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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 8  |  Issue : 1  |  Page : 38-51

Prostanoids and parasitic diseases


Department of Parasitology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Date of Submission10-Dec-2014
Date of Acceptance18-May-2015
Date of Web Publication24-Aug-2015

Correspondence Address:
Amany M Eida
Department of Parasitology, Faculty of Medicine, Suez Canal University, 41522, Ismailia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7942.163408

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  Abstract 

The eicosanoid family includes prostanoids, leukotrienes, and other oxygenated derivatives. Prostanoids are a major class of the eicosanoid family derived from metabolism of arachidonic acid by the action of cyclooxygenase enzymes (COX). They are further subdivided into three main groups: prostaglandins (PGs), thromboxanes (TXs), and prostacyclins. PGs were first discovered as uterotonic substances in human seminal fluid in 1930. In the late 1950s to mid-1960s, their structures were studied and identified as being derived from unsaturated fatty acids. Prostanoids are produced by many cell types such as vascular endothelium, leukocytes, and the pathogens themselves. Prostanoid production is controlled by expression of different enzymes engaged in prostanoid biosynthesis, and by the distribution of different specific prostanoid synthases within those cells that determine their effect on the immune system. The production of prostanoids differs from one cell type to another; for example, dendritic cells predominately produce PG E 2 (PGE 2 ) and TXA 2 , whereas mastocytes produce PGD 2 . All inflammatory cells, including monocytes/macrophages, and neutrophils, are the main source of COX metabolites.
Produced in response to various physiological and pathological stimuli, PGs are noted as key participants in autoimmune immunopathology, infectious diseases, and cancer. Other reports have shown that PGIs are formed by endothelial and smooth muscle cells, and TXAs are formed by platelets and lungs; PGI 2 and some other PGs are produced by interactions between cells using enzymes in adjacent cells; for example, platelet-produced PGH 2 is converted to PGI 2 in the vascular epithelium.
PGs secreted in the saliva of blood-sucking arthropods increase local blood flow and maintain the supply for feeding; they were also reported to increase immune suppression, allowing prolongation of attachment by ticks. Progressive studies demonstrated that, besides insects, pathogenic fungi, protozoa, and parasitic worms produce PGs.
This review focuses on induced efforts to study prostanoids and their relation to different parasitic diseases.

Abbreviations
AA: Arachidonic acid; COXs: Cyclooxygenase enzymes; CyPG: Cyclopentanone; DC: Dendritic cell; GST: Glutathione-S-transferase; GA: Glycyrrhizic acid; MAP: Mitogen-activated protein; MIF: Macrophage migration inhibitory factor; NO: Nitric oxide; PBMC: Peripheral blood mononuclear cells; PG: Prostaglandin; PG12: Prostacyclin; PGE2: Prostaglandin E2; PL: Phospholipase; PPAR: Peroxisome proliferator-activated receptors; TGF: Transforming growth factor; TNF: Tumor necrosis factor; TP: Thromboxan receptor; TX: Thromboxane.

Keywords: anti-inflammatory drugs, dendritic cells, helminthes, immunomodulation, prostanoid receptors, prostanoids, protozoa


How to cite this article:
Eida AM. Prostanoids and parasitic diseases. Parasitol United J 2015;8:38-51

How to cite this URL:
Eida AM. Prostanoids and parasitic diseases. Parasitol United J [serial online] 2015 [cited 2017 Dec 13];8:38-51. Available from: http://www.new.puj.eg.net/text.asp?2015/8/1/38/163408


  Prostanoid synthesis Top


Arachidonic acid (AA) is a 20-carbon polyunsaturated fatty acid. It is derived from linoleic acid and becomes stored as part of glycerophospholipids in the lipid bilayer of the plasma membrane [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] . Released by the action of phospholipase (PL), AA is metabolized by independent metabolic pathways and the COX pathway producing prostaglandins (PGs) and thromboxane A 2 (TXA 2 ) [15] . It is hydrolyzed by COX enzymes to PGH 2 [16] . In humans, there are two COX isoenzymes (COX-1 and COX-2) [16],[17] . Through two sequential reactions the COX isoforms generate PGH 2 , which is the central substrate for synthesis of all PGs and TXA 2 [16],[17],[18] . PGH 2 is the common substrate for a series of cell-specific terminal PG synthases that produce PGD 2 , PGE 2 , PGF 2α, PGI 2 , and TXA 2 [7] ([Figure 1]).
Figure 1 Pathways of prostanoid biosynthesis [7].
PPAR, peroxisome proliferator-activated r eceptor.


