ROLE OF PURINERGIC RECEPTORS IN IMMUNE RESPONSE

Purine receptors are located on immune and somatic cells of animal and human organisms. Summation of signals from purine and TOLL-like receptors takes place on the level of inflammasome formation and results in summation of the first and second signals of innate immunity. The first signal - from PAMPs (pathogen associated molecular patterns), the second - from DAMPs (danger associated molecular patterns). Adenosine triphosphate (ATP) is the most studied DAMP. ATP connects with purine receptors, which include P2 (P2X7 receptors are the best described), that results in opening of channels of these receptors and transit of ATP into the cell. In parallel exit of K+ from cells and entrance of Ca2+ and Na+ into the cells is observed, that is associated with activation of the immune competent cell. Damaged cells dying via necrosis or apoptosis are the source of extracellular ATP, as well as activated immunocytes. Signals from P2 and TOLL-like receptors are summarized in effectors of immune response, and activation of P2 receptors in lymphocytes makes a contribution into activation of cells, mediated by T-cell receptor. Negative side of purine receptor activation is a stimulating effect on proliferation and metastasis of malignant cells. The practical output of knowledge on functioning of purine receptors for clinical immunology is the application of agonists and antagonists of purine receptors, as well as explanation of effect of immune modulators from the position of launch of K+/Na+-pump, resulting in prolonged activation of immune competent cells.

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Abstract 286: Acute Toll-like Receptors 4 Activiation by Lipopolysaccharide Attenuates Afferent Arteriolar Autoregulatory Behavior

Hypertension ◽

10.1161/hyp.62.suppl_1.a286 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Justin P Van Beusecum ◽

Anthony K Cook ◽

Shali Zhang ◽

Styliani Goulopoulou ◽

Zhengrong Guan ◽

...

Keyword(s):

Immune System ◽

Perfusion Pressure ◽

Receptor Activation ◽

Toll Like Receptors ◽

Immune System Activation ◽

Significant Difference ◽

Tlr4 Activation ◽

Molecular Patterns ◽

Arteriolar Diameter ◽

Lps Treatment

Pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) activate toll like receptors (TLRs) that stimulate the innate immune system. Immune system activation is linked to blunted renal autoregulatory behavior. Lipopolysaccharide (LPS), a component of the bacterial wall of gram-negative bacteria, is a ligand for TLR4. Preliminary experiments indicates that TLR4 protein expression is increased approximately by 28% (n=2) in small intrarenal arteries after 4 hours of acute LPS treatment versus control. Accordingly, we hypothesize that acute LPS treatment blunts afferent arteriolar autoregulatory behavior through TLR4 activation. Rats received a bolus injection of LPS (1mg/kg I.P.) and kidneys were harvested 4 hours later for juxtamedullary nephron studies. At a perfusion pressure of 100 mmHg, baseline arteriolar diameters in LPS treated kidneys averaged 11.9 ± 0.5μm (n=15) compared to 14.5 ± 0.7μm (n=14) in untreated controls (P < 0.05). Autoregulatory behavior was assessed in these same groups by increasing perfusion pressure in 15 mmHg increments from 65 to 170 mmHg. In control kidneys, afferent arteriolar diameter decreased by 29 ± 5 % (n=6) as perfusion pressure increased from 65 to 170 mmHg. In LPS treated kidneys, afferent arteriolar diameter actually increased by 3 ± 8% (P < 0.05; n=7) over the same pressure range, indicating marked blunting of pressure-induced vasoconstriction. P2 receptors have been implicated in autoregulatory resistance adjustments. Therefore, we assessed afferent arteriolar responsiveness to P2 receptor activation in vitro. In control kidneys, log concentrations of ATP (10 -8 - 10 -4 mol/L) reduced arteriolar diameter by 4 ± 1, 10 ± 2, 17 ± 4, 26 ± 5, and 32 ± 5% respectively (P < 0.05; n=8). In LPS treated kidneys, ATP reduced arteriolar diameter similarly by 6 ± 1, 11 ± 2, 15 ± 3, 18 ± 4, and 21 ± 5% respectively (P < 0.05; n=8). No significant difference in afferent arteriolar reactivity to ATP was found between the two groups. These data support the hypothesis that TLR4 activation by acute LPS treatment attenuates afferent arteriolar autoregulatory behavior. Accordingly, these data may open novel therapeutic approaches for prevention of inflammatory kidney disease.

