scholarly journals Toll-Like Receptor 4 Activation in Cancer Progression and Therapy

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Alja Oblak ◽  
Roman Jerala
Keyword(s):  
Cancer Progression ◽  
Antitumor Immunity ◽  
Vaccine Adjuvants ◽  
Toll Like Receptor ◽  
Cancer Treatments ◽  
Toll Like Receptor 4 ◽  
Antitumor Vaccine ◽  
Tlr4 Activation ◽  
Opposing Effects ◽  
Intense Research

Cancer immunotherapy has been the focus of intense research since the late 19th century when Coley observed that bacterial components can contribute to cancer regression by eliciting an antitumor immune response. Successful activation and maturation of tumor-specific immune cells is now known to be mediated by bacterial endotoxin, which activates Toll-like receptor 4 (TLR4). TLR4 is expressed on a variety of immune as well as tumor cells, but its activation can have opposing effects. While TLR4 activation can promote antitumor immunity, it can also result in increased tumor growth and immunosuppression. Nevertheless, TLR4 engagement by endotoxin as well as by endogenous ligands represents notable contribution to the outcome of different cancer treatments, such as radiation or chemotherapy. Further research of the role and mechanisms of TLR4 activation in cancer may provide novel antitumor vaccine adjuvants as well as TLR4 inhibitors that could prevent inflammation-induced carcinogenesis.

Synthetic molecules and functionalized nanoparticles targeting the LPS-TLR4 signaling: A new generation of immunotherapeutics

2011 ◽  
Vol 84 (1) ◽  
pp. 97-106 ◽  
Author(s):  
Francesco Peri ◽  
Valentina Calabrese ◽  
Matteo Piazza ◽  
Roberto Cighetti
Keyword(s):  
Myeloid Differentiation ◽  
Vaccine Adjuvants ◽  
Toll Like Receptor ◽  
Differentiation Antigen ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Bacterial Endotoxins ◽  
Pharmacological Interest ◽  
Tlr4 Activation ◽  
New Generation

Toll-like receptor 4 (TLR4), the receptor of bacterial endotoxins in mammalians, plays a pivotal role in the induction of innate immunity and inflammation. TLR4 activation by bacterial lipopolysaccharide (LPS) is achieved by the coordinate and sequential action of three other proteins, the lipopolysaccharide binding protein (LBP), the cluster differentiation antigen CD14, and the myeloid differentiation protein (MD-2) receptors, that bind LPS and present it in a monomeric form to TLR4 by forming the activated [TLR4·MD-2·LPS]2 complex. Small molecules and nanoparticles active in modulating the TLR4 signal by targeting directly the MD-2·TLR4 complex or by interfering in other points of the TLR4 signaling are presented in this paper. These compounds have great pharmacological interest as vaccine adjuvants, immunotherapeutics, anti-sepsis, and anti-inflammatory agents.

scholarly journals Lycopene Inhibits Toll-Like Receptor 4-Mediated Expression of Inflammatory Cytokines in House Dust Mite-Stimulated Respiratory Epithelial Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3127
Author(s):  
Jiyeon Choi ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Epithelial Cells ◽  
A549 Cells ◽  
Cytokine Expression ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Respiratory Epithelial Cells ◽  
Toll Like Receptor 4 ◽  
Mitochondrial Ros ◽  
Tlr4 Activation ◽  
Respiratory Epithelial

House dust mites (HDM) are critical factors in airway inflammation. They activate respiratory epithelial cells to produce reactive oxygen species (ROS) and activate Toll-like receptor 4 (TLR4). ROS induce the expression of inflammatory cytokines in respiratory epithelial cells. Lycopene is a potent antioxidant nutrient with anti-inflammatory activity. The present study aimed to investigate whether HDM induce intracellular and mitochondrial ROS production, TLR4 activation, and pro-inflammatory cytokine expression (IL-6 and IL-8) in respiratory epithelial A549 cells. Additionally, we examined whether lycopene inhibits HDM-induced alterations in A549 cells. The treatment of A549 cells with HDM activated TLR4, induced the expression of IL-6 and IL-8, and increased intracellular and mitochondrial ROS levels. TAK242, a TLR4 inhibitor, suppressed both HDM-induced ROS production and cytokine expression. Furthermore, lycopene inhibited the HDM-induced TLR4 activation and cytokine expression, along with reducing the intracellular and mitochondrial ROS levels in HDM-treated cells. These results collectively indicated that the HDM induced TLR4 activation and increased intracellular and mitochondrial ROS levels, thus resulting in the induction of cytokine expression in respiratory epithelial cells. The antioxidant lycopene could inhibit HDM-induced cytokine expression, possibly by suppressing TLR4 activation and reducing the intracellular and mitochondrial ROS levels in respiratory epithelial cells.

