The Importance of G Protein Signaling in Immune Cell Function: A Novel Role for Active G?i in Cell Adhesion and Migration and the Therapeutic Potential of Targeting G?? in Inflammation PDF Download
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Author: Jesi Lee Anne To Publisher: ISBN: Category : Languages : en Pages : 128
Book Description
Chemotaxis is the directional movement of cells towards a gradient of chemoattractant such as chemokines. Chemokines are small peptides secreted by various cell types and play a role in immune surveillance, inflammation, and development. These molecules bind to their cognate receptors, which belong to the Class A, rhodopsin-like family of G protein-coupled receptors (GPCRs). Downstream effects orchestrated by chemokines include directional migration, reactive oxygen species (ROS) production, proliferation, and survival. Chemokine receptors primarily couple to the Gi/o family of G? proteins. Their activation triggers dissociation of the heterotrimeric G protein, G? and G?? dimer. The role of G?? in chemokine signaling is well established as it regulates multiple downstream effectors critical to cell migration such as phosphoinositide 3-kinase gamma (PI3K?), phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger (P-Rex), p21 activated kinase/PAK-interacting exchange factor alpha (PAK/PIX?), and Ras-associating and diluted domain-containing protein (Radil). However, the role of G?i in chemokine signaling is less understood and is thought to only regulate G?? availability and signaling through their association and disassociation cycle. Here we show that both G?i-GTP and G?? signaling are pivotal to cell migration. We also provide evidence for a novel role of G?i-GTP in regulating cell adhesion and migration. Using a small molecule inhibitor of G?? to inhibit migration, we show its anti-inflammatory therapeutic potential against lupus nephritis. Recently, our lab uncovered a novel role for G?i-GTP signaling in neutrophil adhesion through a cAMP-independent pathway. To discover the mechanism for G?i-GTP regulation of adhesion, we used a constitutively active Rap1a(G12V) and its downstream effector Radil to drive adhesion of neutrophil-like HL-60 and HT-1080 fibrosarcoma cells. A G??-Rap1a-Radil complex is known to drive cell adhesion and migration of these cell types. We found that expression of constitutively active G?i1(Q204L) reversed both Rap1a(G12V) and Radil mediated adhesion, suggesting that G?i-GTP regulates adhesion downstream of Rap1a and Radil. Furthermore, Rap1a and Radil reduced migration of HT1080 cells, which is reversed by G?i1(Q204L) expression. These data identify a novel role for G?i-GTP in the regulation of cell adhesion and migration. Multiple chemokines play a role in propagating inflammation and are associated with lupus nephritis pathogenesis by orchestrating immune cell migration toward the kidneys. The chemokine/receptor system has vast and promiscuous properties as one chemokine can bind to multiple receptors and one receptor can bind to more than one ligand. Therefore, valid targeting of individual chemokine receptors associated with a disease may be challenging and display poor efficacy. We used a well-studied G?? inhibitor, gallein, to study its therapeutic potential in alleviating lupus nephritis. Gallein inhibited PI3K?-mediated PIP3 production in neutrophil-like HL-60 cells and inhibited chemotaxis of primary neutrophils and T-cells in response to chemokines. Gallein treatment significantly reduced renal inflammation and proteinuria in NZB/NZW lupus mice. This study illustrates the therapeutic potential of G?? inhibitors against chronic inflammation. Our laboratory has identified a novel small molecule inhibitor of G?? called ellagic acid. Ellagic acid is a naturally occurring polyphenolic compound and that has anti-inflammatory properties. Our evidence showed ellagic acid directly binding to G?? and inhibited downstream G?? signaling. It significantly blocked N-formyl-Met-Leu-Phe (fMLP) chemotactic peptide-induced intracellular calcium release and weakly inhibited G??-mediated phospholipase C ?2 (PLC?2) activation in vitro compared to gallein and peptide SIGKAFKILGYPDYD (SIGK). Ellagic acid also inhibited fMLP-induced PI3K?mediated membrane phosphatidylinositol 3,4,5-triphosphate (PIP3) production, superoxide production, and migration of neutrophil-like HL60 cells. In this study, we identified ellagic acid as a small molecule inhibitor of G?? signaling in neutrophil-like cells and was sufficient to inhibit chemotaxis. This thesis work focuses on the overall importance of G protein signaling in GPCRmediated chemokine signaling and immune cell function. Both G?i and G?? are important mediators of GPCR-mediated chemokine signaling and immune cell function. Furthermore, our studies provide insights into the novel role of G?i in adhesion and migration of both immune cells and cancer cells. Chemokines are not only important during inflammation, but also contribute to the metastatic potential of cancer cells. We illustrate the importance of G?i and G?? in immune cell function such as adhesion and cell migration and we show alleviation of inflammatory lupus nephritis by inhibiting G?? signaling.
