The role of the interleukin (IL)-6/IL-6 receptor axis in cancer

2018 ◽  
Vol 46 (6) ◽  
pp. 1449-1462 ◽  
Author(s):  
Mustafa Yassin Taher ◽  
David Marc Davies ◽  
John Maher
Keyword(s):  
Cell Activation ◽  
Tumour Microenvironment ◽  
Signalling Pathways ◽  
Signal Transducer ◽  
Growth And Survival ◽  
Signal Transducers ◽  
Membrane Bound ◽  
Neoplastic Disorders ◽  
Tumour Cell Growth

Interleukin-6 (IL-6) is a pleiotropic cytokine that activates a classic signalling pathway upon binding to its membrane-bound receptor (IL-6R). Alternatively, IL-6 may ‘trans-signal’ in a manner that is facilitated by its binding to a soluble derivative of the IL-6 receptor (sIL-6R). Resultant signal transduction is, respectively, driven by the association of IL-6/IL-6R or IL-6/sIL-6R complex with the membrane-associated signal transducer, gp130 (Glycoprotein 130). Distinct JAK (Janus tyrosine kinase)/STAT (signal transducers and activators of transcription) and other signalling pathways are activated as a consequence. Of translational relevance, overexpression of IL-6 has been documented in several neoplastic disorders, including but not limited to colorectal, ovarian and breast cancer and several haematological malignancies. This review attempts to summarise our current understanding of the role of IL-6 in cancer development. In short, these studies have shown important roles for IL-6 signalling in tumour cell growth and survival, angiogenesis, immunomodulation of the tumour microenvironment, stromal cell activation, and ultimate disease progression. Given this background, we also consider the potential for therapeutic targeting of this system in cancer.

The role of membrane-bound LBP, endotoxin aggregates, and the MaxiK channel in LPS-induced cell activation

2003 ◽  
Vol 9 (3) ◽  
pp. 181-186 ◽  
Author(s):  
M. Müller ◽  
O. Scheel ◽  
B. Lindner ◽  
T. Gutsmann ◽  
U. Seydel
Keyword(s):  
Cell Activation ◽  
Membrane Bound ◽  
Maxik Channel

The role of membrane-bound LBP, endotoxin aggregates, and the MaxiK channel in LPS-induced cell activation

2003 ◽  
Vol 9 (3) ◽  
pp. 181-186 ◽  
Author(s):  
M. Müller ◽  
O. Scheel ◽  
B. Lindner ◽  
T. Gutsmann ◽  
U. Seydel
Keyword(s):  
Cell Activation ◽  
Membrane Bound ◽  
Maxik Channel

scholarly journals Activation of permeabilized HL60 cells by vanadate. Evidence for divergent signalling pathways

1990 ◽  
Vol 269 (1) ◽  
pp. 127-131 ◽  
Author(s):  
S Trudel ◽  
G P Downey ◽  
S Grinstein ◽  
M R Pâquet
Keyword(s):  
Cell Activation ◽  
Signalling Pathways ◽  
Actin Assembly ◽  
Oxygen Utilization ◽  
Hl60 Cells ◽  
Permeabilized Cells ◽  
Phosphorylated Proteins ◽  
The Individual ◽  
Inhibitor Treatment

The possible role of tyrosine phosphorylation in the activation of granulocytic HL60 cells was examined using vanadate, a phosphotyrosine phosphatase inhibitor. Treatment of permeabilized cells with micromolar concentrations of vanadate resulted in a substantial accumulation of tyrosine-phosphorylated proteins, detected by immunoblotting. At comparable concentrations, vanadate was also found to elicit an NADPH-dependent burst of oxygen utilization. Actin assembly, studied using 7-nitrobenz-2-oxa-1,3-diazole (NBD)-phallacidin, was similarly stimulated by vanadate, though considerably higher concentrations were required to observe this effect. In contrast with these responses, the secretion of lysozyme was not stimulated by vanadate, nor did vanadate affect calcium-induced secretion. Therefore, accumulation of tyrosine-phosphorylated proteins is associated with stimulation of some, but not all, of the responses characteristic of granulocytic cell activation. This indicates that the effects of vanadate are selective and suggests divergence of the signalling pathways leading to the individual effectors.

scholarly journals Regulation of TGF-β signalling by protein phosphatases

2010 ◽  
Vol 430 (2) ◽  
pp. 191-198 ◽  
Author(s):  
Ting Liu ◽  
Xin-Hua Feng
Keyword(s):  
Growth Factor ◽  
Essential Role ◽  
Transforming Growth Factor ◽  
Protein Phosphatases ◽  
Transforming Growth Factor Β ◽  
Signalling Pathways ◽  
Signal Transducer ◽  
Cellular Functions ◽  
Phosphorylation Cascade