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Targeting Toll like Receptors in Cancer: Role of TLR Natural and Synthetic Modulators

Current Pharmaceutical Design ◽

10.2174/1381612826666200720235058 ◽

2020 ◽

Vol 26 (39) ◽

pp. 5040-5053 ◽

Cited By ~ 2

Author(s):

Arunaksharan Narayanankutty ◽

Aswathi Sasidharan ◽

Joice T. Job

Keyword(s):

Immune Response ◽

Web Of Science ◽

Broad Class ◽

The Body ◽

Toll Like Receptors ◽

Transmembrane Receptors ◽

Molecular Patterns ◽

Tlr Signalling ◽

Detailed Outline

Background: Toll like receptors (TLRs) are a group of transmembrane receptors belonging to the broad class pattern recognition receptors (PRR), involved in recognition of Pathogen Associated Molecular Patterns (PAMPs) thereby inducing an immune response. Apart from these exogenous PAMPs, numerous endogenous PAMPs are also ligands for various TLRs thereby activating the TLR dependent immune response, subsequently leading to the onset of an inflammatory response. Prolonged activation of TLR by these endogenous PAMPs leads to chronic inflammatory insults to the body and which in turn alters the proliferative patterns of the cells, which ultimately leads to the development of cancer. Objectives: The present review aims to provide a detailed outline of the differential roles of various TLRs in cancer and the possible use of them as a therapeutic target. Methods: Data were collected from PubMed/Sciencedirect/Web of Science database and sorted; the latest literature on TLRs was incorporated in the review. Results: Among the different TLRs, few are reported to be anti-neoplastic, which controls the cell growth and multiplication in response to the endogenous signals. On the contrary, numerous studies have reported the procarcinogenic potentials of TLRs. Hence, TLRs have emerged as a potential target for the prevention and treatment of various types of cancers. Several molecules, such as monoclonal antibodies, small molecule inhibitors and natural products have shown promising anticancer potential by effectively modulating the TLR signalling. Conclusion: Toll-like receptors play vital roles in the process of carcinogenesis, hence TLR targeting is a promising approach for cancer prevention.

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The Role of Siglec-G on Immune Cells in Sepsis

Frontiers in Immunology ◽

10.3389/fimmu.2021.621627 ◽

2021 ◽

Vol 12 ◽

Author(s):

William Royster ◽

Ping Wang ◽

Monowar Aziz

Keyword(s):

Immune Response ◽

Sialic Acid ◽

Immune Cells ◽

Myeloid Cells ◽

Cell Receptor ◽

Clinical Syndrome ◽

Clear Understanding ◽

Gm Csf ◽

Life Threatening ◽

Molecular Patterns

Sepsis is a life-threatening clinical syndrome that results from an overwhelming immune response to infection. During sepsis, immune cells are activated by sensing pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) through pattern recognizing receptors (PRRs). Regulation of the immune response is essential to preventing or managing sepsis. Sialic acid-binding immunoglobulin-type lectin-G (Siglec-G), a CD33 group of Siglec expressed in B-1a cells and other hematopoietic cells, plays an important immunoregulatory role. B-1a cells, a subtype of B lymphocytes, spontaneously produce natural IgM which confers protection against infection. B-1a cells also produce IL-10, GM-CSF, and IL-35 to control inflammation. Sialic acids are present on cell membranes, receptors, and glycoproteins. Siglec-G binds to the sialic acid residues on the B cell receptor (BCR) and controls BCR-mediated signal transduction, thereby maintaining homeostasis of Ca++ influx and NFATc1 expression. Siglec-G inhibits NF-κB activation in B-1a cells and regulates B-1a cell proliferation. In myeloid cells, Siglec-G inhibits DAMP-mediated inflammation by forming a ternary complex with DAMP and CD24. Thus, preserving Siglec-G’s function could be a novel therapeutic approach in sepsis. Here, we review the immunoregulatory functions of Siglec-G in B-1a cells and myeloid cells in sepsis. A clear understanding of Siglec-G is important to developing novel therapeutics in treating sepsis.

