Sustained Release of Prostaglandin E2in Fibroblasts Expressing Ectopically Cyclooxygenase 2 Impairs P2Y-Dependent Ca2+-Mobilization

The nucleotide uridine trisphosphate (UTP) released to the extracellular milieu acts as a signaling moleculeviaactivation of specific pyrimidine receptors (P2Y). P2Y receptors are G protein-coupled receptors expressed in many cell types. These receptors mediate several cell responses and they are involved in intracellular calcium mobilization. We investigated the role of the prostanoid PGE2in P2Y signaling in mouse embryonic fibroblasts (MEFs), since these cells are involved in different ontogenic and physiopathological processes, among them is tissue repair following proinflammatory activation. Interestingly, Ca2+-mobilization induced by UTP-dependent P2Y activation was reduced by PGE2when this prostanoid was produced by MEFs transfected with COX-2 or when PGE2was added exogenously to the culture medium. This Ca2+-mobilization was important for the activation of different metabolic pathways in fibroblasts. Moreover, inhibition of COX-2 with selective coxibs prevented UTP-dependent P2Y activation in these cells. The inhibition of P2Y responses by PGE2involves the activation of PKCs and PKD, a response that can be suppressed after pharmacological inhibition of these protein kinases. In addition to this, PGE2reduces the fibroblast migration induced by P2Y-agonists such as UTP. Taken together, these data demonstrate that PGE2is involved in the regulation of P2Y signaling in these cells.

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Emerging role of extracellular vesicles in liver diseases

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00183.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. G739-G749 ◽

Cited By ~ 10

Author(s):

Harmeet Malhi

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Cell Types ◽

Cell Responses ◽

Therapeutic Delivery ◽

Disease States ◽

Therapeutic Uses ◽

Potential Biomarker ◽

Secretion Pathways

Extracellular vesicles (EVs) are membrane-defined nanoparticles released by most cell types. The EVs released by cells may differ quantitatively and qualitatively from physiological states to disease states. There are several unique properties of EVs, including their proteins, lipids and nucleic acid cargoes, stability in circulation, and presence in biofluids, which make them a critical vector for cell-to-cell communication and impart utility as a biomarker. EVs may also serve as a vehicle for selective cargo secretion. Similarly, EV cargo may be selectively manipulated for targeted therapeutic delivery. In this review an overview is provided on the EV classification, biogenesis, and secretion pathways, which are conserved across cell types. Next, cargo characterization and effector cell responses are discussed in the context of nonalcoholic steatohepatitis, alcoholic hepatitis, and acetaminophen-induced liver injury. The review also discusses the potential biomarker and therapeutic uses of circulating EVs.

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Abnormal Cell Responses and Role of TNF-αin Impaired Diabetic Wound Healing

BioMed Research International ◽

10.1155/2013/754802 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 53

Author(s):

Fanxing Xu ◽

Chenying Zhang ◽

Dana T. Graves

Keyword(s):

Wound Healing ◽

Macrophage Polarization ◽

Diabetic Wound ◽

Major Health Problem ◽

Abnormal Cell ◽

Fibroblast Migration ◽

Cell Responses ◽

Impaired Healing ◽

Diabetic Wound Healing

Impaired diabetic wound healing constitutes a major health problem. The impaired healing is caused by complex factors such as abnormal keratinocyte and fibroblast migration, proliferation, differentiation, and apoptosis, abnormal macrophage polarization, impaired recruitment of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), and decreased vascularization. Diabetes-enhanced and prolonged expression of TNF-αalso contributes to impaired healing. In this paper, we discuss the abnormal cell responses in diabetic wound healing and the contribution of TNF-α.

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Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective

Frontiers in Immunology ◽

10.3389/fimmu.2021.645834 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jean M. Kanellopoulos ◽

Cássio Luiz Coutinho Almeida-da-Silva ◽

Sirje Rüütel Boudinot ◽

David M. Ojcius

Keyword(s):

Plasma Membrane ◽

P2y Receptors ◽

Potential Interaction ◽

The Body ◽

Extracellular Nucleotides ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Functional Features ◽