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  Biological functions of prostanoids Top


TX and prostacyclin (PGI 2 ) regulate platelet aggregation, where the former induces coagulation and vasoconstriction and the latter is a vasodilator and anticoagulant [19] . It was shown that products of COX metabolites act as anti-inflammatory lipid mediators during resolution of infection and at later stage of inflammation [20] . While PG and PGI 2 proinflammatory functions are well documented [3] , prostanoids participate in tissue fibrosis and mucus secretion [21],[22] , vascular tone, inflammation, ischemia, and tissue homeostasis [17] . Prostanoids also regulate capillary bed perfusion, vascular endothelium permeability, and expression of selectins and integrin ligands, which allows neutrophils, macrophages, and T lymphocytes to enter into extravascular spaces [23],[24] . They also affect physical interactions between B and T cells in secondary lymphoid organs, leading to production of cytokines and antibodies [25] .

On the other hand, PGs are often associated with anti-inflammatory activities such as inhibition of mediator release from macrophages, neutrophils, mast cells, basophils, and lymphocytes. Thus, they can also downregulate macrophage functions [2] . PGE 2 also has potent proinflammatory effects leading to the classic signs of inflammation such as fever and pain. In addition, PGE 2 has other anti-inflammatory effects such as suppression of lymphocyte proliferation and inhibition of production of certain types of cytokines. Accordingly, PGE 2 plays a role in starting inflammatory processes and in their resolution. However, both the proinflammatory and anti-inflammatory roles of prostanoids depend on the nature of the inflammatory stimulus and the specific prostanoid produced [11] ([Table 1]). Hence, prostanoids may be considered as main factors in the regulation of coagulation and local blood flow, which may be of importance at the site of parasitic invasion [12] .
Table 1 The main biological functions of prostanoids [11]

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  Prostanoids and parasites Top


PGs may play a part in the pathogenesis of parasitic diseases [11] . Although generally invertebrates lack de-novo synthesis of polyunsaturated fatty acids and prostanoids, parasites have been shown to generate PGs and TXs [12] . In addition, because all invertebrates cannot synthesize the precursors of prostanoids, they acquire their polyunsaturated C 20 -fatty acids and AA from the abundant supply available in cellular membranes of mammalian cells, human plasma, and lymph. During inflammation, AA is released from phospholipids by activity of PLs. Parasite enzymes metabolizing prostanoids are poorly characterized. In helminths, COXs as central prostanoid-metabolizing enzymes, have not been detected. On the other hand, glutathione S-transferases (GST), also known to catabolize eicosanoids to PGs, have been demonstrated to express PG synthase activity in nematodes [26] . Recently, another report indicated that a number of parasitic organisms such as E. histolytica and Trypanosoma spp. produce PGs in the same way as their mammalian hosts and by similar enzymatic mechanisms [11] .

Entamoeba histolytica

In 1995, the mechanisms of impairment of cell-mediated immunity in invasive amoebiasis were assessed. Macrophages treated with soluble amoebic proteins suppressed the induction of IFNγ-induced surface Ia antigen molecule expression by 30-61% but had no effect on surface Ia molecules already expressed. It was concluded that E. histolytica suppresses IFNγ-induced macrophage surface Ia molecule synthesis and I-A beta mRNA expression by stimulating the production of PGE 2 , which is important for immunoregulation. The breakdown of macrophage function via PGE 2 biosynthesis is a new way by which the parasite inhibits host defenses [27] . In amoebic liver abscesses, E. histolytica also induces COX-2 expression in macrophages [28] with subsequent production of prostanoids.

