Potential role of diacylglycerol kinases in immune-mediated diseases

2020 ◽  
Vol 134 (13) ◽  
pp. 1637-1658 ◽  
Author(s):  
Gianluca Baldanzi ◽  
Beatrice Ragnoli ◽  
Mario Malerba
Keyword(s):  
Immune Response ◽  
Second Messengers ◽  
Lymphoproliferative Disease ◽  
Signaling Proteins ◽  
Downstream Signaling ◽  
Immune Mediated ◽  
Genetic Perturbations ◽  
Localized Juvenile Periodontitis ◽  
Membrane Shape

Abstract The mechanism promoting exacerbated immune responses in allergy and autoimmunity as well as those blunting the immune control of cancer cells are of primary interest in medicine. Diacylglycerol kinases (DGKs) are key modulators of signal transduction, which blunt diacylglycerol (DAG) signals and produce phosphatidic acid (PA). By modulating lipid second messengers, DGK modulate the activity of downstream signaling proteins, vesicle trafficking and membrane shape. The biological role of the DGK α and ζ isoforms in immune cells differentiation and effector function was subjected to in deep investigations. DGK α and ζ resulted in negatively regulating synergistic way basal and receptor induced DAG signals in T cells as well as leukocytes. In this way, they contributed to keep under control the immune response but also downmodulate immune response against tumors. Alteration in DGKα activity is also implicated in the pathogenesis of genetic perturbations of the immune function such as the X-linked lymphoproliferative disease 1 and localized juvenile periodontitis. These findings suggested a participation of DGK to the pathogenetic mechanisms underlying several immune-mediated diseases and prompted several researches aiming to target DGK with pharmacologic and molecular strategies. Those findings are discussed inhere together with experimental applications in tumors as well as in other immune-mediated diseases such as asthma.

scholarly journals Role of 5-HT7 receptors in the immune system in health and disease

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
Alejandro Quintero-Villegas ◽  
Sergio Iván Valdés-Ferrer
Keyword(s):  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
Immune System ◽  
Blood Platelets ◽  
Pain Tolerance ◽  
Immune Mediated ◽  
The Central Nervous System ◽  
Health And Disease

AbstractIn mammalians, serotonin (5-HT) has critical roles in the central nervous system (CNS), including mood stability, pain tolerance, or sleep patterns. However, the vast majority of serotonin is produced by intestinal enterochromaffin cells of the gastrointestinal tract and circulating blood platelets, also acting outside of the CNS. Serotonin effects are mediated through its interaction with 5-HT receptors (5-HTRs), a superfamily with a repertoire of at least fourteen well-characterized members. 5-HT7 receptors are the last 5-HTR member to be identified, with well-defined functions in the nervous, gastrointestinal, and vascular systems. The effects of serotonin on the immune response are less well understood. Mast cells are known to produce serotonin, while T cells, dendritic cells, monocytes, macrophages and microglia express 5-HT7 receptor. Here, we review the known roles of 5-HT7 receptors in the immune system, as well as their potential therapeutic implication in inflammatory and immune-mediated disorders.

scholarly journals Role of Leptin in the Activation of Immune Cells

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Patricia Fernández-Riejos ◽  
Souad Najib ◽  
Jose Santos-Alvarez ◽  
Consuelo Martín-Romero ◽  
Antonio Pérez-Pérez ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Energy Homeostasis ◽  
Humoral Factors ◽  
Endocrine Organ ◽  
Pathological Conditions ◽  
Immune Mediated ◽  
Infection Susceptibility

Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response, innate and adaptive response, both in normal and pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory pathogenic cytokines. Thus, leptin is a mediator of the inflammatory response.

Activation of Nuclear Factor KappaB in ETV6/FLT3-Transformed Ba/F3 Cells Depends on the FLT3 Tyrosine 591.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4666-4666
Author(s):  
Hoang Anh Vu ◽  
Phan Thi Xinh ◽  
Yasuhiko Kano ◽  
Takaomi Ishida ◽  
Toshiki Watanabe ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Fusion Gene ◽  
Hematologic Malignancies ◽  
Signaling Proteins ◽  
Interleukin 3 ◽  
Downstream Signaling ◽  
Support Cell ◽  
Helix Loop Helix ◽  
Oligomerization Domain