scholarly journals The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Monica Molteni ◽  
Sabrina Gemma ◽  
Carlo Rossetti
Keyword(s):  
Tissue Injury ◽  
Sterile Inflammation ◽  
Research Progress ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Toll Like Receptor 4 ◽  
The Family ◽  
Tlr4 Activation ◽  
Molecular Patterns

Toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors (PRRs). They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns (PAMPs), thus representing the first line of defense against infections. TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response. TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response. This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious (e.g., sterile) inflammation and the effects of TLR4 signaling in some pathological conditions.

scholarly journals 4296 Targeting ERG Through Toll-Like Receptor 4 in Prostate Cancer

2020 ◽  
Vol 4 (s1) ◽  
pp. 17-17
Author(s):  
Ben Greulich ◽  
Josh Plotnik ◽  
Peter Hollenhorst
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Protein Interactions ◽  
Treatment Options ◽  
Clonogenic Survival ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Functional Assays ◽  
Prostate Cells ◽  
Tlr4 Activation

OBJECTIVES/GOALS: The objective of this research was to learn how the oncogenic transcription factor, ERG, is regulated in prostate cancer. If we could learn how ERG is regulated and which genes are important for its oncogenic phenotype in prostate cells, we could design new therapeutic strategies against ERG, which has proven to be difficult to target. METHODS/STUDY POPULATION: We conducted an shRNA screen in prostate cells to determine candidate genes and pathways that are important for ERG function. To validate the findings of the screen, we performed a variety of cell-based functional assays, including trans-well migration, wound healing, and clonogenic survival assays. To further investigate the mechanism between ERG and the genes revealed by the screen, we performed biochemical and molecular biology experiments such as Western blotting and qRT-PCR for protein and mRNA expression, co-immunoprecipitation assays to determine protein-protein interactions, and chromatin immunoprecipitation (ChIP-qPCR) to determine transcription factor binding to DNA sites. RESULTS/ANTICIPATED RESULTS: The screen revealed that genes involved in the toll-like receptor 4 (TLR4) pathway are important for ERG-mediated migration. We tested the effect of a TLR4 inhibitor on ERG function and observed decreased migration and clonogenic survival exclusively in ERG-positive cells. Expression of pMEK and pERG was reduced when TLR4 was inhibited, which suggests a mechanism in which TLR4 upregulates pMEK, leading to the phosphorylation and activation of ERG. This is supported by functional assays in which cells expressing a phosphomimetic ERG are resistant to the TLR4 inhibitor. We demonstrated that ERG drives the transcription of TLR4 and its endogenous ligands HSPA8 and BGN. Therefore, ERG can sensitize the cell to TLR4 activation by increasing the number of receptors as well as providing the ligands needed for stimulation. DISCUSSION/SIGNIFICANCE OF IMPACT: This research provides a new therapeutic pathway for treating ERG-positive patients through TLR4 inhibition. This can be beneficial because many patients become resistant to the standard therapy, leaving very few treatment options. TLR4-based therapies could provide an alternative for patients who have developed resistance.

