BIOMAT Database Logo BIOMAT Database Logo

E-ring 8-isoprostanes are agonists at EP2- and EP4-prostanoid receptors on human airway smooth muscle cells and regulate the release of colony-stimulating factors by activating cAMP-dependent protein kinase. 2005

Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Thoraic Medicine, National Heart and Lung Institute, Imperial College London, London, UK.

8-Isoprostanes are bioactive lipid mediators formed via the nonenzymatic peroxidation of arachidonic acid by free radicals and reactive oxygen species. However, their cognate receptors, biological actions, and signaling pathways are poorly studied. Here, we report the effect of a variety of E- and Falpha-ring 8-isoprostanes on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) from human airway smooth muscle (HASM) cells stimulated with interleukin-1beta (IL-1beta). The elaboration of GM-CSF and G-CSF by IL-1beta was inhibited and augmented, respectively, in a concentration-dependent manner by 8-iso-prostaglandin (PG) E(1) and 8-iso-PGE(2), but not by 8-iso-PGF(1alpha), 8-iso-PGF(2alpha), and 8-iso-PGF(3)alpha. AH 6809 (6-isopropoxy-9-oxoxanthine-2-carboxylic acid), an EP(1)-/EP(2)-/DP-receptor blocking drug, antagonized the inhibitory effect of 8-iso-PGE(1) and 8-iso-PGE(2) on GM-CSF output with an affinity consistent with an interaction at prostanoid receptors of the EP(2)-subtype. In contrast, the facilitation by 8-iso-PGE(1) and 8-iso-PGE(2) of G-CSF release was unaffected by AH 6809 and the selective EP(4)-receptor antagonist L-161,982 [4'-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]. However, when used in combination, AH 6809 and L-161,982 displaced 5-fold to the right the 8-iso-PGE and 8-iso-PGE concentration-response curves. The opposing (1)effect of E-ring (2)8-isoprostanes on GM-CSF and G-CSF release was mimicked by 8-bromo-cAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). Together, these data demonstrate that E-ring 8-isoprostanes regulate the secretion of GM-CSF and G-CSF from HASM cells by a cAMP- and PKA-dependent mechanism. Moreover, antagonist studies revealed that 8-iso-PGE(1) and 8-iso-PGE(2) act solely via EP(2) -receptors to inhibit GM-CSF release, whereas both EP(2)- and EP(4)-receptor subtypes positively regulate G-CSF output.

UI MeSH Term Description Entries
D008297 Male Males
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D003115 Colony-Stimulating Factors Glycoproteins found in a subfraction of normal mammalian plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include INTERLEUKIN-3; (IL-3); GRANULOCYTE COLONY-STIMULATING FACTOR; (G-CSF); MACROPHAGE COLONY-STIMULATING FACTOR; (M-CSF); and GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR; (GM-CSF). MGI-1,Macrophage-Granulocyte Inducer,Colony Stimulating Factor,Colony-Stimulating Factor,MGI-1 Protein,Myeloid Cell-Growth Inducer,Protein Inducer MGI,Cell-Growth Inducer, Myeloid,Colony Stimulating Factors,Inducer, Macrophage-Granulocyte,Inducer, Myeloid Cell-Growth,MGI 1 Protein,MGI, Protein Inducer,Macrophage Granulocyte Inducer,Myeloid Cell Growth Inducer
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000293 Adolescent A person 13 to 18 years of age. Adolescence,Youth,Adolescents,Adolescents, Female,Adolescents, Male,Teenagers,Teens,Adolescent, Female,Adolescent, Male,Female Adolescent,Female Adolescents,Male Adolescent,Male Adolescents,Teen,Teenager,Youths
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults

Related Publications

Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Prostanoid receptors EP2, EP4, and FP are regulated by estradiol in bovine oviductal smooth muscle.
September 2015, Prostaglandins & other lipid mediators,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Vascular endothelial growth factor induction by prostaglandin E2 in human airway smooth muscle cells is mediated by E prostanoid EP2/EP4 receptors and SP-1 transcription factor binding sites.
August 2005, The Journal of biological chemistry,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Functional pharmacology of human prostanoid EP2 and EP4 receptors.
October 2004, European journal of pharmacology,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Beta-adrenergic agonists regulate KCa channels in airway smooth muscle by cAMP-dependent and -independent mechanisms.
January 1994, The Journal of clinical investigation,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Characterization of contractile prostanoid receptors on human airway smooth muscle.
June 1989, European journal of pharmacology,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Release of granulocyte-macrophage colony stimulating factor by human cultured airway smooth muscle cells: suppression by dexamethasone.
February 1997, British journal of pharmacology,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Ca(2+) signals evoked by histamine H1 receptors are attenuated by activation of prostaglandin EP2 and EP4 receptors in human aortic smooth muscle cells.
August 2013, British journal of pharmacology,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Regulation of cAMP content and cAMP-dependent protein kinase activity in airway smooth muscle.
January 1987, Progress in clinical and biological research,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Compartmentalized cAMP responses to prostaglandin EP2 receptor activation in human airway smooth muscle cells.
August 2017, British journal of pharmacology,
Deborah L Clarke, and Maria G Belvisi, and Elizabeth Hardaker, and Robert Newton, and Mark A Giembycz
Differential regulation of phosphorylation of the cAMP response element-binding protein after activation of EP2 and EP4 prostanoid receptors by prostaglandin E2.
July 2005, Molecular pharmacology,
Copied contents to your clipboard!