Where is pge2 made

Another prostaglandin called prostacyclin has the opposite effect to thromboxane, reducing blood clotting and removing any clots that are no longer needed; it also causes the muscle in the blood vessel wall to relax, so that the vessel dilates. The opposing effects that thromboxane and prostacyclin have on the width of blood vessels can control the amount of blood flow and regulate response to injury and inflammation.

Indeed, manufactured forms of prostaglandins - most commonly prostaglandin E 2 - can be used to induce kick-start labour. The chemical reaction that makes the prostaglandins involves several steps; the first step is carried out by an enzyme called cyclooxygenase.

There are two main types of this enzyme: cyclooxygenase-1 and cyclooxygenase When the body is functioning normally, baseline levels of prostaglandins are produced by the action of cyclooxygenase When the body is injured or inflammation occurs in any area of the body , cyclooxygenase-2 is activated and produces extra prostaglandins, which help the body to respond to the injury. The presence of these receptors in different organs throughout the body allows the different actions of each prostaglandin to be carried out, depending on which receptor they interact with.

Prostaglandins are very short-lived and are broken down quickly by the body. They only carry out their actions in the immediate vicinity of where they are produced; this helps to regulate and limit their actions. High levels of prostaglandins are produced in response to injury or infection and cause inflammation, which is associated with the symptoms of redness, swelling, pain and fever.

This means that drugs, which specifically block cyclooxygenase-2, can be used to treat conditions such as arthritis, heavy menstrual bleeding and painful menstrual cramps.

There is also evidence to suggest that these drugs may have a beneficial effect when treating certain types of cancer, including colon and breast cancer, however research in this area is still ongoing. New discoveries are being made about cyclooxygenases which suggest that cyclooxygenase-2 is not just responsible for disease but has other functions.

Jost, S. Control of human viral infections by natural killer cells. Kabashima, K. Prostaglandin E 2 -EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Kalinski, P. Regulation of immune responses by prostaglandin E 2. ILdeficient dendritic cells, generated in the presence of prostaglandin E 2 , promote type 2 cytokine production in maturing human naive T helper cells.

Kanai, N. Identification and characterization of a prostaglandin transporter. Katze, M. Viruses and interferon: a fight for supremacy. Kawai, T. Pathogen recognition with TLRs. Innate immune recognition of viral infection. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.

Kirkpatrick, P. Oestrogen activates COX2 pathway Blocking the route to infection. Discovery 4, — Kline, J. Synergistic activation of the human cytomegalovirus major immediate early promoter by prostaglandin E 2 and cytokines. Lung Res. Konson, A. Cancer Gene Ther. Koonin, E. The ancient virus world and evolution of cells. Direct Krause, P. Blood , — Kuno, S. Prostaglandin E 2 , a seminal constituent, facilitates the replication of acquired immune deficiency syndrome virus in vitro.

Legler, D. Prostaglandin E 2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. Leslie, C. Regulation of the specific release of arachidonic acid by cytosolic phospholipase A 2.

Prostaglandins Leukot. Fatty Acids 4, — Litman, G. Reconstructing immune phylogeny: new perspectives. Liu, L. Influenza A virus induces interleukin through cyclooxygenase-2 and protein kinase A signaling. Liu, T. Virology , 12— Luczak, M. Inhibition of multiplieation of parainfluenza 3 virus in prostaglandin-treated WISH cells. Mackay, I. Innate immunity. MacKenzie, K. Mahic, M. Mailliard, R. October , — Murakami, M. Recent advances in molecular biology and physiology of the prostaglandin E 2 -biosynthetic pathway.

Lipid Res. Prostaglandin E synthase: a novel drug target for inflammation and cancer. Muthuswamy, R. Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation.

Napolitani, G. Nasrallah, R. Chronic kidney disease: targeting prostaglandin E2 receptors. Nishigaki, N. Two Gs-coupled prostaglandin E receptor subtypes, EP2 and EP4, differ in desensitization and sensitivity to the metabolic inactivation of the agonist. Nokta, M. Human cytomegalovirus-induced immunosuppression relationship to and prostaglandin E 2 in human monocytes.

Invest 97, — PubMed Abstract. Obermajer, N. Positive feedback between PGE 2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Olivier, M. Orange, J. Human natural killer cell deficiencies and susceptibility to infection.