G Protein Coupled

Extracellular nucleotides are important mediators of activation, triggering various responses through plasma membrane P2 and P1 receptors. P2 receptors are further subdivided into ionotropic P2X receptors and G protein-coupled P2Y receptors. P2X4 is an ATP-gated cation channel broadly expressed in most tissues of the body. Within the P2X family, P2X4 has a unique subcellular distribution, being preferentially localized in lysosomes. In these organelles, high ATP concentrations do not trigger P2X4 because of the low pH. However, when the pH increases to 7.4, P2X4 can be stimulated by intra-lysosomal ATP, which is in its active, tetra-anionic form. Elucidation of P2X4, P2X3 and P2X7 structures has shed some light on the functional differences between these purinergic receptors. The potential interaction between P2X4 and P2X7 has been extensively studied. Despite intensive effort, it has not been possible yet to determine whether P2X4 and P2X7 interact as heterotrimers or homotrimers at the plasma membrane. However, several publications have shown that functional interactions between P2X4 and P2X7 do occur. Importantly, these studies indicate that P2X4 potentiates P2X7-dependent activation of inflammasomes, leading to increased release of IL-1β and IL-18. The role of P2X4 in various diseases could be beneficial or deleterious even though the pathophysiological mechanisms involved are still poorly defined. However, in diseases whose physiopathology involves activation of the NLRP3 inflammasome, P2X4 was found to exacerbate severity of disease. The recent production of monoclonal antibodies specific for the human and mouse P2X4, some of which are endowed with agonist or antagonist properties, raises the possibility that they could be used therapeutically. Analysis of single nucleotide polymorphisms of the human P2RX4 gene has uncovered the association of P2RX4 gene variants with susceptibility to several human diseases.

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Endothelial Cell Inflammation and Barriers Are Regulated by the Rab26-Mediated Balance between β2-AR and TLR4 in Pulmonary Microvessel Endothelial Cells

Mediators of Inflammation ◽

10.1155/2019/7538071 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Huaping Chen ◽

Ming Yuan ◽

Chunji Huang ◽

Zhi Xu ◽

Mingchun Li ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Cell Membrane ◽

Cell Surface ◽

Cell Types ◽

Tlr4 Expression ◽

Barrier Dysfunction ◽

Surface Receptors ◽

G Protein Coupled

Rab26 GTPase modulates the trafficking of cell surface receptors, such as G protein-coupled receptors including α2-adrenergic receptors in some cell types. However, the effect of Rab26 on β2-adrenergic receptor (β2-AR) trafficking or/and Toll-like receptor 4 (TLR4) expression in human pulmonary microvascular endothelial cells (HPMECs) is still unclear. Here, we investigated the role of Rab26 in regulating the expression of β2-ARs and TLR4 in HPMECs and the effect of these receptors’ imbalance on endothelial cell barrier function. The results showed that there was unbalance expression in these receptors, where β2-AR expression was remarkably reduced, and TLR4 was increased on the cell membrane after lipopolysaccharide (LPS) treatment. Furthermore, we found that Rab26 overexpression not only upregulated β2-ARs but also downregulated TLR4 expression on the cell membrane. Subsequently, the TLR4-related inflammatory response was greatly attenuated, and the hyperpermeability of HPMECs also was partially relived. Taken together, these data suggest that basal Rab26 maintains the balance between β2-ARs and TLR4 on the cell surface, and it might be a potential therapeutic target for diseases involving endothelial barrier dysfunction.

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The role of adenosine and P2Y receptors expressed by multiple cell types in pain transmission

Brain Research Bulletin ◽

10.1016/j.brainresbull.2019.02.011 ◽

2019 ◽

Vol 151 ◽

pp. 132-143 ◽

Cited By ~ 5

Author(s):

Giulia Magni ◽

Stefania Ceruti

Keyword(s):

Cell Types ◽

P2y Receptors ◽

Pain Transmission ◽

Multiple Cell

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Purinergic Receptors Crosstalk with CCR5 to Amplify Ca2+ Signaling

Cellular and Molecular Neurobiology ◽

10.1007/s10571-020-01002-1 ◽

2020 ◽

Author(s):

Mizuho Horioka ◽

Emilie Ceraudo ◽

Emily Lorenzen ◽

Thomas P. Sakmar ◽

Thomas Huber

Keyword(s):

Signaling Pathways ◽

G Protein ◽

Purinergic Receptors ◽

P2y Receptors ◽

G Protein Signaling ◽

Protein Signaling ◽

Extracellular Milieu ◽

Immunodeficiency Virus ◽

Intracellular Ca ◽

G Protein Coupled

AbstractMany G protein-coupled receptors (GPCRs) signal through more than one subtype of heterotrimeric G proteins. For example, the C–C chemokine receptor type 5 (CCR5), which serves as a co-receptor to facilitate cellular entry of human immunodeficiency virus 1 (HIV-1), normally signals through the heterotrimeric G protein, Gi. However, CCR5 also exhibits G protein signaling bias and certain chemokine analogs can cause a switch to Gq pathways to induce Ca2+ signaling. We want to understand how much of the Ca2+ signaling from Gi-coupled receptors is due to G protein promiscuity and how much is due to transactivation and crosstalk with other receptors. We propose a possible mechanism underlying the apparent switching between different G protein signaling pathways. We show that chemokine-mediated Ca2+ flux in HEK293T cells expressing CCR5 can be primed and enhanced by ATP pretreatment. In addition, agonist-dependent lysosomal exocytosis results in the release of ATP to the extracellular milieu, which amplifies cellular signaling networks. ATP is quickly degraded via ADP and AMP to adenosine. ATP, ADP and adenosine activate different cell surface purinergic receptors. Endogenous Gq-coupled purinergic P2Y receptors amplify Ca2+ signaling and allow for Gi- and Gq-coupled receptor signaling pathways to converge. Associated secretory release of GPCR ligands, such as chemokines, opioids, and monoamines, should also lead to concomitant release of ATP with a synergistic effect on Ca2+ signaling. Our results suggest that crosstalk between ATP-activated purinergic receptors and other Gi-coupled GPCRs is an important cooperative mechanism to amplify the intracellular Ca2+ signaling response.

