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Studies of Prostaglandin E Formation in Human Monocytes

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Studies of Prostaglandin E Formation in Human Monocytes Faculty of Technology and Science Biomedical Sciences Sofia Karlsson Studies of prostaglandin E2 formation in human monocytes Karlstad University Studies 2009:43 Sofia Karlsson Studies of prostaglandin E2 formation in human monocytes Karlstad University Studies 2009:43 Sofia Karlsson Studies of prostaglandin E2 formation in human monocytes Licentiate thesis Karlstad University Studies 2009:43 ISSN 1403-8099 ISBN 978-91-7063-266-2 © The Author Distribution: Faculty of Technology and Science Biomedical Sciences SE-651 88 Karlstad +46 54 700 10 00 www.kau.se Printed at: Universitetstryckeriet, Karlstad 2009 ABSTRACT Prostaglandin (PG) E 2 is an eicosanoid derived from the polyunsaturated twenty carbon fatty acid arachidonic acid (AA). PGE 2 has physiological as well as pathophysiological functions and is known to be a key mediator of inflammatory responses. Formation of PGE 2 is dependent upon the activities of three specific enzymes involved in the AA cascade; phospholipase A 2 (PLA 2), cyclooxygenase (COX) and PGE synthase (PGEs). Although the research within this field has been intense for decades, the regulatory mechanisms concerning the PGE 2 synthesising enzymes are not completely established. PGE 2 was investigated in human monocytes with or without lipopolysaccharide (LPS) pre-treatment followed by stimulation with calcium ionophore, opsonised zymosan or phorbol myristate acetate (PMA). Cytosolic PLA 2α (cPLA 2α) was shown to be pivotal for the mobilization of AA and subsequent formation of PGE 2. Although COX-1 was constitutively expressed, monocytes required expression of COX-2 protein in order to convert the mobilized AA into PGH 2. The conversion of PGH 2 to the final product PGE 2 was to a large extent due to the action of microsomal PGEs-1 (mPGEs-1). In addition, experiments with inhibitors of extracellular signal regulated kinase and p38 activation, indicated that phosphorylation of cPLA 2α was markedly advantageous for the formation of PGE 2. Ellagic acid, a natural polyphenolic compound found in fruits and nuts, was shown to inhibit stimuli induced release of PGE2 in human monocytes. The effect of ellagic acid was not due to a direct effect on the activities of the enzymes but rather to inhibition of the LPS-induced protein expression of COX-2, mPGEs-1 and cPLA 2α. i LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals I. Karlsson, S . and Wijkander, J. Requirement of cyclooxygenase-2 expression for cytosolic phospholipase A 2 mediated prostaglandin E 2 formation in human monocytes. Manuscript II Karlsson, S ., Nånberg, E., Fjaeraa, C. and Wijkander, J. (2009) Ellagic acid inhibits lipopolysaccharide-induced expression of enzymes involved in the synthesis of prostaglandin E 2 in human monocytes. British Journal of Nutrition. Accepted. Grant Support : This study was supported by grants from Värmland County Council and the Royal Swedish Academy of Sciences. ii ABBREVIATIONS AA Arachidonic acid [3H]AA Tritiated arachidonic acid AP Activating protein BEL Bromoenol lactone CBR Calcium binding regions COX Cyclooxygenase cPGEs Cytosolic prostaglandin E synthase cPLA 2 Cytosolic phospholipase A 2 Egr-1 Early growth response factor -1 ERK Extracellular signal-regulated kinase GRE Glucocorticoid response element HETE Hydroxyeicosatetraenoic acid HPETE Hydroperoxyeicosatetraenoic acid IL Interleukin iPLA 2 Calcium independent phospholipase A 2 IκB Inhibitor kappa B LO Lipoxygenase LPS Lipopolysaccharide LT Leukotriene MAPK Mitogene activated protein kinase mPGEs Microsomal prostaglandin E synthase NF κB Nuclear factor kappa B NSAIDs Non-steroidal anti-inflammatory drugs PG Prostaglandin PGEs Prostaglandin E synthase PIP2 Phosphatidylinositol 4,5-bisphosphate PKC Protein kinase C PC Phosphatidylcholine PLA 2 Phospholipase A 2 PMA Phorbol myristate acetate sn Stereospecific nomenclature sPLA 2 Secretory phospholipase A 2 TNF α Tumor necrosis factor alfa TX Thromboxane iii TABLE OF CONTENTS ABSTRACT..................................................................................................i LIST OF PUBLICATIONS .......................................................................ii ABBREVIATIONS ...................................................................................iii TABLE OF CONTENTS .........................................................................iv INTRODUCTION..................................................................................... 1 Monocytes and their role in inflammation............................................. 1 Arachidonic acid and eicosanoids.......................................................... 