Recent Progress in the Cellular and Molecular Biology of Prostaglandin Synthesis
Section snippets
• Prostaglandins and Prostaglandin Synthases Play a Central Role in Many Biological Processes
Nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin and ibuprofen, are used to treat pain, fever, chronic inflammatory diseases, acute infection, and a variety of other illnesses. In addition, aspirin is able to reduce substantially the morbidity of colon cancer (Thun et al. 1991). With the discovery that aspirin and the other NSAIDs block the production of prostaglandins by inhibiting the activity of prostaglandin synthase [reviewed by Vane (1994)], this enzyme became implicated in a
• The Discovery of an Inducible Prostaglandin Synthase, PGS2, Created a Paradox Regarding Prostaglandin Synthesis
Until recently, the conventional view of prostanoid synthesis has been that the rate-limiting step for prostaglandin production is the ligand-stimulated activation of latent phospholipase(s), which then releases free arachidonic acid from membrane phospholipids. According to this model, constitutive prostaglandin synthase is available for conversion of free arachidonic acid, released from membrane phospholipids, to PGH2; PGS is present in excess, and the availability of free arachidonic acid is
• Prostaglandin Synthase 2 Plays a Major Role in Production of Prostanoids in Inflammatory Reactions and Is the Primary Target of Most Nonsteroidal Antiinflammatory Drugs
Studies with animal models (Masferrer et al. 1996) demonstrated that, in vivo, acute and chronic inflammatory responses are accompanied by PGS2 induction. The major side effects of aspirin and the majority of other NSAIDs, namely, gastric ulcers and nephrotoxicity, are now thought to occur as a result of their inhibition of the constitutive PGS1 enzyme. With the discovery of PGS2, and the demonstration that this enzyme is induced by inflammatory stimuli, the pharmaceutical industry entered into
• Ligand-Stimulated Prostaglandin Synthesis in Fibroblasts and Macrophages Requires PGS2 Synthesis and Activity
PGE2 production in mitogen-stimulated fibroblasts or endotoxin-treated macrophages begins slowly, after an initial lag phase, and accelerates during a 2- to 6-hour period (Kujubu and Herschman 1992, Herschman 1996). During our initial characterization of PGS2 enzyme production following ligand stimulation, we showed that mitogen-induced enzyme accumulation in 3T3 fibroblasts was, as expected, blocked by cycloheximide treatment to block protein synthesis. In addition, cycloheximide prevented
• Mast Cell Experiments Demonstrate Two Distinct Pathways of Prostaglandin Synthesis
Aggregation of mast cell IgE receptors leads to degranulation and the release of histamine and serotonin. In addition, activation of mast cells induces the synthesis and secretion of PGD2. We found that activated mast cells produce PGD2 in two distinct phases (Kawata et al. 1995). The early phase of PGD2 synthesis is complete within 10–15 minutes. The delayed phase begins at about 1–2 hours after activation and is completed within 6–8 hours (Fig. 1). Using PGS1 and PGS2 inhibitors, we
• Type V sPLA2 Mediates the Early Phase of PGD2 Production in Activated Mast Cells
Type IIa sPLA2 had been thought to be the isoform that mediates PGD2 release in activated macrophages (Fonteh et al. 1994). However, mast cells from mice homozygous for a mutation in the PLA2G2A gene, encoding type IIa sPLA2, produce PGD2 normally after activation (Bingham et al. 1996, Reddy et al. 1997). Moreover, sPLA2 activity is secreted by mast cells derived from type IIa sPLA2 mutant mice after activation (Reddy et al. 1997). Northern blot and polymerase chain reaction analysis
• sPLA2 Released from Activated Mast Cells Initiates Transcellular Prostaglandin Synthesis
We speculated that sPLA2, released from mast cells in response to aggregation of IgE receptors, might transcellularly activate prostaglandin synthesis in distal cells via a PGS1-mediated pathway (Fig. 3). Using mixed mast cell/fibroblast cell cultures, sPLA2 inhibitors, and mast cell supernatants, we demonstrated that type V sPLA2 released from activated mast cells can induce rapid, PGS1-dependent PGE2 synthesis in fibroblasts. Moreover, this “transcellular” prostaglandin synthesis uses
• Aspirin-Modified PGS2 Plays a Role in the Transcellular Synthesis of a New Class of Antiinflammatory and Antiproliferative Compounds
Aspirin inhibits both PGS1 and PGS2 by covalently modifying specific serine residues in these enzymes. In contrast, most other NSAIDs do not covalently modify the PGS enzymes. Aspirin acetylation of PGS1 blocks essentially all conversion of arachidonic acid to any product. In contrast, aspirin-acetylated PGS2 converts arachidonic acid to (15R)-15-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid (15R-HETE), rather than to PGG2 (Holtzman et al. 1992, Meade et al. 1993,
Mancini et al. 1994,
• Key Regulatory Elements of the PGS2 Gene, Transcription Factors Mediating Ligand-Induced PGS2 Gene Expression, and Signal Transduction Pathways Leading to PGS2 Gene Expression Have Been Identified
We cloned and sequenced the 5′ regulatory region of the murine PGS2 gene (Fletcher et al. 1992). Using deletion analysis, with chimeric luciferase reporter constructs, we identified the region of the PGS2 promoter required for v-src (Xie et al. 1994) and platelet-derived growth factor (Xie and Herschman 1996) induction. Mutational analysis identified the cAMP response element (CRE) present at nucleotides −56 to −48 from the transcription start site as the critical cis-acting element of the PGS2
Acknowledgements
The preparation of this article was supported by grants (H.R.H.) from the National Institute of Allergy and Infectious Diseases, the National Institute of Environmental Health Sciences, and the National Institute of General Medical Sciences.