Poly‐gamma‐glutamate induced antitumor immunity is toll‐like receptor 4 dependent

2008 ◽  
Vol 22 (S2) ◽  
pp. 517-517
Author(s):  
Haryoung Poo ◽  
Tae Young Lee ◽  
Yang Hyun Kim ◽  
Sun Woo Yoon ◽  
Moon Hee Sung
Keyword(s):  
Antitumor Immunity ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents

2004 ◽  
Vol 4 (7) ◽  
pp. 1129-1138 ◽  
Author(s):  
Jory R Baldridge ◽  
Patrick McGowan ◽  
Jay T Evans ◽  
Christopher Cluff ◽  
Sally Mossman ◽  
...  
Keyword(s):  
Human Disease ◽  
Vaccine Adjuvants ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Respiratory Syncytial Virus Fusion Protein-Induced Toll-Like Receptor 4 (TLR4) Signaling Is Inhibited by the TLR4 Antagonists Rhodobacter sphaeroides Lipopolysaccharide and Eritoran (E5564) and Requires Direct Interaction with MD-2

mBio ◽  
2012 ◽  
Vol 3 (4) ◽  
Author(s):  
Prasad Rallabhandi ◽  
Rachel L. Phillips ◽  
Marina S. Boukhvalova ◽  
Lioubov M. Pletneva ◽  
Kari Ann Shirey ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Rhodobacter Sphaeroides ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
F Protein ◽  
Terminal Domain ◽  
Syncytial Virus ◽  
Tlr4 Activation

ABSTRACTRespiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Toll-like receptor 4 (TLR4), a signaling receptor for structurally diverse microbe-associated molecular patterns, is activated by the RSV fusion (F) protein and by bacterial lipopolysaccharide (LPS) in a CD14-dependent manner. TLR4 signaling by LPS also requires the presence of an additional protein, MD-2. Thus, it is possible that F protein-mediated TLR4 activation relies on MD-2 as well, although this hypothesis has not been formally tested. LPS-free RSV F protein was found to activate NF-κB in HEK293T transfectants that express wild-type (WT) TLR4 and CD14, but only when MD-2 was coexpressed. These findings were confirmed by measuring F-protein-induced interleukin 1β (IL-1β) mRNA in WT versus MD-2−/−macrophages, where MD-2−/−macrophages failed to show IL-1β expression upon F-protein treatment, in contrast to the WT. BothRhodobacter sphaeroidesLPS and synthetic E5564 (eritoran), LPS antagonists that inhibit TLR4 signaling by binding a hydrophobic pocket in MD-2, significantly reduced RSV F-protein-mediated TLR4 activity in HEK293T-TLR4–CD14–MD-2 transfectants in a dose-dependent manner, while TLR4-independent NF-κB activation by tumor necrosis factor alpha (TNF-α) was unaffected.In vitrocoimmunoprecipitation studies confirmed a physical interaction between native RSV F protein and MD-2. Further, we demonstrated that the N-terminal domain of the F1 segment of RSV F protein interacts with MD-2. These data provide new insights into the importance of MD-2 in RSV F-protein-mediated TLR4 activation. Thus, targeting the interaction between MD-2 and RSV F protein may potentially lead to novel therapeutic approaches to help control RSV-induced inflammation and pathology.IMPORTANCEThis study shows for the first time that the fusion (F) protein of respiratory syncytial virus (RSV), a major cause of bronchiolitis and death, particularly in infants and young children, physically interacts with the Toll-like receptor 4 (TLR4) coreceptor, MD-2, through its N-terminal domain. We show that F protein-induced TLR4 activation can be blocked by lipid A analog antagonists. This observation provides a strong experimental rationale for testing such antagonists in animal models of RSV infection for potential use in people.

scholarly journals MP98-20 THE ROLE OF TOLL-LIKE RECEPTOR 4 IN BLADDER CANCER PROGRESSION.

2017 ◽  
Vol 197 (4S) ◽  
Author(s):  
Tomoya Fukawa ◽  
Terumichi Shintani ◽  
Kei Daizumoto ◽  
Tomoharu Fukumori ◽  
Masayuki Takahashi ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Novel Roles in Human MD-2 of Phenylalanines 121 and 126 and Tyrosine 131 in Activation of Toll-like Receptor 4 by Endotoxin