2 From phospholipids to the final product prostaglandin E 2 ................... 2 Phospholipase A 2 .................................................................................... 3 Intracellular phospholipase A 2 ..............................................................................4 Cytosolic phospholipase A 2 .............................................................................4 Calcium independent phospholipase A 2 .......................................................6 Secretory phospholipase A 2 ...................................................................................7 Cyclooxygenases ..................................................................................... 8 Cyclooxygenase-1.....................................................................................................9 Cyclooxygenase-2...................................................................................................10 Cyclooxygenase-3...................................................................................................10 Differences between cyclooxygenase-1 and cyclooxygenase-2....................11 Cyclooxygenase inhibitors ...................................................................................12 Prostaglandin E synthases.................................................................... 12 Microsomal prostaglandin E synthase-1...........................................................13 Microsomal prostaglandin E synthase-2...........................................................14 Cytosolic prostaglandin E synthase ...................................................................14 Prostaglandin E 2 ................................................................................... 15 PRESENT INVESTIGATION ............................................................... 17 Background and aim............................................................................. 17 Methodology ......................................................................................... 19 Results and discussion.......................................................................... 22 Conclusions........................................................................................... 31 ACKNOWLEDGEMENTS ..................................................................... 32 REFERENCES ........................................................................................ 33 iv INTRODUCTION Monocytes and their role in inflammation Inflammation is an important part of our defence against pathological agents that we more or less are constantly exposed to. The inflammatory response is dependent on the production of different cytokines, chemokines and eicosanoids [1-3]. These inflammatory mediators are produced in a tightly regulated way primarily in white blood cells, leukocytes. Monocytes are large leukocytes of the myeloid lineage, circulating in the peripheral bloodstream. Upon activation, due to infection or mechanically damaged tissue, the monocytes migrate to the site of inflammation, penetrate the arterial wall and enter the surrounding tissue where they may differentiate into long-lived macrophages or dendritic cells [4]. Once at the infected area, monocytes act as professional phagocytes and recognise infecting agents via specific receptors. Subsequently, these agents are destroyed by degrading enzymes and fragments of the phagocytosed material are presented on the surface of the monocytes allowing lymphocytes to recognise them and initiate the adaptive immune response [5]. Furthermore, monocytes produce a variety of different pro-inflammatory mediators, such as interleukin (IL)-1, tumor necrosis factor alfa (TNFα) and different eicosanoids, which may act stimulating in an autocrine or paracrine way or act as recruiters of other cells important for the inflammatory response [6]. Monocytes expressing large amounts of CD14 but not CD16 on their surface are referred to as classical monocytes. The non-classical monocytes, which are CD14 as well as CD16 positive, are known as highly pro-inflammatory and represent, under normal conditions, about 10 % of the peripheral blood monocytes [7]. However, the amount of these cells can increase dramatically during inflammation. Monocytes have also been ascribed a role in the resolution of inflammation by producing for example anti-inflammatory mediators such as IL-10 [8]. This is highly important although inflammation is our essential defense against pathogens, if not tightly regulated, this defense can become our enemy. Chronic inflammation is a part of the cause for several more or less severe diseases, where elevated levels of the enzymes involved in the 1 arachidonic acid (AA) cascade as well as the produced metabolites, the eicosanoids, have been detected. Arachidonic acid and eicosanoids AA (20:4n-6; AA)
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