In 2001, another study was conducted to assess whether colonic amoebiasis induces the expression of COX-2 and to determine the contribution of PGs to the host response. The researchers infected human fetal intestinal xenografts subcutaneously implanted in susceptible mice with E. histolytica. The results showed that colonic amoebiasis induces the expression of COX-2 in both epithelial cells and macrophages. Moreover, PGs produced through COX-2 enhanced neutrophil response to infection and epithelial permeability. Treatment of mice with indomethacin (COX-2 inhibitor) decreased PGE 2 levels and caused neutrophil infiltration [29] .

Two years later, it was concluded that COX-like activity and immunoreactive proteins were present in the nuclear fraction of E. histolytica. Little homology existed at the nucleotide and amino acid levels between the amoebic COX and COX-1/2 enzymes from different species. The AA-binding domain and heme-coordinating and catalytic sites present in other species were absent in amoeba. Amoeba COX expressed in  Escherichia More Details coli demonstrated COX-like enzyme activity in vitro by converting AA into PGE 2 but not into PGD 2 or PGF 2a . The authors added that COX activity was inhibited with 1 mmol/l aspirin. Thus, it was concluded that E. histolytica produces PGE 2 by means of a previously undescribed ancestral COX-like enzyme and that PGE 2 plays a main role in pathogenesis and immune evasion of the organism [30] .

In a study conducted by Lejeune et al. [31] , the pathological role of E. histolytica-derived PGE 2 in the onset of diarrhea was established. It was reported that amoeba-derived PGE 2 alters ion permeability of paracellular tight junctions (TJs) in colon epithelium. This loss of mucosal barrier integrity corresponds with increased ion permeability across TJs. The authors added that the significant alteration of TJ protein (claudin-4) leads to increased sodium ion permeability through TJs toward the lumen with increased luminal chloride secretion. Thus, the NaCl gradient, created across epithelia, could serve as a trigger for the osmotic water flow that leads to diarrhea.

It was also shown that PGE 2 produced by live amoebae acts as an IL-8-stimulating molecule. This was proved by treating trophozoites with COX inhibitors resulting in inhibition of PGE 2 biosynthesis and IL-8 production. The initiation and amplification of acute inflammation associated with intestinal amoebiasis was explained by the binding of PGE 2 through the PG receptors 'EP4' in colonic epithelial cells. This results in stimulation of potent neutrophil chemokine and activation of IL-8 production leading to acute host inflammatory response. Hence, it was recommended that EP4 antagonists targeting receptors are potentially therapeutically important in the treatment of amoebiasis [32] .

Cryptosporidium parvum

Using a suckling rat model, it was shown that malabsorptive syndrome occurs in cryptosporidiosis without involvement of PGs. Rather it was reported to be due to impairment of electrogenic transport across the ileal mucosa, as well as transcellular and paracellular permeability and leucine and glutamate absorption [33] . One year later, Gookin et al. [34] showed that PGs actually play a central role in regulating intestinal fluid secretion in animal models of cryptosporidiosis; PGE 2 and PGI 2 were found at higher concentrations in infected tissues. This increased mucosal PG production leads to increase in calcium and cAMP, which inhibit neutral NaCl absorption. Consequently, this results in decreased paracellular water absorption by the villus, stimulation of anion secretion, and secretory diarrhea. It was further reported that PGI 2 might act on components of the enteric nervous system by stimulating the nicotinic ganglia and cholinergic motor neurons that innervate the intestinal mucosa, whereas PGE 2 acts directly on enterocytes [35] . It was also shown that mesenchymal epithelial cells in the lamina propria as well as infiltrating and resident leukocytes in the mucosa (e.g. macrophages) have a role in producing high levels of PGs during cryptosporidiosis [34] . However, inhibition of neutrophil migration into infected tissue proved to have no effect on PG synthesis [36] . Meanwhile, it was demonstrated that treatment of infected or inflamed mucosa with a PG synthesis inhibitor will restore normal electrolyte transport and water despite the villous atrophy, showing that the transporters are fully functional, even in the immature enterocytes [37],[38] .