Owaki, T. STAT3 is indispensable to ILmediated cell proliferation but not to ILinduced Th1 differentiation and suppression of proinflammatory cytokine production. Park, J. Identification of novel membrane-associated prostaglandin E synthase-1 mPGES-1 inhibitors with anti-influenza activities in vitro.

Prostaglandin E 2 synthesis and secretion: the role of PGE 2 synthases. Pasare, C. Toll-like receptors: linking innate and adaptive immunity. Phipps, R. A new view of prostaglandin E regulation of the immune response. Today 12, — Reid, G. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs.

Ricciotti, E. Prostaglandins and inflammation. Immunomodulators released during rotavirus infection of polarized Caco-2 cells. Viral Immunol. Romagnani, S. Type 1 T helper and type 2 T helper cells: functions, regulation and role in protection and disease. Rossen, J. Inhibition of cyclooxygenase activity reduces rotavirus infection at a postbinding step.

Rouse, B. Immunity and immunopathology to viruses: what decides the outcome? Russel, F. Trends Pharmacol. Samikkannu, T. Immunopathogenesis of HIV infection in cocaine users: Role of arachidonic acid.

Samuel, C. Antiviral actions of interferons. Sant, A. Inhibition of cyclooxygenase activity blocks cell-to-cell spread of human cytomegalovirus. Schuster, V. Prostaglandin transport. Serezani, C. Serhan, C. Success of prostaglandin E 2 in structure-function is a challenge for structure-based therapeutics. Sharma, S. Simkin, N. Inhibition of human B cell responsiveness by prostaglandin E 2. Smith, W. The eicosanoids and their biochemical mechanisms of action.

Snijdewint, F. Prostaglandin E 2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. Sonnenfeld, G.

The role of interferon in viral infections. Springer Semin. Soontrapa, K. Prostaglandin E 2 -prostaglandin E receptor subtype 4 EP4 signaling mediates UV irradiation-induced systemic immunosuppression. Stavnezer, J. Evolution of isotype switching. Steinman, R. Some interfaces of dendritic cell biology. APMIS , — Sugimoto, Y. Prostaglandin E receptors. Distribution and function of prostanoid receptors: studies from knockout mice. Sun, H. Increased Th17 cells contribute to disease progression in patients with HBV-associated liver cirrhosis.

Tai, H. Prostaglandin catabolizing enzymes. Takeuchi, O. Innate immunity to virus infection. Thiry, E. Thivierge, M. Prostaglandin E 2 induces resistance to human immunodeficiency virus-1 infection in monocyte-derived macrophages: downregulation of CCR5 expression by cyclic adenosine monophosphate. Blood 92, 40— Tung, W. Prostaglandin-E 2 is a potent inhibitor of human interleukin 12 production.

Vivier, E. Functions of natural killer cells. Walker, J. Oncolytic herpes simplex virus 1 encoding prostaglandin dehydrogenase mitigates immune suppression and reduces ectopic primary and metastatic breast cancer in mice. Walker, W. Immunology , — Walsh, P. A randomized placebo controlled trial of Ibuprofen for respiratory syncytial virus infection in a bovine nodel.

Wang, H. Xagorari, A. Toll-like receptors and viruses: induction of innate antiviral immune responses. Open Microbiol. Xie, H. Potent cell growth inhibitory effects in hepatitis B virus X protein positive hepatocellular carcinoma cells by the selective cyclooxygenase-2 inhibitor celecoxib. Xie, Y. FEMS Immunol. Xu, X. Prostaglandin E 2 suppresses lipopolysaccharide-stimulated IFN- production.

Xue-Song, L. Changes of Treg and Th17 cells balance in the development of acute and chronic hepatitis B virus infection. BMC Gastroenterol. Yamashiro, Y. Prostaglandins in the plasma and stool of children with rotavirus gastroenteritis. Yang, B. Increased Th17 cells and interleukin contribute to immune activation and disease aggravation in patients with chronic hepatitis B virus infection.

Zambrano-Zaragoza, J. Th17 Cells in Autoimmune and Infectious Diseases. Zhu, H. Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication.