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Normal Lymphocyte Development but Delayed Humoral Immune Response in CD81-null Mice

Journal of Experimental Medicine ◽

10.1084/jem.185.8.1505 ◽

1997 ◽

Vol 185 (8) ◽

pp. 1505-1510 ◽

Cited By ~ 181

Author(s):

Holden T. Maecker ◽

Shoshana Levy

Keyword(s):

T Cells ◽

B Cells ◽

Cell Types ◽

Normal Numbers ◽

Cell Surface Molecule ◽

Humoral Immune ◽

Signaling Complex ◽

Cell Responses ◽

A Cell

CD81 is a cell surface molecule expressed on many cell types and associated with the CD19/ CD21/Leu13 signal-transducing complex on B cells. A recent report implies that CD81 expression on thymic stromal cells is important in the maturation of thymocytes from CD4− CD8− to CD4+CD8+. However, we have produced CD81-null mice by gene targeting, and find that they undergo normal development of thymocytes and express normal numbers of T cells. B cells are also found in normal numbers in the spleen, blood, and peritoneal cavity of CD81-null mice, but they express a lower level of CD19 compared to heterozygous littermates. Finally, early antibody responses to the protein antigen ovalbumin are weaker in CD81null mice compared to their heterozygous littermates. This is consistent with the proposed role of the CD19/CD21/CD81-signaling complex in lowering the threshold for B cell responses. These results show that CD81 is not required for maturation of T cells, but is important for optimal expression of CD19 on B cells and optimal stimulation of antibody production.

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Role of the teneurins, teneurin C-terminal associated peptides (TCAP) in reproduction: clinical perspectives

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2015-0032 ◽

2015 ◽

Vol 24 (2) ◽

Cited By ~ 2

Author(s):

David A. Lovejoy ◽

Téa Pavlović

Keyword(s):

Cell Types ◽

Reproductive Physiology ◽

Corticotropin Releasing Factor ◽

Peptide Sequence ◽

Gene Duplications ◽

Terminal Exon ◽

Numerous Cell ◽

Multicellular Organisms ◽

G Protein Coupled

AbstractIn humans, the teneurin gene family consists of four highly conserved paralogous genes that are the result of early vertebrate gene duplications arising from a gene introduced into multicellular organisms from a bacterial ancestor. In vertebrates and humans, the teneurins have become integrated into a number of critical physiological systems including several aspects of reproductive physiology. Structurally complex, these genes possess a sequence in their terminal exon that encodes for a bioactive peptide sequence termed the ‘teneurin C-terminal associated peptide’ (TCAP). The teneurin/TCAP protein forms an intercellular adhesive unit with its receptor, latrophilin, an Adhesion family G-protein coupled receptor. It is present in numerous cell types and has been implicated in gamete migration and gonadal morphology. Moreover, TCAP is highly effective at reducing the corticotropin-releasing factor (CRF) stress response. As a result, TCAP may also play a role in regulating the stress-associated inhibition of reproduction. In addition, the teneurins and TCAP have been implicated in tumorigenesis associated with reproductive tissues. Therefore, the teneurin/TCAP system may offer clinicians a novel biomarker system upon which to diagnose some reproductive pathologies.

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Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. V. Role of idiotypes in the suppressor pathway.

Journal of Experimental Medicine ◽

10.1084/jem.152.1.161 ◽

1980 ◽

Vol 152 (1) ◽

pp. 161-169 ◽

Cited By ~ 62

Author(s):

J Z Weinberger ◽

R N Germain ◽

B Benacerraf ◽

M E Dorf

Keyword(s):

Cell Population ◽

Direct Evidence ◽

Suppressor Cells ◽

Suppressor Cell ◽

Cell Types ◽

Induction Phase ◽

Antigen Binding ◽

Binding Properties ◽

Cell Responses

4-Hydroxy-3-nitrophenyl (NP) derivatized syngeneic spleen cells injected intravenously stimulate maturation of an antigen-binding, idiotype-bearing induction-phase suppressor cell population, as well as an idiotype-binding anti-idiotype-bearing effector-phase suppressor cell population. Both cell types are present simultaneously in the spleen cell population 7-d after their induction. Furthermore, the cell population with antigen-binding properties can, in the presence of NP-derivatized syngeneic cells, induce a population of effector suppressor cells. The precursors of the effector suppressor population are not sensitive to concentrations of cyclophosphamide which prevented the generation of induction phase suppressor cells. These data provide direct evidence in support of the theory of network regulation of immune suppression. X

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