On the other hand, Gookin et al. [39] showed that cryptosporidiosis is associated with increased synthesis of nitric oxide (NO), PGE 2 , and increased mucosal permeability. This was shown by the nonselective inhibition of NOS (NG-nitro-L-arginine methyl ester) that inhibited PG production, leading to a greater increase in paracellular permeability. Baseline permeability was also restored in the absence of NO by exogenous PGE 2 . The mechanism by which PGE 2 causes epithelial barrier function of C. parvum-infected mucosa is not clearly understood but it was hypothesized that it may involve the maintenance of paracellular space closure rather than have a direct effect on the epithelium [39] .

Later, it was demonstrated that NO serves as a proximal mediator of PGE 2 synthesis and epithelial barrier function in cryptosporidiosis. Reactive nitrogen species have also been demonstrated to activate COX enzymes and stimulate PG-mediated secretion when NO production is augmented by arginine supplementation [40],[41] . As indicated, this in turn increases the severity of infection with subsequent increase in epithelial chloride secretion and diarrhea. Epithelial secretion by infected mucosa from L-arginine-supplemented piglets was fully inhibited by the COX inhibitor indomethacin, indicating that PG synthesis was responsible for this effect [41] .

Giardia lamblia

Current knowledge regarding the role of prostanoids in giardiasis is scarce. The synthesis and metabolism of phospholipids and fatty acids in G. lamblia was first investigated by Jarroll et al. [42] almost three decades ago, and it was postulated that Giardia spp. had little or no ability to synthesize its own lipid molecules de novo. Ellis et al. [43] failed to detect lipid-bound AA, the precursor of PGG 2 synthesis, in Giardia trophozoites, suggesting that it might be present only in trace amounts.

In 2000, it was found that radiolabeled bases such as choline, inositol, ethanolamine, serine, and glycerol become incorporated into phospholipids of trophozoites when added to the culture medium. Thus, it was concluded that G. lamblia trophozoites colonized in the small intestine utilize preformed lipids and fatty acids from the lipid-rich environment. Many of these exogenous lipids/fatty acids were reported to undergo remodeling before they were incorporated into giardial membranes [44],[45] . This fact was supported by finding that radiolabeled fatty acids are directly incorporated into membrane phospholipids, suggesting that Giardia spp. might have many cellular mechanisms to form new phospholipids [46] . Special procedures, as in the Lands cycle, were used by G. lamblia to obtain lipids, such as through deacylation/reacylation reactions. This led to the conclusion that lipid remodeling pathways play key roles in regulating the growth and differentiation of Giardia spp., thus presenting a potential drug target [47] .

The established genome database (http://www.giardiadb.org), which includes the Giardia genome, and Morrison et al. [48] revealed the presence of metabolic genes and lipid synthesis. The researchers also added that there are several classes of phospholipid-transport, ATPases, or flippases (FLIPs) that allow Giardia spp. to uptake aminophospholipids efficiently from the environment of the small intestine. Genomic and lipidomic data obtained in another study indicated that Giardia spp. change lipids taken from the environment by base-exchange reactions to synthesize fatty acids, phospholipids, and neutral lipids. It was postulated that two of the major phospholipids, phosphatidyl-glycerols and phosphatidylethanolamines, might be produced via base-exchange reactions, suggesting that the parasite could synthesize prostanoids from its phospholipid pool and that these two mediators may play a role in the pathogenesis of giardiasis [49] .

However, in spite of the expression of five sphingolipid metabolic genes, Giardia spp. was found to exhibit limited lipid synthesis capacity de novo, where it obtains ceramide and sphingolipids from its host for growth, survival, and encystation [50] . Therefore, it was concluded that products of gspt and gglct-1 genes are important for cellular functions rather than for the synthesis of new sphingolipids, and that blocking the latter results in decreased growth and Giardia encystation. It remains to be seen whether Giardia spp., like other parasites, are capable of synthesizing eicosanoids or PGs [51],[52],[53] .