Author: Jesi Lee Anne To Publisher: ISBN: Category : Languages : en Pages : 128
Book Description
Chemotaxis is the directional movement of cells towards a gradient of chemoattractant such as chemokines. Chemokines are small peptides secreted by various cell types and play a role in immune surveillance, inflammation, and development. These molecules bind to their cognate receptors, which belong to the Class A, rhodopsin-like family of G protein-coupled receptors (GPCRs). Downstream effects orchestrated by chemokines include directional migration, reactive oxygen species (ROS) production, proliferation, and survival. Chemokine receptors primarily couple to the Gi/o family of G? proteins. Their activation triggers dissociation of the heterotrimeric G protein, G? and G?? dimer. The role of G?? in chemokine signaling is well established as it regulates multiple downstream effectors critical to cell migration such as phosphoinositide 3-kinase gamma (PI3K?), phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger (P-Rex), p21 activated kinase/PAK-interacting exchange factor alpha (PAK/PIX?), and Ras-associating and diluted domain-containing protein (Radil). However, the role of G?i in chemokine signaling is less understood and is thought to only regulate G?? availability and signaling through their association and disassociation cycle. Here we show that both G?i-GTP and G?? signaling are pivotal to cell migration. We also provide evidence for a novel role of G?i-GTP in regulating cell adhesion and migration. Using a small molecule inhibitor of G?? to inhibit migration, we show its anti-inflammatory therapeutic potential against lupus nephritis. Recently, our lab uncovered a novel role for G?i-GTP signaling in neutrophil adhesion through a cAMP-independent pathway. To discover the mechanism for G?i-GTP regulation of adhesion, we used a constitutively active Rap1a(G12V) and its downstream effector Radil to drive adhesion of neutrophil-like HL-60 and HT-1080 fibrosarcoma cells. A G??-Rap1a-Radil complex is known to drive cell adhesion and migration of these cell types. We found that expression of constitutively active G?i1(Q204L) reversed both Rap1a(G12V) and Radil mediated adhesion, suggesting that G?i-GTP regulates adhesion downstream of Rap1a and Radil. Furthermore, Rap1a and Radil reduced migration of HT1080 cells, which is reversed by G?i1(Q204L) expression. These data identify a novel role for G?i-GTP in the regulation of cell adhesion and migration. Multiple chemokines play a role in propagating inflammation and are associated with lupus nephritis pathogenesis by orchestrating immune cell migration toward the kidneys. The chemokine/receptor system has vast and promiscuous properties as one chemokine can bind to multiple receptors and one receptor can bind to more than one ligand. Therefore, valid targeting of individual chemokine receptors associated with a disease may be challenging and display poor efficacy. We used a well-studied G?? inhibitor, gallein, to study its therapeutic potential in alleviating lupus nephritis. Gallein inhibited PI3K?-mediated PIP3 production in neutrophil-like HL-60 cells and inhibited chemotaxis of primary neutrophils and T-cells in response to chemokines. Gallein treatment significantly reduced renal inflammation and proteinuria in NZB/NZW lupus mice. This study illustrates the therapeutic potential of G?? inhibitors against chronic inflammation. Our laboratory has identified a novel small molecule inhibitor of G?? called ellagic acid. Ellagic acid is a naturally occurring polyphenolic compound and that has anti-inflammatory properties. Our evidence showed ellagic acid directly binding to G?? and inhibited downstream G?? signaling. It significantly blocked N-formyl-Met-Leu-Phe (fMLP) chemotactic peptide-induced intracellular calcium release and weakly inhibited G??