Zijlstra, R. Malnutrition modifies pig small intestinal inflammatory responses to rotavirus. Zurier, R. Mackey, N. Rose, B. Diamond, and A. Keywords: inflammation, prostaglandin E 2 , immunity, viral infection, therapeutic agents. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. Pohl, PohlCH ufs. Sander , Hester G. Multiple bacterial pathogens elicit an increase in PGE 2 production upon infection. Levels of PGE 2 are highly regulated in the lung and gastrointestinal tract to maintain the integrity of the mucosal barrier Takeuchi et al.

In fact, enhanced PGE 2 synthesis by immune cells appears to be a conserved event during bacterial infections within the mucosa, and this will be discussed in the following sections.

Salmonella is a Gram-negative facultative intracellular bacillus that is able to infect and survive inside several cell types including intestinal epithelial cells and macrophages. Several serotypes of Salmonella including S. One of Salmonella 's most well-characterized virulence factors is the pathogenicity island 2 SPI This pathogenicity island is necessary for growth within the macrophage and is an important virulence factor in establishing infection in mice Ochman et al.

Salmonella -induced PGE 2 activates the protein kinase A PKA pathway and upregulates IL production by macrophages, promoting an immunosuppressive phenotype and impaired killing ability.

COX inhibition by indomethacin or SC restores the bactericidal properties of macrophages during Salmonella infection in vitro Uchiya and Nikai, Salmonella dam mutants are unable to promote COX-2 expression, leading to reduced PGE 2 production in infected murine macrophages Cristina Cerquetti et al. During experimental salmonellosis with S. At early stages of acute infection in the mouse model, COX-2 inhibition with celecoxib leads to an increase in bacterial loads in the mesenteric lymph nodes; however, at later stages of infection, COX-2 inhibition enhances host survival Bowman and Bost, Thus, while PGE 2 may have beneficial proinflammatory properties during acute Salmonella infection, prolonged exposure to PGE 2 may be detrimental and promote an environment susceptible to chronic disease.

Enteropathogenic E. This also suggests bacteria utilize active signaling mechanisms to exploit PGE 2 for intracellular survival. High concentrations of E. Accordingly, COX-2 inhibition may represent a therapeutic strategy in controlling infection with pathogenic E.

It is not surprising that additional enteric pathogens are able to elicit a PGE 2 response upon infection. Vibrio cholerae is an enteric bacterial pathogen whose infection leads to acute watery diarrhea and an increase in PGE 2 secretion in infected intestinal tissues. Specifically, jejunal fluids from patients presenting with acute cholera infection contain increased concentrations of PGE 2 Speelman et al. Both children and adults infected with V. However, there is no significant difference in plasma PGE 2 levels in these patients, suggesting the PGE 2 response is restricted to the infected mucosa Qadri et al.

Similarly, stimulation of isolated intestinal rabbit cells with CT leads to an increase in PGE 2 concentrations Peterson et al. Other enteric bacterial pathogens demonstrate an ability to induce PGE 2 production by infected cells. Both pediatric and adult patients presenting with acute shigellosis exhibit significantly higher concentrations of PGE 2 in stool samples when compared to healthy controls Raqib et al. Further studies must be conducted in order to determine the mechanisms by which enteric pathogens elicit PGE 2 production in infected cells.

Moreover, it will be necessary to determine how PGE 2 concentrations affect both the host immune response and bacterial pathogenesis at various stages of enteric infection. Mycobacteria are acid-fast bacilli that cause progressive or latent pulmonary disease after aerosol inhalation Torrado et al. Several Mycobacteria species induce PGE 2 production during infection.

In the mouse model, M. In particular, the presence of PGE 2 has been noted in the sera and cerebrospinal fluid of tuberculosis patients Bansal et al. Mice infected with M. Granuloma formation, a hallmark of tuberculosis infection, is comprised of macrophages exhibiting high levels of COX-2 expression and PGE 2 synthesis in the mouse model Rangel Moreno et al. Interestingly, the avirulent M.

Similar results were reported by Rangel Moreno et al. Clearly modulation of PGE 2 can impact disease outcome during M. Therapeutic strategies targeting PGE 2 may lead to alternative therapies in controlling Mycobacterium infection in the lung. Community-acquired pneumonia is one of the leading causes of death worldwide Finch, , and is most commonly caused by S.