Trichomonads species

In vivo studies regarding the role of prostanoids in trichomoniasis are limited. In a study by Shaio et al. [54] , the possibility that prostanoid production by trichomonads is responsible for neutrophil activation was observed. Leukotriene B 4 , which is produced by leukocytes during inflammation, but not TXB 2 or PGE 2 , is generated by T. vaginalis, indicating that T. vaginalis could follow a different AA-metabolic pathway than that of mammalian cells.

Sayed et al. [55] linked T. vaginalis pathogenesis with cervical cancer. The enhanced synthesis of PGs induced by COX-2, which is often upregulated in many inflammatory diseases, stimulates cancer cell proliferation [56] , inhibits apoptosis, and promotes angiogenesis [57] . The overexpression of COX was recorded in various cell types of primary and metastatic epithelial cancers, including prostate and cervical cancers [58] . It was postulated that a similar situation might be present during trichomoniasis as in H. pylori infection, which is in turn linked to gastric cancer [59] .

In the year 2005, the first study to understand the basis of interaction of trichomonads with host cells and the corresponding host responses triggered by the parasites was conducted by Kucknoor et al. [60] . The researchers analyzed COX-2 protein expression by T. vaginalis using western blot and immunofluorescence assays. They showed that p38 mitogen-activated protein (MAP) kinases and tyrosine kinases play a role in COX-2 induction. The authors added that T. vaginalis and Tritrichomonas foetus but not Pentatrichomonas hominis possess some soluble factors that induce COX-2 gene expression and that COX-2 may also be induced by the upregulation of cytokines and other growth factors that are initiated by T. vaginalis adherence. It was suggested that COX-2 induction is important for the pathogenesis of T. vaginalis. However, several recent studies did not confirm the association between T. vaginalis and cervical cancer. Two studies determined that T. vaginalis might be a concomitant infection with high-risk human papilloma virus infection and other cervical cytological abnormalities and thus should not be considered influential in predisposing to cervical cancer [61],[62] .

Leishmania species

The role of PGs in the infection of mouse macrophages by L. amazonensis was assessed. The results showed that macrophage infection by Leishmania spp. is enhanced by PGs produced by macrophages [63] . Previous studies reported that PGE 2 production associated with leishmaniasis might favor Leishmania spp. persistence and progression [64],[65] . Pérez-Santos and Talamás-Rohana [64] added that treatment with indomethacin enhanced the intracellular killing of L. mexicana parasites in infected BALB/c mice. They concluded that indomethacin suppressed PGs promoting the development of a protective Th1 type response in susceptible mice by enhancement of IL-12, IFN-γ, and NO production.

It has also been shown that Leishmania spp. induce the production of the inflammatory lipid mediator PGE 2 from macrophages [66],[67],[68] , leading to the successful survival of the parasites inside the host cells. In confirmation, it was found that wild-type mice treated with indomethacin, an inhibitor of PGE 2 synthesis, during the first 3 weeks of L. amazonensis infection developed smaller lesions and lower parasitic load when compared with the control group. The lesion of indomethacin-treated groups consisted of macrophages without vacuoles and small or absent necrotic areas, indicating that PGE 2 is a susceptibility factor to L. amazonensis infection. Although PGE 2 leads to inhibition of mechanisms responsible for destruction of the L. amazonensis parasite, the deficiency of this factor is not enough to cure infection. Thus, it has been suggested that a direct inhibitory action is exerted in the macrophages by the parasite, and/or the participation of other factors in mediating susceptibility/resistance to L. amazonensis infection exists [50],[69] .

It was demonstrated that the HIV-1 Tat protein enhances Leishmania replication in human macrophages. Leishmania spp. growth doubled in HIV-1-infected macrophages and the anti-Tat antibody decreased the protozoan replication by 70%. Tat enhanced COX-2 expression and PGE 2 production, and a COX-2 inhibitor abolished the Tat-mediated augmentation of Leishmania replication. Moreover, PGE2 increased Leishmania spp. growth, which was stopped by anti-transforming growth factor (TGF)-β1 monoclonal antibodies [70] .