Tight regulation of TGF-β (transforming growth factor-β) superfamily signalling is important for normal cellular functions and tissue homoeostasis. Since TGF-β superfamily signalling pathways are activated by a short phosphorylation cascade, from receptor phosphorylation to subsequent phosphorylation and activation of downstream signal transducer R-Smads (receptor-activated Smads), reversible phosphorylation serves as a critical step to assure proper TGF-β signalling. The present article will review the current progress on the understanding of dynamic phosphorylation in TGF-β signalling and the essential role of protein phosphatases in this process.

scholarly journals IL-6 Activities in the Tumour Microenvironment. Part 1

2019 ◽  
Vol 7 (14) ◽  
pp. 2391-2398 ◽  
Author(s):  
Dimitur Chavdarov Chonov ◽  
Maria Magdalena Krasimirova Ignatova ◽  
Julian Rumenov Ananiev ◽  
Maya Vladova Gulubova
Keyword(s):  
Target Genes ◽  
Elevated Serum ◽  
Serum Levels ◽  
Tumour Microenvironment ◽  
High Endothelial Venules ◽  
Tumour Immunity ◽  
Membrane Bound ◽  
In Trans ◽  
Transcription 3

The predominant role of IL-6 in cancer is its key promotion of tumour growth. IL-6 binds IL-6 receptor (IL-6R) and the membrane-bound glycoprotein gp130. The complex I-6/IL-6R/gp130 starts the Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3) or JAK/STAT3 pathway. IL-6R exits in two forms: a membrane-bound IL-6Rα subunit (mIL-6R) that participates in classic signalling pathway and soluble IL-6R subunit (sIL-6R) engaged in trans-signalling. The pro-tumour functions of IL-6 are associated with STAT3, a major oncogenic transcription factor that triggers up-regulation of target genes responsible for tumour cell survival. IL-6 combined with TGF-β induces proliferation of pathogenic Th17 cells. The anti-tumour function of IL-6 is the promotion of anti-tumour immunity. IL-6 trans-signaling contributed to transmigration of lymphocytes in high endothelial venules (HEV). Dendritic cell (DC) secreted IL-6 in the lymph node influences the activation, distribution and polarisation of the immune response. Elevated serum levels of IL-6 and increased expression of IL-6 in tumour tissue are negative prognostic marker for patients’ survival.

scholarly journals The presence of membrane bound CD99 ligands on leukocyte surface

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Nuchjira Takheaw ◽  
Supansa Pata ◽  
Witida Laopajon ◽  
Sittiruk Roytrakul ◽  
Watchara Kasinrerk
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Regulation ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
T Cell Regulation ◽  
Membrane Bound

Abstract Objective CD99, a leukocyte surface molecule, reportedly plays an important role in several cellular processes. However, the role of CD99 in T cell regulation remains unclear, as the CD99 ligand associated with T-cell regulation has not yet been identified. Our previous study showed that recombinant CD99 bound to CD99 ligands was expressed on monocytes, NK cells and dendritic cells. This interaction regulates the expression of IL-6 and TNF-α in CD3 + T cells following T cell activation. In the present study, we confirmed the presence of CD99 ligands in immune cells. Results A recombinant CD99-human IgG fusion protein, CD99HIgG, was produced and used to search for CD99 ligand expression in various hematopoietic cell lines. Among several cell lines, THP-1 monocytic cell line showed strong positive reaction for CD99HIgG, and CD99 and CD99 ligand complexes were pulled-down using a DTSSP cross-linker. The study demonstrated the presence of the membrane bound CD99 ligand, and CD99 ligand candidates were identified via LC–MS/MS. These results may be useful to further identify the CD99 ligands, and to fully comprehend the role of CD99 in immunoregulation.

