scholarly journals Fish macrophages express a cyclo-oxygenase-2 homologue after activation

1999 ◽  
Vol 340 (1) ◽  
pp. 153-159 ◽  
Author(s):  
Jun ZOU ◽  
Norman F. NEUMANN ◽  
Jason W. HOLLAND ◽  
Miodrag BELOSEVIC ◽  
Charles CUNNINGHAM ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Reading Frame ◽  
Goldfish Carassius Auratus ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Multiple Copies ◽  
Cox 2 ◽  
Inhibitor Of Protein Synthesis ◽  
Cox 1

In mammals, the increased generation of prostaglandins (PG) during the onset of inflammatory responses and activation of immune cell types has been attributed to the induction of a novel cyclo-oxygenase (COX) isoform, termed COX-2, which is distinct from the well-characterized constitutive activity (COX-1). Goldfish (Carassius auratus) macrophages exposed to bacterial lipopolysaccharide and leucocyte-derived macrophage-activating factor(s) showed a significant increase in the generation of the major COX product, PGE2, within the first 6 h of stimulation. The selective COX-2 inhibitor, NS398, inhibited this elevated generation of PGE, whereas the basal level of this product synthesized by unstimulated macrophages was unaffected by such exposure. PGE generation by goldfish macrophages was similarly inhibited by the glucocorticoid, dexamethasone, and an inhibitor of protein synthesis, cycloheximide, suggesting that this stimulation may be due to an inducible enzyme equivalent to mammalian COX-2. The complete coding sequence of rainbow trout (Oncorhynchus mykiss) COX-2 was obtained by PCR. The gene contains a 61 bp 5ʹ-untranslated region (UTR), a 1821 bp open reading frame and a 771 bp 3ʹUTR containing multiple copies of an mRNA instability motif (ATTTA). The predicted translation product had high homology to known mammalian and chicken COX-2 (83-84%) and COX-1 (77%) sequences. Reverse-transcriptase PCR with cDNA from control and bacterially challenged fish revealed that trout COX-2 expression was not constitutive but could be induced. Overall, these studies show for the first time that the inducible isoform of COX has a long evolutionary history, probably dating back to the evolution of fish over 500 million years ago.

Cyclooxygenase cloning in dogfish shark, Squalus acanthias, and its role in rectal gland Cl secretion

2002 ◽  
Vol 283 (3) ◽  
pp. R631-R637 ◽  
Author(s):  
T. Yang ◽  
S. J. Forrest ◽  
N. Stine ◽  
Y. Endo ◽  
A. Pasumarthy ◽  
...  
Keyword(s):  
Cdna Sequence ◽  
Chloride Secretion ◽  
Protein Product ◽  
Rectal Gland ◽  
Peak Response ◽  
Reading Frame ◽  
Acid Protein ◽  
Elasmobranch Species ◽  
Cox 2 ◽  
Cox 1

The present studies were carried out with the aims to determine the cDNA sequence for cyclooxygenase (COX) in an elasmobranch species and to study its role in regulation of chloride secretion in the perfused shark rectal gland (SRG). With the use of long primers (43 bp) derived from regions of homology between zebrafish and rainbow trout COX-2 genes, a 600-bp product was amplified from SRG and was found to be almost equally homologous to mammalian COX-1 and COX-2 (65%). The full-length cDNA sequence was obtained by 5′-RACE and by analyzing an EST clone generated by the EST Project of the Mt. Desert Island Biological Laboratory Marine DNA Sequencing Center. The longest open reading frame encodes a 593-amino acid protein that has 68 and 64% homology to mammalian COX-1 and COX-2, respectively. The gene and its protein product is designated as shark COX (sCOX). The key residues in the active site (Try385, His388, and Ser530) are conserved between the shark and mammalian COX. sCOX contains Val523 that has been shown to be a key residue determining the sensitivity to COX-2-specific inhibitors including NS-398. The mRNA of sCOX, detected by RT-PCR, was found in all tissues tested, including rectal gland, kidney, spleen, gill, liver, brain, and heart, but not in fin. In the perfused SRG, vasoactive intestinal peptide (VIP) at 5 nM induced rapid and marked Cl− secretion (basal: <250 μeq · h−1 · g−1; peak response: 3,108 ± 479 μeq · h−1 · g−1). In the presence of 50 μM NS-398, both the peak response (2,131 ± 307 μeq · h−1 · g−1) and the sustained response to VIP were significantly reduced. When NS-398 was removed, there was a prompt recovery of chloride secretion to control values. In conclusion, we have cloned the first COX in an elasmobranch species (sCOX) and shown that sCOX inhibition suppresses VIP-stimulated chloride secretion in the perfused SRG.