In 2008, the in vitro and in vivo effect of PLA 2 on experimental cutaneous leishmaniasis was investigated. The study showed that PLA 2 may cause extension of cutaneous leishmaniasis by suppressing the effect on IL-2 levels and the generated PGE 2 [71] . It was concluded that L. major infection might lead to polarization of T cells to Th2 through PGE 2 [10] .

Later in 2012, a study was conducted to assess the effect of glycyrrhizic acid and its immunomodulatory potential in a model of experimental visceral leishmaniasis. Results showed that glycyrrhizic acid treatment increased macrophage effector responses through inhibition of Cox-2-mediated PGE 2 release in L. donovani-infected macrophages [72] . In another study conducted in 2013, Díaz-Gandarilla et al. [73] found that 6k-PGF , PGE 1 , and PGF production increased, whereas both PGE 2 and PGF production decreased after Leishmania spp. infection, and increased in treated and infected macrophages. They added that use of peroxisome-proliferating activated receptor (PPAR) promoters and anti-cPLA 2 diminished 6k-PGF , PGE 1 , and PGF production after Leishmania spp. infection. It became clear that PGE 2 is able to inhibit COX-2 expression in the presence of these proinflammatory cytokines and that cPLA 2 inhibition also inhibits COX-2 expression through PPARγ [74] . All these results may explain why, during PPARγ activation, PGE 2 production was found to be increased by macrophages infected with L. mexicana [73] .

In a study by Penke et al. [75] , the contribution of four PG receptors EP1, EP2, EP3, and EP4 to infection with Leishmania spp. was investigated. Authors reported that L. major enhanced EP1 and EP3 expressions but reduced EP2 and EP4. Treatment of L. major-infected susceptible BALB/c mice with EP1 and EP3 antagonists or treatment with EP2 and EP4 contenders resulted in significant reduction of parasites in the draining lymph node. This observation revealed the selective targeting of PGE 2 receptor as a main therapeutic agent. The researchers added that diminution of EP2 and EP4 expression may represent one of the parasite's immune evasion strategies [76] .

Toxoplasma gondii

It was found that the interaction of T. gondii with platelets resulted in marked increase in TXB 2 production. TX plays a role in platelet-induced cytotoxicity. Both the TXA 2 -generating platelet microsome system and stable TXA 2 correspondents cause damage to Toxoplasma spp. cellular membranes. Thus, it was deduced that involvement of platelets in the host defense against T. gondii is by release of both TX types, which may be important in this cytolytic process [77] . In addition, it was found that tachyzoites cause a noticeable change in prostanoids released by human mononuclear phagocytes. Adherent human monocytes isolated after 2 h of culture released both TXB 2 and PGE 2 and leukotriene products when stimulated by heat-killed tachyzoites. However, after 5 days the monocytes lost their ability to release TXB 2 and PGE 2 [78] .

In 1995, a study evaluated the role of human granulocyte-macrophage colony-stimulating factor (GM-CSF) in the static activity of Toxoplasma spp. and in the production of H 2 O 2 and PGE 2 by human monocytes. Results showed that incubation of monocytes from healthy controls with GM-CSF led to a dose-dependent decrease in Toxoplasma static activity and H 2 O 2 production. GM-CSF-treated monocytes produced more PGE 2 compared with untreated cells. Furthermore, incubation of these cells with indomethacin resulted in a reduction in PGE 2 release and return of Toxoplasma static activity. It was concluded that GM-CSF decreases Toxoplasma static activity of monocytes through production of PGE 2 [79] .

Macrophages invaded by T. gondii are also involved in PGE 2 synthesis where the parasite was reported to regulate macrophage functions by regulating AA production through a calcium-dependent pathway and induction of COX-2 expression. This leads to increased release of immunosuppressive molecules PGE 2 , in macrophages in a time-dependent manner [80] . In other cell types, studies showed that enzymatic conversion of AA into PG down modulates the cell-mediated immune response allowing survival of both intracellular pathogens and the host [80],[81] .