Similarly, AECs, alveolar macrophages, and vascular endothelial cells of human lung tissue in vitro exhibit time-dependent increases in both COX-2 expression and PGE 2 production post-infection with S. Streptococcal toxins also promote PGE 2 production in immune cells. Particularly, pneumolysin produced by S. Enhanced PGE 2 production by neutrophils treated with pneumolysin inhibits an effective immune response by obstructing neutrophil activation and migration Takenawa et al.

Inhibiting PGE 2 production during Streptococcus infection enhances macrophage phagocytosis and generation of reactive oxygen species, aiding in bacterial clearance Stables et al.

Animal survival may be associated with a heightened production of pro-inflammatory cytokines, such as ILp40 Aronoff et al. EP3 also plays a large role in PGE 2 signaling post-infection with Streptococcus both in vitro and in a mouse model. Other species of Streptococcus induce an increase in PGE 2 synthesis during pulmonary infection as well.

Group B Streptococcus is a leading cause of neonatal sepsis and pneumonia, and infection with this bacterial pathogen leads to enhanced expression of COX-2 and increased concentrations of PGE 2 in A human lung epithelial cells Glibetic et al. Pharmacological inhibition of PGE 2 synthesis by PKI 14—22 or genetic ablation of COX-2 expression promotes bacterial clearance and improves disease outcome in the mouse model Goldmann et al. In a murine model of P.

COXdeficient mice display enhanced bacterial clearance post-infection when compared to wildtype control mice. Recruitment of inflammatory cells in COXdeficient mice does not differ from those of control mice post-infection, suggesting bacterial clearance is associated with impaired effector functions of immune cells Sadikot et al.

Inhibition of COX-2 expression also decreases the severity of P. Burkholderia pseudomallei is a facultative intracellular Gram- negative bacillus that causes a fatal disease known as melioidosis. Patients acquire the infection through different routes and can present with a wide range of clinical symptoms including debilitating pneumonia and septic shock Cheng and Currie, Recent work from our laboratory has demonstrated that PGE 2 plays a critical role in the pathogenesis of B.

PGE 2 promotes B. Treatment of bone marrow-derived macrophages with NS reduces endogenous PGE 2 production and intracellular survival of B. Administration of NS or Celecoxib significantly enhances mouse survival from lethal pulmonary infection with B.

Burkholderia cepacia is a Gram-negative bacterium that causes fatal lung infections in cystic fibrosis patients. In human lung epithelial cells, B. Further research is warranted to identify the mechanisms behind which various pulmonary pathogens modulate PGE 2 responses in the lung in order to aid infection.

When inactivated, many bacteria are unable to elicit a strong PGE 2 response by host cells. For example, when compared to live bacteria, UV-irradiated S.

Similarly, UV-irradiated S. Both live and gamma-irradiated M. Heat inactivation of B. The reduced ability of inactivated bacteria to elicit a strong PGE 2 response during infection suggests these bacteria have evolved active mechanisms to alter host cell signaling to promote PGE 2 synthesis that may aid infection. Type three secretion systems T3SS are important bacterial secretion systems, some of which stimulate PGE 2 production during bacterial pathogenesis Sato et al.

This cytotoxin possesses phospholipase activity and induces rapid AA release from the cell wall and enhances PGE 2 production during the infection of human epithelial cells Sato and Frank, ; Saliba et al. Mice infected with ExoU-deficient P. Taken together, these studies highlight a conserved mechanism among bacterial T3SSs that induce PGE 2 production during infection, and elucidation of these effectors may identify new therapeutic targets.

Since PGE 2 production has inhibitory effects on immune cells, particularly those involved in innate immune responses, inhibition of PGE 2 may benefit the host during bacterial infection Goto et al. In support of this, mice deficient in COX-2 demonstrate enhanced survival post-infection with several bacterial pathogens. COXdeficient mice also demonstrate greater survival rates and exhibit lower bacterial loads in the liver and spleen after intravenous infection with S.

COX inhibitors, which are already widely used in the human population for the relief of pain and inflammation, block the production of PGE 2 and other prostaglandins and may offer therapeutic benefit during bacterial infections. For example, non-selective COX inhibitors such as ibuprofen and indomethacin, significantly reduce the bacterial load and PGE 2 production in the bronchoalveolar lavage BAL after intratracheal P. COX-2 inhibition by NS also significantly improves mouse survival post-intratracheal infection with lethal doses of P.