Abstract The FLT3 gene is one of the most frequently mutated genes in hematologic malignancies. Mutated FLT3 has been found to lead to strong constitutive activation of several signaling proteins such as STAT5, CBL, VAV, SHP2, NF-kB, and AKT. Recently, we have reported that FLT3 contributed to leukemogenesis through generating a ETV6/FLT3 fusion gene in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation, which is the first report to show that FLT3 fusion gene can be involved in leukemogenesis. The ETV6/FLT3 which contained the helix-loop-helix oligomerization domain of ETV6 fused to the juxtamembrane (JM) domain plus tyrosine kinase (TK) domains of FLT3, conferred interleukin-3-independent growth on Ba/F3 cells (Vu HA, et al. LEUKEMIA20:1414–21, 2006). To assess a role of the JM domain of FLT3 in the ETV6/FLT3 protein, we generated a series of ETV6/FLT3 mutants (tyrosine to phenylalanine substitution and deletion of the JM domain or N-terminal region of the TK1 domain). Each mutant was introduced into Ba/F3 cells and downstream signaling as well as cell proliferation was investigated. We found that the wild-type ETV6/FLT3 in Ba/F3 cells was a constitutively activated tyrosine kinase that led to activation of STAT5, AKT, MAPK, and NF-kB pathways as well as up-regulation of PIM-1. Deletion of the JM domain retained compatible level of autophosphorylation of the fusion protein as well as activation of STAT5, AKT and MAPK, suggesting that the JM domain is dispensable for STAT5, MAPK and AKT activations. In contrast, deletion of the JM domain did abrogate interleukin-3-independent growth of Ba/F3 cells, PIM-1 up-regulation, and activation of NF-kB. Importantly, while substitutions of other 3 tyrosines (589, 597, and 599) had no affect on NF-kB activation, the substitution of tyrosine 591 to phenylalanine abrogated this activation. Our results suggest that the tyrosine 591 in JM domain of FLT3 in ETV6/FLT3 is critical for NF-kB activation to support cell survival and PIM-1 up-regulation.

scholarly journals Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis

2010 ◽  
Vol 207 (8) ◽  
pp. 1609-1616 ◽  
Author(s):  
Andrea Cruz ◽  
Alexandra G. Fraga ◽  
Jeffrey J. Fountain ◽  
Javier Rangel-Moreno ◽  
Egídio Torrado ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Effective Vaccine ◽  
Interleukin 17 ◽  
Mycobacterial Antigen ◽  
Gene Encoding ◽  
Immune Mediated ◽  
Antigenic Exposure ◽  
Acquired Immune Responses

Infection usually leads to the development of acquired immune responses associated with clearance or control of the infecting organism. However, if not adequately regulated, immune-mediated pathology can result. Tuberculosis is a worldwide threat, and development of an effective vaccine requires that the protective immune response to Mycobacterium tuberculosis (Mtb) be dissected from the pathological immune response. This distinction is particularly important if new vaccines are to be delivered to Mtb-exposed individuals, as repeated antigenic exposure can lead to pathological complications. Using a model wherein mice are vaccinated with bacille Calmette-Guérin after Mtb infection, we show that repeated vaccination results in increased IL-17, tumor necrosis factor, IL-6, and MIP-2 expression, influx of granulocytes/neutrophils, and lung tissue damage. This pathological response is abrogated in mice deficient in the gene encoding IL-23p19 or in the presence of IL-17–blocking antibody. This finding that repeated exposure to mycobacterial antigen promotes enhanced IL-17–dependent pathological consequences has important implications for the design of effective vaccines against Mtb.

scholarly journals Deletion of Fcγ Receptor IIB Renders H-2b Mice Susceptible to Collagen-induced Arthritis

1999 ◽  
Vol 189 (1) ◽  
pp. 187-194 ◽  
Author(s):  
Takae Yuasa ◽  
Satoshi Kubo ◽  
Tadashi Yoshino ◽  
Azusa Ujike ◽  
Kimio Matsumura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Response ◽  
Critical Role ◽  
Type Ii Collagen ◽  
Genetic Studies ◽  
Cellular Activation ◽  
Effector Cells ◽  
Immune Mediated ◽  
Deficient Mice