An in vivo study showed that, during acute infection of mice with T. gondii, inflammatory monocytes were associated with production of the lipid mediator PGE 2 . These monocytes could also inhibit neutrophil activation in a PGE 2 -dependent manner. Moreover, mice developed severe neutrophil-mediated pathological reactions in the absence of inflammatory monocytes, which was controlled by analogous PGE 2 treatment. On the other hand, inhibition of PGE 2 led to increased neutrophil activation with a high mortality rate. Thus, inflammatory monocyte-derived PGE 2 can be considered to be at the center of a regulatory mechanism that is important for control of host-pathogen-induced inflammation. The researchers concluded that modulation of the PGE 2 metabolism may represent an important future therapeutic approach in the management of many inflammatory and infectious diseases [82] .

Another recent study attempted to test the role of the macrophage migration inhibitory factor (MIF) proinflammatory cytokines in the production of the mediator PGE 2 and on the susceptibility of Toxoplasma spp. in in vitro-infected human trophoblast BeWo cultured cells. Results showed that treatment with low concentrations of MIF increased the production of PGE 2 , whereas treatment with high concentrations controlled the parasites. Treatment with tachyzoite-soluble antigen also did not alter PGE 2 release. The researchers concluded that PGE 2 is an important factor for the persistence of T. gondii at the maternal-fetal interface and that MIF is unable to control toxoplasmosis at low concentrations. The expression of activated PGE 2 reflects its efficiency as a mediator in promoting parasite proliferation [83] .

Infection of skeletal muscle cells with T. gondii also promotes modulation of PGE 2 production and COX-2 gene induction. Recent research showed that certain factors led to the establishment and preservation of infection by T. gondii in the muscle tissue causing chronic toxoplasmosis. These factors comprised the close association between the parasitophorous vacuole and the sarcoplasmic reticulum and lipid droplets, providing a source of lipids and other nutrients for the parasite's survival, as well as increased levels of IL-12, INF-γ, and the inflammatory indicators PGE 2 and COX-2 [84] .

Trypanosoma species

As with the above observation in toxoplasmosis [84] , Melo et al. [85] had reported earlier that lipid bodies and lipid-rich inclusions present in inflammatory cells may have a role in prostanoid production in Chagas disease. Recently, it was demonstrated that lipid bodies in macrophages are the sites of PGE synthesis. The fatty acid synthase inhibitor C75 was found to inhibit lipid body biogenesis by reversing the effect of apoptotic cells on lipid body formation, prostanoid synthesis, and parasite replication. These findings demonstrated the role of the highly regulated lipid bodies in releasing PGE 2 lipid mediator by macrophages, indicating that they are potentially involved in Trypanosoma cruzi immune evasion mechanisms [86] .

Another comparative study showed that the mediators PGF 2a , 6-keto-PGF1a, and TXB 2 could be mainly associated with protective mechanisms in acute infection but seem not to be involved in its maintenance in the chronic infections [87] . In contrast, it was suggested that PGs mediate the immunosuppression observed in the acute phase of Chagas disease [88] .

It was also reported that TXA 2 , which is the predominant prostanoid present in all life stages of T. cruzi, is released by infected human endothelial cells. Parasite-derived TXA 2 accounts for the majority of its circulating levels in infected wild-type mice, and affect host physiology. Deficiency of the TXA 2 gene receptor in mice resulted in higher mortality and more severe parasitism and cardiac pathology compared with wild-type mice. It was concluded that the host response to parasite-derived TXA 2 in Chagas disease may prove to be an important regulator of parasitism and mortality, which may enhance its future use as a novel therapeutic target [89] .