References (40)
- et al.
Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10 encoded protein is a functional prostaglandin G/H synthase
J Biol Chem
(1992) Prostaglandin synthase 2
Biochim Biophys Acta
(1996)- et al.
Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines
J Biol Chem
(1993) - et al.
Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene
J Biol Chem
(1992) - et al.
Mutation of serine-516 in human prostaglandin G/H synthase-2 to methionine or aspirin acetylation of this residue stimulates 15-R-HETE synthesis
FEBS Lett
(1994) - et al.
Cyclooxygenase-2 inhibitors: a new class of anti-inflammatory agents that spare the gastrointestinal tract
Gastroenterol Clin North Am
(1996) - et al.
Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs
J Biol Chem
(1993) - et al.
Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase)
J Biol Chem
(1988) - et al.
Transcellular prostaglandin production following mast cell activation is mediated by proximal secretory phospholipase A2 and distal prostaglandin synthase 1
J Biol Chem
(1996) - et al.
Prostaglandin synthase-1 and prostaglandin synthase-2 are coupled to distinct phospholipases for the generation of prostaglandin D2 in activated mast cells
J Biol Chem
(1997)
Prostaglandin endoperoxide synthase: structure and catalysis
Biochim Biophys Acta
Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions
Proc Natl Acad Sci USA
Aspirin-triggered lipoxins (15-epi-LX) are generated by the human lung adenocarcinoma cell line (A549)-neutrophil interactions and are potent inhibitors of cell proliferation
Mol Med
Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence
Proc Natl Acad Sci USA
Cloning and characterization of a growth factor-inducible cyclooxygenase gene from rat intestinal epithelial cells
Am J Physiol
Evidence that secretory phospholipase A2 plays a role in arachidonic acid release and eicosanoid biosynthesis by mast cells
J Immunol
Primary response genes induced by growth factors and tumor promoters
Annu Rev Biochem
Human cyclooxygenase-2 cDNA
Proc Natl Acad Sci USA
Cited by (21)
Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology
2017, Molecular Aspects of MedicineCitation Excerpt :Although the proinflammatory roles of LT and PG are well appreciated (Marcus, 1999; Weissmann, 1991), new evidence emerged regarding other eicosanoids derived from arachidonate, namely lipoxins (LXs) and their endogenous analogs, the aspirin-triggered 15-epimer lipoxins (ATL), potent counterregulators of PMN-mediated injury and acute inflammation (Chiang et al., 1999; Clària and Serhan, 1995; Serhan et al., 1995). Acetylation of COX-2 by aspirin (ASA) prevents the formation of prostanoids (Herschman, 1998), but the acetylated enzyme remains active in situ, generating 15R-hydroeicosatetraenoic acid (15R-HETE) from C20:4 (Chiang et al., 1998; Xiao et al., 1997), which is converted by inflammatory cells to 15-epimeric lipoxins (ATL, a.k.a. aspirin-triggered lipoxins). Synthetic analogs of these natural local mediators with prolonged bio-half-life display potent anti-inflammatory properties (Chiang et al., 1999; Clish et al., 1999; Serhan, 1999), providing evidence that cell-cell “cross-talk” can convert arachidonic acid to mediators with anti-inflammatory properties (Serhan et al., 2000b), thus changing our view of the mechanism of action of this drug.
Lipoxins and Aspirin-Triggered 15-epi-Lipoxins: Mediators in Anti-inflammation and Resolution
2003, Handbook of Cell Signaling: Volume 1-3Colonic anti-inflammatory mechanisms of conjugated linoleic acid
2002, Clinical NutritionDiesel exhaust particle extracts and associated polycyclic aromatic hydrocarbons inhibit Cox-2-dependent prostaglandin synthesis in murine macrophages and fibroblasts
2002, Journal of Biological ChemistryCitation Excerpt :Dose-response curves suggest that PQ may be a slightly better inhibitor than the other PAHs (data not shown), but differences in inhibitory activity among the various PAHs are not striking. Prostaglandin production in response to ligand stimulation is usually dependent on COX-2 induction (12, 26). The induction pathway leading to COX-2 expression is similar in fibroblasts (27), mast cells (28), and osteoblasts (29) but differs from these cell types in endotoxin-stimulated macrophages (30).
Developments in specific cyclooxygenase therapy for acute pain
2002, Acute PainLipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: An update and role in anti-inflammation and pro-resolution
2002, Prostaglandins and Other Lipid Mediators