Prostaglandins (FA0301)

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Basics

Cyclooxygenase is a membrane-bound hemoprotein, present in two isoforms: COX1 and COX2. COX1 is a constitutive form, almost ubiquitously expressed, that regulates low prostaglandin synthesis required for cell homeostasis, while COX2 is an inducible form almost undetectable or present at low level in resting state but is synthesised de novo in response to intracellular and extracellular stimuli in inflammatory processes (Hetu et al., 2005). However, COX2 can be also expressed constitutively in brain (Minghetti et al., 2004), kidney (Harris et al.1994) and lung (Ermert et al. 1998). It has been shown that COX-1 is located in the endoplasmic reticulum (ER) and perinuclear membranes, whereas COX-2 resides predominantly in the perinuclear envelope (Ueno et al., 2005). There is a third type of cyclooxygenase, COX3, also known as COX-1b, which is an acetaminophen-sensitive splice variant of COX1 and identified in canine tissues of still unknown function (Botting, 2000). Prostaglandins are ubiquitously produced and act locally in an autocrine and juxtacrine manner and modulate many physiological systems including the CNS, cardiovascular, gastrointestinal, endocrine, respiratory and immune system.

Genelist - Pro- and antiinflammatory effects of prostaglandins

As potent proinflammatory mediators they are synthesised in cancer, inflammation, cardiovascular disease, hypertension. Pharmacologically their synthesis is blocked by the use of the cyclooxygenase-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs). Prostaglandin H2 is subsequently isomerised by tissue specific prostaglandin synthases to structurally similar Prostaglandins: PGE2, PGD2, PGF2α, PGI2 (known as prostacyclin) and thromboxane A2, which represent active lipid molecules. There are at least 9 known prostaglandin receptors. Four bind PGE2 (EP1-EP4), two bind PGD2 (DP1, DP2), FP, IP and TP (TPa and TPb) receptors bind PGF2α, PGI2 and TXA2 respectively (Cha et al. 2006, Reid HM, 2003). With the exception of the DP2 receptor, which is a member of the chemoattractant receptor subgroup, the rest belongs to the G protein-coupled receptor superfamily and signal through different G proteins (Tab.5).

Pharmacological properties of prostanoid receptors

Table 5. Pharmacological properties of prostanoid receptors (Hata et al, 2004)

Figure 15: Conversion of PGJ2 to d12-PGJ2 and 15d-PGJ2. (Ginger L et al., 2005)

PGD2 is formed by the actions of two types of PGD2 synthase isoforms, one is present in the central nervous system, testis, and the human heart and is called lipocalin PGD2 synthase and the second is present in the spleen and hematopoietic system (hPGD2S), being widely distributed in antigen presenting cells, T helper Th2 lymphocytes, megakaryocytes and mast cells (Trivedi et al. 2006). Dendritic cells, helper Th2-type and T cells produce PGD2 suggesting a modulatory role of this prostaglandin in antigen-specific immune responses. PGD2 is released into the airways and skin following acute allergic response (Barr et al. 1988). Additionally, PGD2 can inhibit platelet aggregation, smooth muscle relaxation and contraction, vasodilation and vasoconstriction (Hata et al. 2004). PGD2 binds and activates two distinct GPCRs – DP and CRTH2 (DP2), which both mediate inflammatory properties of their ligand. CRTH2 is expressed in TH2 lymphocytes, eosinophils and basophils and mediates PGD2-stimulated chemotaxis and leukocyte mobilization (Hirai et al. 2001, Shichijo et al. 2003). The DP receptor is expressed on bronchial epithelium and mediates production of chemokines and cytokines that recruit inflammatory lymphocytes and eosinophils leading to sympthoms resembling asthma (Kabashima et al. 2003).

Prostaglandin E2 (PGE2) is synthesized mainly in kidney, platelets, blood vessels and macrophages. It is a proinflammatory mediator, which induces fever, increases vascular permeability and vasodilation, enhances pain and oedema, caused by other factors as bradykinin and histamine (Calder, 2005). Studies in cultured fibroblasts revealed that PGE2 could stimulate its own generation through the induction of COX2 (Bagga et al. 2003). It has been reported however that PGE2 acts also anti-inflammatory as it can inhibit 5-LOX and decrease the production of inflammatory leukotrienes (Levy et al. 2001). Simultaneously 15-LOX is induced and anti-inflammatory lipoxins are formed.

PGE2 signals through four receptors (EP1-EP4) Prostacyclin I2 (PGI2) is synthesized in endothelial cells, macrophages, lung and kidney. It plays a role as a potent vasodilator and inhibitor of platelet aggregation and this activity is mediated through coupling of the PGI2 IP receptor to Gs-type G protein (Cook, 2005). Thromboxane A2 is synthesized in platelets, monocytes, macrophages and lung. It promotes platelet aggregation. It signals through the TP receptor that exists in two alternatively splice variants, TPα (placenta, platelets) and TPß (endothelial cells) (Hata et al. 2004). It couples to Gs, Gi, Gh and G12-type of G proteins and coupling to Gq leads to activation of PLC β, IP3/DAG generation and mobilization of intracellular calcium. This pathway is responsible for thromboxane receptor-mediated platelet aggregation.

Thromboxane A2 and PGI2 are biological antagonists and the balance between them is crucial for maintaining a healthy state of the vasculature. PGF2α is produced during menstrual cycle by secretory endometrium and plays a role in mammalian reproduction (Hata et al. 2004) and changes in PGF2α lead to reproductive abnormalities. Increased expression of receptor for PGF2α has been documented in endometrial adenocarcinoma growth (Sales et al. 2004). Additionally, PGF2α is important in renal function, cardiac hypertrophy and regulation of intraocular pressure. As well as the above mentioned PGJ2 and PGA2 can be also synthesized from PGD2 and PGE2, respectively. Bell-Parikh LC et al have shown that the dehydration process can occur not just in vitro but also in vivo. PGJ2 has further derivates (see figure 15).

Delta-12-PGJ2 has antitumor and antiviral activity. It is also able to induce neuronal death and to impair 26 S proteasome assembly (Zhiyou Wang et al.: 2006). 15-deoxy-PGJ2 has an anti-inflammatory property as a ligand of PPAR-gamma meanwhile it also blocks IKK (Straus DS, Glass CK.: 2001). Interestingly, it has as well a positive effect on VEGF generation which is a know factor of neoangiogenesis in different tumor cells. (Ginger L et al., 2005)

Anti-inflammatory effect of 15d-PGJ2. (Straus DS, Glass CK.: 2001)

In the presence of omega-3 PUFAs (polyunsaturated fatty acid) 3-series of Prostaglandins are synthesized by COX enzymes instead of 2-series of PGs. There are different types of PUFAs. Alpha-linolenic acid can be found in plants, especially in flaxseed. The best sources of EPA (eicosapentaenoic-acid) and [Docosahexaenoic acid (DHA) are oily, cold-water fish. There is clinical evidence of anti-inflammatory property of omega3s in different inflammatory diseases, such as rheumatoid arthritis, skin dermatitis and posterior blepharitis. In the Western diets the ratio of omega-3 and omega-6 PUFAs is about 1:10-20. The desired ratio would be 1: 1.4-2.0. (Simopoulos AP: Poult Sci. 2000 Jul;79(7):961-70.) As these two essential fatty acid groups have antagonistic effect their balance in the diet is highly recommended. Hence, it is advised to decrease omega-6 and increase omega-3 PUFA level. (Simopoulos AP: Lipids. 2001;36 Suppl:S83-9.)

Pathways involved in the metabolism and function of prostanoids derived from AA and EPA (Smith WL, 2005)

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