scholarly journals Interleukin-4 in the Generation of the AERD Phenotype: Implications for Molecular Mechanisms Driving Therapeutic Benefit of Aspirin Desensitization

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
John W. Steinke ◽  
Spencer C. Payne ◽  
Larry Borish
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Cell Types ◽  
Therapeutic Benefit ◽  
Interleukin 4 ◽  
Prostaglandin E ◽  
Aspirin Desensitization ◽  
Over Expression ◽  
Cysteinyl Leukotriene ◽  
Cox 2

Aspirin-exacerbated respiratory disease (AERD) is explained in part by over-expression of 5-lipoxygenase, leukotriene C4 synthase (LTC4S) and the cysteinyl leukotriene (CysLT) receptors (CysLT1 and 2), resulting in constitutive over-production of CysLTs and the hyperresponsiveness to CysLTs that occurs with aspirin ingestion. Increased levels of IL-4 have been found in the sinus mucosa and nasal polyps of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the upregulation of LTC4S by mast cells and the upregulation of CysLT1 and 2 receptors on many immune cell types. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD reflecting diminished expression of cyclooxygenase (COX)-2. IL-4 can inhibit basal and stimulated expression of COX-2 and microsomal PGE synthase 1 leading to decreased capacity for PGE2 secretion. Thus, IL-4 plays an important pathogenic role in generating the phenotype of AERD. This review will examine the evidence supporting this hypothesis and describe a model of how aspirin desensitization provides therapeutic benefit for AERD patients.

scholarly journals Multiple Beneficial Roles of Repressor of Estrogen Receptor Activity (REA) in Suppressing the Progression of Endometriosis

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 900-912 ◽  
Author(s):  
Yuechao Zhao ◽  
Yiru Chen ◽  
Ye Kuang ◽  
Milan K. Bagchi ◽  
Robert N. Taylor ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Gene Dosage ◽  
Cell Types ◽  
Host Cells ◽  
Cell Cycle Regulators ◽  
Uterine Tissue ◽  
Donor Tissue ◽  
Ectopic Tissue

Abstract Endometriosis is an estrogen-dependent, inflammation-driven gynecologic disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, leading to pelvic pain and impaired fertility. Although dysregulated estrogen receptor (ER) signaling has been implicated, understanding of this disease is incomplete and current therapies are of limited benefit. Using an immunocompetent syngeneic murine model, we used combinations of donor uterine tissue and/or recipient host mice with partial genetic deletion of the ER coregulator, repressor of ER activity (REA) (also known as prohibitin 2), to investigate roles of REA in the contributions of donor uterine tissue and host cell influences on endometriosis establishment and progression. Ectopic lesions derived from donor tissue with half the wild-type gene dosage of REA (REA+/−) grown in REA+/− hosts displayed enhanced proliferation, vascularization, and markedly increased neuron innervation and inflammatory responses, including elevated cytokine production, nuclear factor kappa B activation, cyclooxygenase-2 expression, and immune cell infiltration. Although lesion progression was greatest when REA was reduced in both donor tissue and host animals, other donor/host combinations indicated that distinct stimulatory inputs were derived from ectopic tissue (proliferative signals) and host cells (inflammatory signals). Importantly, depletion of REA in primary human endometriotic stromal cells led to elevated proliferation and expression of cell cycle regulators. Notably, REA was significantly lower in human endometriotic tissue versus normal human endometrium. Thus, REA modulates cross talk among multiple cell types in the uterine tissue and host background, serving as a brake on the estradiol-ER axis and restraining multiple aspects that contribute to the pathologic progression of endometriosis.

scholarly journals OTME-6. Deep sequencing reveals heterogeneity of brain metastasis-associated macrophages and microglia and uncovers their cell type-specific functions within the tumor microenvironment

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii14-ii14
Author(s):  
Michael Schulz ◽  
Tijna Alekseeva ◽  
Julian Anthes ◽  
Jandranka Macas ◽  
Birgitta Michels ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Whole Brain Radiotherapy ◽  
Cell Types ◽  
Therapy Resistance ◽  
Cell Type ◽  
Cell Functions ◽  
Brain Radiotherapy ◽  
Cell Type Specific