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Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases

Immunotherapy ◽

10.2217/imt-2019-0096 ◽

2020 ◽

Vol 12 (5) ◽

pp. 311-322

Author(s):

Lizdany Flórez-Álvarez ◽

Lanie Ruiz-Perez ◽

Natalia Taborda ◽

Juan C Hernandez

Keyword(s):

Immune Response ◽

Immune Responses ◽

Inflammatory Diseases ◽

Adaptive Immune Response ◽

Treatment Strategies ◽

Toll Like Receptors ◽

Tumor Treatment ◽

Special Report ◽

Adaptive Immune ◽

Molecular Patterns

Toll-like receptors (TLRs) are widely expressed pattern recognition receptors that bind to conserved molecular patterns expressed by pathogens and damaged cells. After recognition, activated TLRs induce the expression of various proinflammatory and antiviral molecules. Thus, TLRs are potential targets for treatment strategies aimed at boosting the adaptive immune response to vaccines, controlling infections, enhancing immune responses during tumor treatment and attenuating immune responses in inflammatory disorders. This Special Report examines the potential of TLRs as targets for the treatment of cancer, infections and inflammatory diseases. Here, we make a particular emphasis on molecules capable of modulating TLRs and their therapeutic applications.

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Faculty Opinions recommendation of Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1127070.584209 ◽

2008 ◽

Author(s):

Brigitte Huber

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Membrane Binding ◽

Cell Receptor ◽

Receptor Activation ◽

Dynamic Membrane

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Human urothelial bladder cancer generates a clonal immune response: The results of T-cell receptor sequencing

immuneACCESS ◽

10.21417/as2019uo ◽

2019 ◽

Author(s):

A Sankin ◽

D Chand ◽

M Schoenberg ◽

X Zang

Keyword(s):

Immune Response ◽

Bladder Cancer ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Urothelial Bladder Cancer ◽

Urothelial Bladder

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Peptidomimetic 1-Benzyl-5-methyl-4-(n-octylamino)pyrimidin-2(1H)-one Showed Cardioprotection Effect in a Myocardial Ischemia (MI) Mouse Model

Proceedings ◽

10.3390/proceedings2019022072 ◽

2019 ◽

Vol 22 (1) ◽

pp. 72

Author(s):

Lena Trifonov ◽

Vadim Nudelman ◽

Michael Zhenin ◽

Guy Cohen ◽

Krzysztof Jozwiak ◽

...

Keyword(s):

Immune Response ◽

Pattern Recognition ◽

Myocardial Ischemia ◽

Mouse Model ◽

Innate Immune Response ◽

Pattern Recognition Receptor ◽

Innate Immune ◽

Microbial Pathogens ◽

Toll Like Receptors ◽

Recognition Receptor

TLR4, a member of the toll-like receptors (TLRs) family, serves as a pattern recognition receptor in the innate immune response to different microbial pathogens. [...]

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Phosphorylation of the RB C-terminus regulates condensin II release from chromatin

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.016511 ◽

2020 ◽

pp. jbc.RA120.016511

Author(s):

Seung J Kim ◽

James I MacDonald ◽

Frederick A. Dick

Keyword(s):

Cell Cycle ◽

Genome Stability ◽

Cell Cycle Control ◽

Cell Receptor ◽

Receptor Activation ◽

Biologically Relevant ◽

C Terminus ◽

Independent Functions ◽

Phosphorylation Event ◽

Rb Phosphorylation

The retinoblastoma tumour suppressor protein (RB) plays an important role in biological processes such as cell cycle control, DNA damage repair, epigenetic regulation, and genome stability. The canonical model of RB regulation is that cyclin-CDKs phosphorylate, and render RB inactive in late G1/S, promoting entry into S phase. Recently, mono-phosphorylated RB species were described to have distinct cell-cycle independent functions, suggesting that a phosphorylation code dictates diversity of RB function. However, a biologically relevant, functional role of RB phosphorylation at non-CDK sites has remained elusive. Here, we investigated S838/T841 dual phosphorylation, its upstream stimulus, and downstream functional output. We found that mimicking T-cell receptor activation in Jurkat leukemia cells induced sequential activation of downstream kinases including p38 MAPK, and RB S838/T841 phosphorylation. This signaling pathway disrupts RB and condensin II interaction with chromatin. Using cells expressing a WT or S838A/T841A mutant RB fragment, we present evidence that deficiency for this phosphorylation event prevents condensin II release from chromatin.

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