Moreover, NS administered post-exposure to mice infected with B. COX-2 inhibition results in higher bacterial loads during acute S.

Because COX-2 inhibition impairs the production of prostaglandins in addition to PGE 2 , it is important to consider the potential contribution of other prostaglandins in such studies. Furthermore, additional studies in highly relevant animal models are needed to determine the therapeutic efficacy of COX inhibitors against mucosal bacterial infections.

Specific targeting of one or more PGE 2 receptors may also hold therapeutic promise. EP2 is a major receptor responsible for the immunosuppressive activities of PGE 2 signaling Fujino et al.

Impaired EP2 signaling improves disease outcome in P. Inhibition of EP3 may also be beneficial in controlling bacterial infections. EP3-deficient alveolar macrophages demonstrate increased phagocytic activity and nitric oxide production, and enhanced bacterial killing during S. Specific EP inhibitors or antagonists may aid in therapeutically controlling microbial infection and require further study. PGE 2 is an important lipid mediator that regulates inflammation and immune responses during infection Phipps et al.

Four principle PGE 2 receptors respond to varying concentrations of PGE 2 in order to elicit dynamic downstream signaling events during immune responses. It is increasingly evident that PGE 2 biosynthesis and its inhibitory actions on innate immune defenses can impact bacterial pathogenesis and disease outcome. For infected macrophages, PGE 2 production correlates with diminished phagocytosis, nitric oxide production, and intracellular killing Marotta et al.

The conserved ability of many bacterial pathogens to promote PGE 2 responses during infection suggests a common signaling mechanism to deter protective pro-inflammatory immune responses. Inhibition of PGE 2 production and signaling during infection may represent a therapeutic alternative to treat certain bacterial infections. Further study of the immunosuppressive effects of PGE 2 on innate immunity will lead to a better understanding of potential therapeutic targets within the PGE 2 pathway.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Alba-Loureiro, T. Evidence that arachidonic acid derived from neutrophils and prostaglandin E2 are associated with the induction of acute lung inflammation by lipopolysaccharide of Escherichia coli.

Aronoff, D. Cyclooxygenase inhibition in sepsis: is there life after death? E-prostanoid 2 receptor signaling suppresses lung innate immunity against Streptococcus pneumoniae. Prostaglandins Other Lipid Mediat. Prostaglandin E2 inhibits alveolar macrophage phagocytosis through an E-prostanoid 2 receptor-mediated increase in intracellular cyclic AMP. Pubmed Abstract Pubmed Full Text. E-prostanoid 3 receptor deletion improves pulmonary host defense and protects mice from death in severe Streptococcus pneumoniae infection.

Asakrah, S. Post-exposure therapeutic efficacy of COX-2 inhibition against Burkholderia pseudomallei. PLoS Negl.

Trop Dis. Ballinger, M. Critical role of prostaglandin E2 overproduction in impaired pulmonary host response following bone marrow transplantation. Bankhurst, A. The modulation of human natural killer cell activity by prostaglandins. Bansal, K. Berthelot, P. Genotypic and phenotypic analysis of type III secretion system in a cohort of Pseudomonas aeruginosa bacteremia isolates: evidence for a possible association between O serotypes and exo genes.

Bowman, C. Cyclooxygenasemediated prostaglandin E2 production in mesenteric lymph nodes and in cultured macrophages and dendritic cells after infection with Salmonella. Bozyk, P. Prostaglandin E2 and the pathogenesis of pulmonary fibrosis. Cell Mol. Burch, R. Cholera toxin and pertussis toxin stimulate prostaglandin E2 synthesis in a murine macrophage cell line. Burelout, C. Prostaglandin E2 inhibits the phospholipase D pathway stimulated by formyl-methionyl-leucyl-phenylalanine in human neutrophils.

Involvement of EP2 receptors and phosphatidylinositol 3-kinase gamma. Chen, M. Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. Cheng, A. Melioidosis: epidemiology, pathophysiology, and management. Cirillo, D. Macrophage-dependent induction of the Salmonella pathogenicity island 2 type III secretion system and its role in intracellular survival.

Cockeran, R.