-mediated phospholipase C ?2 (PLC?2) activation in vitro compared to gallein and peptide SIGKAFKILGYPDYD (SIGK). Ellagic acid also inhibited fMLP-induced PI3K?mediated membrane phosphatidylinositol 3,4,5-triphosphate (PIP3) production, superoxide production, and migration of neutrophil-like HL60 cells. In this study, we identified ellagic acid as a small molecule inhibitor of G?? signaling in neutrophil-like cells and was sufficient to inhibit chemotaxis. This thesis work focuses on the overall importance of G protein signaling in GPCRmediated chemokine signaling and immune cell function. Both G?i and G?? are important mediators of GPCR-mediated chemokine signaling and immune cell function. Furthermore, our studies provide insights into the novel role of G?i in adhesion and migration of both immune cells and cancer cells. Chemokines are not only important during inflammation, but also contribute to the metastatic potential of cancer cells. We illustrate the importance of G?i and G?? in immune cell function such as adhesion and cell migration and we show alleviation of inflammatory lupus nephritis by inhibiting G?? signaling.
Author: Klaus Ley Publisher: Frontiers Media SA ISBN: 2889194302 Category : Chemokines Languages : en Pages : 109
Book Description
Arrest chemokines are a small group of chemokines that promote leukocyte arrest from rolling by triggering rapid integrin activation. Arrest chemokines have been described for neutrophils, monocytes, eosinophils, naïve lymphocytes and effector memory T cells. Most arrest chemokines are immobilized on the endothelial surface by binding to heparin sulfate proteoglycans. Whether soluble chemokines can promote integrin activation and arrest is controversial (Alon-Gerszten). Many aspects of the signaling pathway from the GPCR chemokine receptor to integrin activation are the subject of active investigation. Leukocyte adhesion deficiency III is a human disease in which chemokine-triggered integrin activation is defective because of a mutation in the cytoskeletal protein kindlin-3. About 10 different such mutations have been described. The defects seen in patients with LAD-III elucidate the importance of rapid integrin activation for host defense in humans. We welcome reports that help clarifying this crucial first step in the process of leukocyte transendothelial migration.
Author: Bharat B. Aggarwal Publisher: Springer ISBN: 3034808372 Category : Medical Languages : en Pages : 489
Book Description
This volume examines in detail the role of chronic inflammatory processes in the development of several types of cancer. Leading experts describe the latest results of molecular and cellular research on infection, cancer-related inflammation and tumorigenesis. Further, the clinical significance of these findings in preventing cancer progression and approaches to treating the diseases are discussed. Individual chapters cover cancer of the lung, colon, breast, brain, head and neck, pancreas, prostate, bladder, kidney, liver, cervix and skin as well as gastric cancer, sarcoma, lymphoma, leukemia and multiple myeloma.
Author: Z. Kmiec Publisher: Springer Science & Business Media ISBN: 3642565530 Category : Science Languages : en Pages : 154
Book Description
It is only during the last decade that the functions of sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, pit cells and other intrahepatic lymphocytes have been better understood. The development of methods for isolation and co-culturing various types of liver cells has established that they communicate and cooperate via secretion of various intercellular mediators. This monograph summarizes multiple data that suggest the important role of cellular cross-talk for the functions of both normal and diseased liver. Special features of the book include concise presentation of the majority of detailed data in 19 tables. Original schemes allow for the clear illustration of complicated intercellular relationships. This is the first ever presentation of the newly emerging field of liver biology, which is important for hepatic function in health and disease and opens new avenues for therapeutic interventions.