Abstract Macrophages represent a highly plastic cell type,indispensable for tissue and organ homeostasis, as well as innate immunity. Basic and translational research attributed tumor-promoting functions to macrophages, and their presence is often associated to poor patient prognosis and therapy resistance. While brain-resident macrophages, the so-called microglia (MG), represent the major immune cell type in the parenchyma under normal conditions, primary and metastatic brain tumors induce the recruitment of different immune cell types from the periphery, including monocyte-derived macrophages (MDM). Controversy remained about the redundancy of disease-associated molecular signatures and functions. The identification of markers that reliably distinguish brain-resident from blood-borne tumor-associated macrophages (TAMs) allowed the interrogation of molecular traits of different TAM populations in mouse and human brain tumors. Using RNA-Seq, we demonstrated that TAMs rapidly acquire disease-associated transcriptional programs upon initial tumor infiltration, while gene expression remained stable during different stages of BrM progression. Across different BrM models, disease-associated transcriptional changes revealed lineage-specific, non-redundant functions of TAM populations, which was further reflected by cell type-specific occupation of different niches within the BrM microenvironment. Furthermore, we observed dose- and cell type-specific immune modulatory effects of whole brain radiotherapy on myeloid cells in BrM leading to a transient loss of disease-associated transcriptional programs predominately in blood-borne myeloid populations. This effect can at least in part be attributed to a replenishment of the recruited macrophage pool. This observation was further supported by scRNA-Seq analyses revealing higher heterogeneity of TAM-MDM compared to TAM-MG under treatment-naïve conditions and in response to radiotherapy. Together, our results point towards the phenotypic plasticity of TAMs, especially MDMs, and the contribution of each compartment in instigating cancer-associated inflammation or the establishment of an immuno-suppressive TME. While TAM-MG exert functions related to pro-inflammatory responses, TAM-MDM are rather involved in tissue repair and regulation of adaptive immune cell functions.

Oxygen-dependent energetics of anoxia-tolerant and anoxia-intolerant hepatocytes

2000 ◽  
Vol 203 (5) ◽  
pp. 951-959 ◽  
Author(s):  
G. Krumschnabel ◽  
P.J. Schwarzbaum ◽  
J. Lisch ◽  
C. Biasi ◽  
W. Wieser
Keyword(s):  
Acute Hypoxia ◽  
Lactate Production ◽  
Cell Types ◽  
Cellular Respiration ◽  
Metabolic Depression ◽  
Membrane Function ◽  
Goldfish Carassius Auratus ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Rate Of Oxygen Consumption ◽  
Atp Supply

The oxygen-dependence of cellular energetics was investigated in hepatocytes from goldfish Carassius auratus (anoxia-tolerant) and rainbow trout Oncorhynchus mykiss (anoxia-intolerant). In goldfish hepatocytes, an approximately 50 % reduction in the rate of oxygen consumption was observed in response to both acute and prolonged hypoxia, the latter treatment shifting the threshold for this reduction to a higher oxygen level. A concomitant increase in the rate of lactate production did not compensate for the decreased aerobic ATP supply, resulting in an overall metabolic depression of 26 % during acute hypoxia and of 42 % during prolonged hypoxia. Trout hepatocytes showed a similar suppression of cellular respiration after prolonged hypoxia but were unresponsive to acute hypoxia. Similarly, the rate of lactate production was unaltered during acute hypoxia but was increased during prolonged hypoxia, metabolic depression amounting to 7 % during acute hypoxia and 30 % during prolonged hypoxia. In both species, the affinity of hepatocytes for oxygen decreased during hypoxia, but this alteration was not sufficient in absolute terms to account for the observed decrease in aerobic ATP supply. Protein synthesis was suppressed in both cell types under hypoxia, whereas Na(+)/K(+)-ATPase activity decreased in trout but not in goldfish hepatocytes, emphasising the importance of membrane function in these cells during conditions of limited energy supply.

scholarly journals Integrating Mendelian randomization and multiple-trait colocalization to uncover cell-specific inflammatory drivers of autoimmune and atopic disease

2018 ◽  
Author(s):  
Lucy M. McGowan ◽  
George Davey Smith ◽  
Tom R. Gaunt ◽  
Tom G. Richardson
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Analytical Framework ◽  
Receptor Protein ◽  
Cytokine Receptors ◽  
Mendelian Randomisation ◽  
Human Populations ◽  
Multiple Trait ◽  
Causal Pathways