Regulated intramembrane proteolysis: emergent role in cell signalling pathways

2017 ◽  
Vol 45 (6) ◽  
pp. 1185-1202 ◽  
Author(s):  
Aonghus J. McCarthy ◽  
Caroline Coleman-Vaughan ◽  
Justin V. McCarthy
Keyword(s):  
Cell Signalling ◽  
Signalling Pathways ◽  
Tumour Necrosis Factor Receptor ◽  
Intramembrane Proteolysis ◽  
Receptor Signalling ◽  
Regulated Intramembrane Proteolysis ◽  
Specific Receptors ◽  
Membrane Bound

Receptor signalling events including those initiated following activation of cytokine and growth factor receptors and the well-characterised death receptors (tumour necrosis factor receptor, type 1, FasR and TRAIL-R1/2) are initiated at the cell surface through the recruitment and formation of intracellular multiprotein signalling complexes that activate divergent signalling pathways. Over the past decade, research studies reveal that many of these receptor-initiated signalling events involve the sequential proteolysis of specific receptors by membrane-bound proteases and the γ-secretase protease complexes. Proteolysis enables the liberation of soluble receptor ectodomains and the generation of intracellular receptor cytoplasmic domain fragments. The combined and sequential enzymatic activity has been defined as regulated intramembrane proteolysis and is now a fundamental signal transduction process involved in the termination or propagation of receptor signalling events. In this review, we discuss emerging evidence for a role of the γ-secretase protease complexes and regulated intramembrane proteolysis in cell- and immune-signalling pathways.

scholarly journals MicroRNAs and miRceptors: a new mechanism of action for intercellular communication

2017 ◽  
Vol 373 (1737) ◽  
pp. 20160486 ◽  
Author(s):  
Muller Fabbri
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Mechanism Of Action ◽  
Intercellular Communication ◽  
Target Genes ◽  
Tumour Microenvironment ◽  
Signalling Pathways ◽  
Non Coding Rnas ◽  
Cancerous Cells

MicroRNAs (miRs) are small non-coding RNAs (ncRNAs) that control the expression of target genes by modulating (usually inhibiting) their translation into proteins. This ‘traditional’ mechanism of action of miRs has been recently challenged by new discoveries pointing towards a role of miRs as ‘hormones’, capable of binding to proteic receptors (miRceptors) and triggering their downstream signalling pathways. These findings harbour particular significance within the tumour microenvironment (TME), defined as the variety of non-cancerous cells surrounding cancer cells, but are relevant also for other diseases. In recent years it has become clearer that the TME does not passively assist the growth of cancer cells but contributes to its biology. Some of the mediators of the intercellular communication between cancer cells and TME are miRs shuttled within exosomes, a subtype of cellular released extracellular vesicles. This article will highlight the most recent findings on the biological implications of miR–miRceptor interactions for the biology of the TME and other diseases, and will provide some perspectives on the future development of this fascinating research. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

scholarly journals Ionic Regulation of T-Cell Function and Anti-Tumour Immunity

2021 ◽  
Vol 22 (24) ◽  
pp. 13668
Author(s):  
Pierpaolo Ginefra ◽  
Helen Carrasco Hope ◽  
Mattia Spagna ◽  
Alessandra Zecchillo ◽  
Nicola Vannini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
T Cell Function

The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism.

scholarly journals The Innate Immune Signalling Pathways: Turning RIG-I Sensor Activation against Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3158
Author(s):  
Sandra Iurescia ◽  
Daniela Fioretti ◽  
Monica Rinaldi
Keyword(s):  
T Cell ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Tumour Microenvironment ◽  
Innate Immune ◽  
Cytotoxic T Cell ◽  
Signalling Pathways ◽  
Type I ◽  
Tumour Immunity

Over the last 15 years, the ability to harness a patient’s own immune system has led to significant progress in cancer therapy. For instance, immunotherapeutic strategies, including checkpoint inhibitors or adoptive cell therapy using chimeric antigen receptor T-cell (CAR-T), are specifically aimed at enhancing adaptive anti-tumour immunity. Several research groups demonstrated that adaptive anti-tumour immunity is highly sustained by innate immune responses. Host innate immunity provides the first line of defence and mediates recognition of danger signals through pattern recognition receptors (PRRs), such as cytosolic sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMP) signals. The retinoic acid-inducible gene I (RIG-I) is a cytosolic RNA helicase, which detects viral double-strand RNA and, once activated, triggers signalling pathways, converging on the production of type I interferons, proinflammatory cytokines, and programmed cell death. Approaches aimed at activating RIG-I within cancers are being explored as novel therapeutic treatments to generate an inflammatory tumour microenvironment and to facilitate cytotoxic T-cell cross-priming and infiltration. Here, we provide an overview of studies regarding the role of RIG-I signalling in the tumour microenvironment, and the most recent preclinical studies that employ RIG-I agonists. Lastly, we present a selection of clinical trials designed to prove the antitumour role of RIG I and that may result in improved therapeutic outcomes for cancer patients.

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