Author: Brian D. Gulbransen Publisher: Biota Publishing ISBN: 1615046615 Category : Medical Languages : en Pages : 72
Book Description
The enteric nervous system (ENS) is a complex neural network embedded in the gut wall that orchestrates the reflex behaviors of the intestine. The ENS is often referred to as the “little brain” in the gut because the ENS is more similar in size, complexity and autonomy to the central nervous system (CNS) than other components of the autonomic nervous system. Like the brain, the ENS is composed of neurons that are surrounded by glial cells. Enteric glia are a unique type of peripheral glia that are similar to astrocytes of the CNS. Yet enteric glial cells also differ from astrocytes in many important ways. The roles of enteric glial cell populations in the gut are beginning to come to light and recent evidence implicates enteric glia in almost every aspect of gastrointestinal physiology and pathophysiology. However, elucidating the exact mechanisms by which enteric glia influence gastrointestinal physiology and identifying how those roles are altered during gastrointestinal pathophysiology remain areas of intense research. The purpose of this e-book is to provide an introduction to enteric glial cells and to act as a resource for ongoing studies on this fascinating population of glia. Table of Contents: Introduction / A Historical Perspective on Enteric Glia / Enteric Glia: The Astroglia of the Gut / Molecular Composition of Enteric Glia / Development of Enteric Glia / Functional Roles of Enteric Glia / Enteric Glia and Disease Processes in the Gut / Concluding Remarks / References / Author Biography
Author: Ah-Ng Tony Kong Publisher: CRC Press ISBN: 1466503718 Category : Medical Languages : en Pages : 631
Book Description
Increasing scientific evidence suggests that the majority of diseases including cancer are driven by oxidative stress and inflammation, attributed to environmental factors. These factors either drive genetic mutations or epigenetically modify expression of key regulatory genes. These changes can occur as early as gestational fetal development, and
Author: Publisher: Academic Press ISBN: 0124079385 Category : Science Languages : en Pages : 307
Book Description
Store-operated calcium channels are found in most animal cells and regulate many cellular functions including cell division, growth, differentiation, and cell death. This volume provides a concise and informative overview of the principles of store-operated calcium entry and the key developments in the field from researchers who have led these advances. The overall goal of the volume is to provide interested students and investigators with sufficient information to enable a broad understanding of the progress and current excitement in the field. The volume contains a wealth of information that even experienced investigators in the field will find useful. The volume provides a comprehensive overview of the mechanisms and functions of store-operated calcium channels Contributors are authoritative researchers who have produced important advances in the field The volume is well-illustrated with cartoons and data to facilitate easy comprehension of the subject
Author: Manzoor M. Khan Publisher: Springer Science & Business Media ISBN: 0387779760 Category : Medical Languages : en Pages : 275
Book Description
During the past decades, with the introduction of the recombinant DNA, hybridoma and transgenic technologies there has been an exponential evolution in understanding the pathogenesis, diagnosis and treatment of a large number of human diseases. The technologies are evident with the development of cytokines and monoclonal antibodies as therapeutic agents and the techniques used in gene therapy. Immunopharmacology is that area of biomedical sciences where immunology, pharmacology and pathology overlap. It concerns the pharmacological approach to the immune response in physiological as well as pathological events. This goals and objectives of this textbook are to emphasize the developments in immunology and pharmacology as they relate to the modulation of immune response. The information includes the pharmacology of cytokines, monoclonal antibodies, mechanism of action of immune-suppressive agents and their relevance in tissue transplantation, therapeutic strategies for the treatment of AIDS and the techniques employed in gene therapy. The book is intended for health care professional students and graduate students in pharmacology and immunology.