2007 ◽  
Vol 283 (3) ◽  
pp. 1257-1266 ◽  
Author(s):  
Athmane Teghanemt ◽  
Fabio Re ◽  
Polonca Prohinar ◽  
Richard Widstrom ◽  
Theresa L. Gioannini ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cell Activation ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Protein Protein Interactions ◽  
Lipopolysaccharide Binding Protein ◽  
Toll Like Receptor 4 ◽  
Dependent Cell ◽  
Cellular Responsiveness ◽  
Tlr4 Activation

Potent mammalian cell activation by Gram-negative bacterial endotoxin requires sequential protein-endotoxin and protein-protein interactions involving lipopolysaccharide-binding protein, CD14, MD-2, and Toll-like receptor 4 (TLR4). TLR4 activation requires simultaneous binding of MD-2 to endotoxin (E) and the ectodomain of TLR4. We now describe mutants of recombinant human MD-2 that bind TLR4 and react with E·CD14 but do not support cellular responsiveness to endotoxin. The mutants F121A/K122A MD-2 and Y131A/K132A MD-2 react with E·CD14 only when co-expressed with TLR4. Single mutants K122A and K132A each react with E·CD14 ± TLR4 and promote TLR4-dependent cell activation by endotoxin suggesting that Phe121 and Tyr131 are needed for TLR4-independent transfer of endotoxin from CD14 to MD-2 and also needed for TLR4 activation by bound E·MD-2. The mutant F126A MD-2 reacts as well as wild-type MD-2 with E·CD14 ± TLR4. E·MD-2F126A binds TLR4 with high affinity (Kd ∼ 200 pm) but does not activate TLR4 and instead acts as a potent TLR4 antagonist, inhibiting activation of HEK/TLR4 cells by wild-type E·MD-2. These findings reveal roles of Phe121 and Tyr131 in TLR4-independent interactions of human MD-2 with E·CD14 and, together with Phe126, in activation of TLR4 by bound E·MD-2. These findings strongly suggest that the structural properties of E·MD-2, not E alone, determine agonist or antagonist effects on TLR4.

scholarly journals Leishmania pifanoi Proteoglycolipid Complex P8 Induces Macrophage Cytokine Production through Toll-Like Receptor 4

2008 ◽  
Vol 76 (5) ◽  
pp. 2149-2156 ◽  
Author(s):  
Shanta M. Whitaker ◽  
Maria Colmenares ◽  
Karen Goldsmith Pestana ◽  
Diane McMahon-Pratt
Keyword(s):  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Cytokines And Chemokines ◽  
Inflammatory Protein ◽  
Tlr4 Ligand ◽  
Factor Alpha ◽  
Tlr4 Activation

ABSTRACT The P8 proteoglycolipid complex (P8 PGLC) is a glyconjugate expressed by Leishmania mexicana complex parasites. We previously have shown that vaccination with P8 PGLC provides protection against cutaneous leishmaniasis in susceptible BALB/c mice. However, the biological importance of this complex remains unknown. Here we show that P8 PGLC localizes to the surface of Leishmania pifanoi amastigotes and that upon exposure to macrophages, P8 PGLC binds and induces inflammatory cytokine and chemokine mRNAs such as tumor necrosis factor alpha and RANTES early after stimulation. Our studies indicate that cytokine and chemokine induction is dependent upon Toll-like receptor 4 (TLR4). Interestingly, key inflammatory cytokines and chemokines (such as interleukin-6 [IL-6], macrophage inflammatory protein 1β, and beta interferon [IFN-β]) that can be induced through TLR4 activation were not induced or only slightly upregulated by P8 PGLC. Activation by P8 PGLC does not occur in the presence of TLR4 alone and requires both CD14 and myeloid differentiation protein 2 for signaling; this requirement may be responsible for the limited TLR4 response. This is the first characterization of a TLR4 ligand for Leishmania. In vitro experiments indicate that L. pifanoi amastigotes induce lower levels of cytokines in macrophages in the absence of TLR4; however, notably higher IL-10/IFN-γ ratios were found for TLR4-deficient mice than for BALB/c mice. Further, increased levels of parasites persist in BALB/c mice deficient in TLR4. Taken together, these results suggest that TLR4 recognition of Leishmania pifanoi amastigotes is important for the control of infection and that this is mediated, in part, through the P8 PGLC.

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