling pathways called the MyD88 -dependent and the TRIF -dependent one after the adaptor proteins involved in their induction. The MyD88-dependent signaling

3315-487: The long-term side-effects of opioid analgesic drugs. Various μ-opioid receptor ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as (+)-morphine being TLR4 agonists, while opioid antagonists such as naloxone were found to be TLR4 antagonists. Activation of TLR4 leads to downstream release of inflammatory modulators including TNF-α and Interleukin-1 , and constant low-level release of these modulators

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3380-409: The molecule. If the molecule has not been well characterized or has only one mAb, it is usually given the provisional indicator "w" (as in " CDw186 "). For instance, CD2 mAbs are reagents that react with a 50‐kDa transmembrane glycoprotein expressed on T cells . The CD designations were used to describe the recognized molecules but had to be clarified by attaching the term antigen or molecule to

3445-453: The others have not demonstrated to be direct activators of TLR4 and could therefore act as chaperones for TLR4 or as promoters of LPS internalization. Cluster of differentiation The CD nomenclature was proposed and established in the 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), held in Paris in 1982. This system was intended for

3510-448: The phagocytic activity of microglia, leading to enhanced clearance of damaged tissue and abnormal protein aggregates associated with several different CNS diseases. Repeated injections of MPL, at doses that are nonpyrogenic, were found to significantly improved AD-related pathology mice. MPL led to a significant reduction in Aβ load in the brain, as well as enhanced cognitive function. MPL induced

3575-600: The polysaccharide domain and the molecular structure of Lipid A moiety of the LPS molecules. Hexa-acylated and diphosphorylated LPS, like Escherichia coli LPS (O111:B4), is one of the most potent agonists of TLR4 whereas under-acylated LPS and dephosphorylated LPS species have a weaker pro-inflammatory activity especially in human cells. Structural determinants of this phenomenon are found in the TLR4/MD-2 complex and also in CD14 protein. The polysaccharide portion covalently bound to lipid A plays also and indispensable role in TLR4 activation through CD14/TLR4/MD-2. However, in addition to

3640-437: The potential association of this TLR4 polymorphism with cancer risk, but the data are highly conflicting. However, some meta-analyses suggest an association of SNP D299G with gastric, viral-induced and female-specific cancers (cervix, ovary). Growing evidence suggests an implication of TLR4 in the development and progression of neurogenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. In

3705-468: The prevailing causes of severe sepsis in humans.Some studies have linked TLR4 polymorphisms (Asp299Gly and Thr399Ile SNPs) to an increased susceptibility to sepsis due to gram-negative infection but other studies failed to confirm this. The role of the TLR4 in the control of cancer progression and in cancer therapy is well documented. Stimulation of TLR4 by natural derivatives and LPS is well known to induce potent antitumor activity. This anti-tumor activity

3770-531: The protein to bind to Toll-like receptor 4 (TLR4). The morphine-induced TLR4 activation attenuates pain suppression by opioids and enhances the development of opioid tolerance and addiction , drug abuse , and other negative side effects such as respiratory depression and hyperalgesia. Drug candidates that target TLR4 may improve opioid-based pain management therapies. Apart from LPS and its derivatives, up to 30 natural TLR4 agonists with diverse chemical structures have been postulated. However, besides DAMPs,

3835-439: The response to LPS by compromising MyD88 and TRIF recruitment to TLR4, and thus cytokine secretion, but without affecting TLR4 expression Structural analyses of human TLR4 with SNP D299G suggest that this amino acid change affects van der Waals interaction and hydrogen bonding in leucine-rich repeats, modulating its surface properties which may affect LPS ligand binding to TLR4. TLR4 has been reported to play both friend and foe in

3900-515: The secretion of pro-inflammatory and type I interferons cytokines, chemokines. Production levels of these cytokines/chemokines vary according to the degree of activation of the MyD88 and TRIF signaling pathways by TLR4 agonist molecules. TLR4 activation also induces the stimulation of antigen presentation and upregulation of costimulatory molecules (such as CD40 , CD80 and CD86 ) on innate immune cells which are required for antigen presentation for T lymphocytes. This explains why TLR4 activation by LPS

3965-577: The therapeutic efficacy of a mixed bacterial vaccine, so-called “Coley’s toxin”, to human cancer. Since then, a number of developments have been made in the treatment or prevention of cancer using bacterial mixtures strongly activating TLR4 due to LPS content. The antituberculosis vaccine Bacillus Calmette–Guérin (BCG) was approved by the Federal Drug Administration (FDA) in 1990 for the local treatment of superficial bladder cancer. BCG promotes dendritic cell maturation, and this effect

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4030-501: The tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). DAMPs, such as HMGB1, S100 proteins, and heat shock proteins (HSPs), were found to strongly activate inflammatory pathways and release IL-1, IL-6, LT-β, IFN-γ, TNF, and transforming growth factor (TGF)-β promoting inflammation, immunosuppression, angiogenesis, and tumor cell proliferation. Several studies have evaluated

4095-457: The ubiquitin ligase TRAF3 followed by the activation of non-canonical IKK kinases: TANK binding kinase 1 (TBK1) and IKKε. TBK1 phosphorylates the pLxIS consensus motif of TRIF that is necessary to recruit interferon regulatory factor (IRF) 3. IRF3 is also phosphorylated by TBK1 and then dissociates from TRIF, dimerizes and translocates to the nucleus. Finally, IRF3 induces the expression of genes encoding type I IFN such as interferon beta (IFN-β),

4160-431: The unnatural enantiomers of opioid antagonists, such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs, while leaving the μ-opioid receptor mediated analgesic activity unaffected. This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia. Morphine causes inflammation by binding to the protein lymphocyte antigen 96 , which, in turn, causes

4225-467: Was the recognition of exogenous molecules from pathogens (PAMPs), in particular LPS molecules from gram-negative bacteria. As pattern recognition receptor , TLR4 plays a fundamental role in pathogen recognition and activation of innate immunity which is the first line of defense against invading micro-organisms. During infection, TLR4 responds to the LPS present in tissues and the bloodstream and triggers pro-inflammatory reactions facilitating eradication of

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