AbstractImmune mediated diseases (IMDs) arise from a lack of immune tolerance, causing chronic inflammation. Despite their growing prevalence, targeted therapies to treat IMDs are lacking. Cytokines and their receptors, which mediate inflammation, have been associated with IMD susceptibility. However, the complex signalling networks and multiple cell-types required to orchestrate inflammatory responses have made it difficult to pinpoint specific cytokines and immune cell-types which drive IMDs.In this study, we developed an analytical framework which integrates Mendelian randomisation (MR) and multiple-trait colocalization (moloc) analyses to determine putative cell-specific drivers of IMDs. We used MR to determine the likelihood of causal associations between the levels of 10 circulating cytokines/cytokine receptors and 9 IMDs within human populations of European descent. Conservative (single SNP) and liberal (multiple SNP) MR analysis supported a causal role for IL-18 in inflammatory bowel disease (P = 1.17 × 10−4) and eczema/dermatitis (P = 2.81 × 10−3), as well as roles for IL-2rα and IL-6R in several IMDs.Where associations between cytokines/cytokine receptors and IMDs were discovered using MR, we undertook moloc analyses. This was to assess the likelihood that cytokine/cytokine receptor protein quantitative trait loci (pQTL) and IMD-associated loci share a causal genetic variant along with expression QTL (eQTL) using data from 3 immune cell-types: monocytes, neutrophils and T cells. We found a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis, amongst evidence supporting several other cell-specific inflammatory drivers of IMDs. Our study helps to elucidate causal pathways for the pathogeneses of IMDs which, together with other studies, highlights possible therapeutic targets for their treatment.

Expression and role of cyclooxygenase isoforms in alveolar and peritoneal macrophages

1995 ◽  
Vol 268 (2) ◽  
pp. L294-L301 ◽  
Author(s):  
J. Wilborn ◽  
D. L. DeWitt ◽  
M. Peters-Golden
Keyword(s):  
Steady State ◽  
Cell Types ◽  
Peritoneal Macrophages ◽  
Prostaglandin Synthesis ◽  
Steady State Levels ◽  
Cox 2 ◽  
Synthetic Capacity ◽  
Cyclooxygenase Isoforms ◽  
Cox 1

Prostaglandin synthesis represents one means by which macrophages modulate inflammation. The initial enzyme in the metabolism of arachidonic acid to prostaglandins is cyclooxygenase (COX). Both constitutive (COX-1) and inducible (COX-2) isoforms are recognized. We previously showed that COX activity of rat peritoneal macrophages (PM) exceeds that of alveolar macrophages (AM). In this study, we correlated the steady-state levels of COX-1 and COX-2 proteins with COX activity in resident AM and PM. Freshly obtained AM contained lower levels of COX-1 than did fresh PM. Neither contained substantial amounts of COX-2 in the basal state, but both cell types demonstrated induction when cultured with lipopolysaccharide; once again, COX-2 levels in PM exceeded those in AM. Despite COX-2 induction under these circumstances, its contribution to prostaglandin production appeared to be modest. We conclude that, although both isoforms of COX are expressed in rat AM and PM, COX-1 is responsible for the majority of enzyme activity in both the basal and stimulated states. The lesser prostaglandin synthetic capacity of AM than of PM appears to be the consequence of lower steady-state levels of both COX proteins.

Key enzymes for renal prostaglandin synthesis: site-specific expression in rodent kidney (rat, mouse)

2003 ◽  
Vol 285 (1) ◽  
pp. F19-F32 ◽  
Author(s):  
Valentina Câmpean ◽  
Franziska Theilig ◽  
Alex Paliege ◽  
Matthew Breyer ◽  
Sebastian Bachmann
Keyword(s):  
Mesangial Cells ◽  
Collecting Duct ◽  
Juxtaglomerular Apparatus ◽  
Cell Types ◽  
Arachidonic Acid Metabolism ◽  
Antigen Retrieval ◽  
Specific Expression ◽  
Key Enzymes ◽  
Cox 2 ◽  
Cox 1