Autoimmune diseases, like rheumatoid arthritis, result from a dysregulation of the immune response culminating in hyperactivation of effector cells leading to immune-mediated injury. To maintain an appropriate immune response and prevent the emergence of autoimmune disease, activation signals must be regulated by inhibitory pathways. Biochemical and genetic studies indicate that the type IIB low-affinity receptor for immunoglobulin (Ig)G (FcγRIIB) inhibits cellular activation triggered through antibody or immune complexes and may be an important component in preventing the emergence of autoimmunity. To investigate the role of FcγRIIB in the development of type II collagen (CII)-induced arthritis (CIA), a model for rheumatoid arthritis in humans, we have examined its contribution in determining the susceptibility to CIA in the nonpermissive H-2b haplotype. H-2b mice immunized with bovine CII do not develop appreciable disease. In contrast, immunization of the FcγRIIB-deficient, H-2b mice with bovine CII induced CIA at an incidence of 42.2%. The maximal arthritis index of the FcγRIIB-deficient mice developing CIA (6.9 ± 3.6) was comparable to that of DBA/1 mice (8.6 ± 1.9), an H-2q strain susceptible for CIA induction. IgG1, IgG2a, and IgG2b antibody responses against CII were elevated in the FcγRIIB-deficient animals, especially in those mice showing arthritis, but less pronounced than DBA/1 mice. Histological examinations of the arthritic paws from FcγRIIB-deficient mice revealed that cartilage was destroyed and bone was focally eroded in association with marked lymphocyte and monocyte/macrophage infiltration, very similar to the pathologic findings observed in DBA/1 mice. These results indicate that a nonpermissive H-2b haplotype can be rendered permissive to CIA induction through deletion of FcγRIIB, suggesting that FcγRIIB plays a critical role in suppressing the induction of CIA.

scholarly journals Mechanisms of AT1a receptor-mediated uptake of angiotensin II by proximal tubule cells: a novel role of the multiligand endocytic receptor megalin

2014 ◽  
Vol 307 (2) ◽  
pp. F222-F233 ◽  
Author(s):  
Xiao C. Li ◽  
Jia L. Zhuo
Keyword(s):  
Proximal Tubule ◽  
Map Kinases ◽  
Signaling Proteins ◽  
Ang Ii ◽  
Proximal Tubule Cells ◽  
Downstream Signaling ◽  
Tubule Cells ◽  
At1a Receptor ◽  
Si Rna

The present study tested the hypothesis that the multiligand endocytic receptor megalin is partially involved in the uptake of ANG II and downstream signaling responses in mouse proximal tubule cells (mPCT) by interacting with AT1a receptors. mPCT cells of wild-type (WT) and AT1a receptor-deficient (AT1a-KO) mice were treated with vehicle, the AT1 receptor blocker losartan (10 μM), or a selective megalin small interfering (si) RNA for 48 h. The uptake of fluorescein (FITC)-labeled ANG II (10 nM, 37°C) and downstream signaling responses were analyzed by fluorescence imaging and Western blotting. AT1a receptors and megalin were abundantly expressed in mPCT cells, whereas AT1a receptors were absent in AT1a-KO mPCT cells ( P < 0.01). In WT mPCT cells, FITC-ANG II uptake was visualized at 30 min in the cytoplasm and in the nuclei 1 h after exposure. Losartan alone completely blocked the uptake of FITC-ANG II, whereas megalin siRNA inhibited only 30% of the response ( P < 0.01). The remaining FITC-ANG II uptake in the presence of megalin siRNA was completely abolished by losartan. ANG II induced threefold increases in phosphorylated MAP kinases ERK1/2 and a onefold increase in phosphorylated sodium and hydrogen exchanger 3 (NHE3) proteins, which were also blocked by losartan and megalin-siRNA. By contrast, losartan and megalin siRNA had no effects on these signaling proteins in AT1a-KO mPCT cells. We conclude that the uptake of ANG II and downstream MAP kinases ERK1/2 and NHE3 signaling responses in mPCT cells are mediated primarily by AT1a receptors. However, megalin may also play a partial role in these responses to ANG II.

A pro-inflammatory role of type 2 innate lymphoid cells in murine immune-mediated hepatitis

2015 ◽  
Vol 53 (12) ◽  
Author(s):  
K Karimi ◽  
K Neumann ◽  
J Meiners ◽  
R Voetlause ◽  
W Dammermann ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Immune Mediated
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