Prostanoids derived from endogenous cylooxygenase (COX)-mediated arachidonic acid metabolism play important roles in the maintenance of renal blood flow and salt and water homeostasis. The relative importance of COX-1 and COX-2 isoforms is under active investigation. We have performed a comprehensive histochemical analysis by comparing rat and mouse kidneys for cellular and subcellular localization of COX-1 and -2 and microsomal-type PGE synthase (PGES), the rate-limiting biosynthetic enzyme in PGE2 synthesis. A choice of different sera was compared, and the results were confirmed by antigen-retrieval techniques, in situ hybridization, RT-PCR, and the use of COX knockout mice. In the glomerulus, significant COX-1 expression was detected in a subset of mesangial cells. Along the renal tubule, the known COX-2 expression in cTAL and macula densa was paralleled by PGES staining. In the terminal distal convoluted tubule, connecting tubule, and cortical and medullary collecting ducts, a significant COX-1 signal was colocalized with PGES; COX-2 was not found in these sites. Intercalated cells were generally negative. Cortical fibroblasts were COX-1 and PGES positive in mice, whereas in rats only PGES could be reliably detected. Lipid-laden interstitial cells of the inner medulla were COX-1, -2, and PGES positive. Vascular smooth muscle cells were not stained. The present data support prominent functions of renal prostanoids, predominantly PGE2, by defining expression sites of the key enzymes for their biosynthesis in the rat and mouse. Results define the renal cell types involved in prostaglandin autacoid functions within spatially restricted sites such as the juxtaglomerular apparatus, mesangium, distal convolutions and collecting duct, and in compartments of the renal interstitium.

scholarly journals Differential Effect of Cyclooxygenases 1 and 2 in Late Reproductive Age Women

2019 ◽  
pp. 13-18
Keyword(s):  
Inflammatory Responses ◽  
Vascular Inflammation ◽  
Bioactive Compound ◽  
Reproductive Age ◽  
Endometrial Cells ◽  
Uterine Contractions ◽  
Reproductive Age Women ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Cyclooxygenases enzymes (COX) are related with ovulation, apoptosis and menstrual disorder. Several studies demonstrate that COX 1 is one of the major sources of prostaglandin but COX 2 is more important in the late reproductive age women. Prostaglandin is bioactive compound excreted from Arachidonic acid by Cox 1 and Cox 2, play role in the fertility and ovulation but when increased above the normal level especially in menstrual cycle, ectopic pregnancy is attributed to this cause. Cox 1 and Cox 2 inhibitors have been regulated the inflammatory responses include cytokines and tumor growth factors which produced from neutrophil cells by cyclooxygenases activation, it has been used to regular prostaglandin action, especially PGG2 and PGH2. Any changes in the endometrial cells lead to increased vascular inflammation that developed to the late reproductive disease. Steroidogenesis characterized by increased levels of estrogen in the uterus caused uterine infections and elevated cyclooxygenases levels especially during uterine contractions process.

scholarly journals Competitive Control of Independent Programs of Tumor Necrosis Factor Receptor-Induced Cell Death by TRADD and RIP1

2006 ◽  
Vol 26 (9) ◽  
pp. 3505-3513 ◽  
Author(s):  
Lixin Zheng ◽  
Nicolas Bidere ◽  
David Staudt ◽  
Alan Cubre ◽  
Jan Orenstein ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis Factor ◽  
Cell Fate ◽  
Tumor Necrosis ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Types ◽  
Death Domain ◽  
Necrosis Factor

ABSTRACT Stimulation of tumor necrosis factor receptor 1 (TNFR1) can initiate several cellular responses, including apoptosis, which relies on caspases, necrotic cell death, which depends on receptor-interacting protein kinase 1 (RIP1), and NF-κB activation, which induces survival and inflammatory responses. The TNFR-associated death domain (TRADD) protein has been suggested to be a crucial signal adaptor that mediates all intracellular responses from TNFR1. However, cells with a genetic deficiency of TRADD are unavailable, precluding analysis with mature immune cell types. We circumvented this problem by silencing TRADD expression with small interfering RNA. We found that TRADD is required for TNFR1 to induce NF-κB activation and caspase-8-dependent apoptosis but is dispensable for TNFR1-initiated, RIP1-dependent necrosis. Our data also show that TRADD and RIP1 compete for recruitment to the TNFR1 signaling complex and the distinct programs of cell death. Thus, TNFR1-initiated intracellular signals diverge at a very proximal level by the independent association of two death domain-containing proteins, RIP1 and TRADD. These single transducers determine cell fate by triggering NF-κB activation, apoptosis, and nonapoptotic death signals through separate and competing signaling pathways.

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