The role of PGE 2 in cardiac lesions caused by Chagas disease was investigated in 2008. It was observed that treatment with COX-2 inhibitors decreased the synthesis of PGE 2 by spleen cells, which was accompanied by reduced numbers of parasites, infiltration by inflammatory cells, and cardiac fibrosis. The researchers concluded that treatment with COX-2 inhibitors leads to inhibition of PGE 2 synthesis and reduction of cardiac damage observed during the acute phase of experimental Chagas disease [90] . On the other hand, it was shown that prostanoids may be involved in oxidative stress in host defenses against this disease. Induced production of COXs-mediated PGs is considered a basic mediator in the control of parasite burden and erythrocyte oxidative stress during infection by T. cruzi in mice [91] . In Wistar rats with immunosuppression due to infection with T. cruzi, the combined treatment with melatonin and meloxicam significantly enhanced the blockage of PGE 2 synthesis, release of IL-2 and IFN-γ into the animals' serum, and release of NO by macrophages. As a result there was significant reduction in parasitemia [92] . An attempt to evaluate the effects of 15d-PGJ 2 administration during the acute phase of infection in mice showed decreased inflammatory infiltration in skeletal muscles, decreased number of white blood cells, and decreased density of amastigotes in cardiac muscle. This was associated with a statistically significant increase in IL-10 levels and no change in IFN-γ levels. It was concluded that treatment with 15d-PGJ 2 in the acute phase of Chagas disease enhanced immune response and decreased numbers of amastigote collections [93] . In COX-1-null mice infected with the Brazil strain of T. cruzi, Mukherjee et al. [94] studied the effects of aspirin on the parasite and host biosynthetic pathways. Aspirin treatment diminished parasite-derived and host-derived circulating PGs with subsequent increase in mortality and parasitemia. However, there was no significant differences in histopathology or cardiac structure or function. Delayed treatment with aspirin did not increase parasitemia or mortality but improved ejection fraction of the heart. The infected COX-1-null mice exhibited reduction in circulating levels of TXA 2 and PGF with increased parasitemia as compared with aspirin-treated infected mice, indicating that the effect of aspirin on mortality had little to do with inhibition of PG metabolism. In a more recent study, treatment of macrophages with either NOS inhibitors or PGE 2 restored the invasive action of T. cruzi in macrophages previously treated with aspirin. The results of this study indicated that PGE 2 , NO, and lipoxins are involved in regulation of anti-T. cruzi activity by macrophages. This clarified the role of PGs in the innate inflammatory response to Chagas disease, and presented the possibility of future research in specific immune intervention [95] . Another report indicated that T. cruzi infection in mice induces myocardial gene expression of Cox-2 and TX synthase. The parasite's collaboration with the endothelial vasoconstricting peptide (ET-1) activates the Ca 2+ /calcineurin (Cn)/nuclear factor of activated T-cells signaling pathway in atrial myocytes. This leads to COX-2 protein expression and increased release of PGE 2 and PGF , TXA 2 eicosanoids [96] .

Other reports also showed that many changes that occur during acute and chronic Chagas disease can be accounted for by the effects of prostanoids such as PGs and TXs. This was demonstrated by the treatment with COX inhibitors during acute infection that led to increased parasite load and mortality, whereas treatment during chronic infection beneficially led to improvement in cardiac function and decreased mortality. The majority of TXA 2 liberated during Chagas disease is derived from the parasite. TXA 2 is a potent vasoconstrictor that contributes to the pathogenesis of the associated cardiovascular disease. It may also control parasite differentiation and proliferation, allowing the infection to progress to a chronic state. It was concluded that the same mediators that initially ensure host survival may later cause cardiovascular damage [97] . Thus, as indicated, prostanoids may be considered as prospective targets for treatment of Chagas disease [98] . Moreover, studying T. cruzi-infected neonatal cardiac cells, researchers considered 15d-PGJ 2 to be a potent modulator of the inflammatory process and regulator of parasite growth through PPARg-dependent and PPARg-independent (Erk-MAPK and NF-kB) pathways. It was found that calcium-independent PLA2g (iPLA2g) accounts for the majority of PLA 2 activity and is responsible for AA and PGE 2 release in rabbit ventricular myocytes. This study demonstrated that T. cruzi infection activates iPLA2g in cardiac muscle cells, which results in increased release of AA and PGE 2 mediators that may be essential for host survival during acute infection. Thus, iPLA2g acts as a cardioprotective agent during the acute stage of Chagas disease [99] .

Mukherjee et al. [100] provided evidence that epimastigotes, trypomastigotes, and amastigotes of T. cruzi express a biologically active prostanoid-like receptor mainly present in their flagellar membranes. This receptor is similar to TP receptors in human platelets.

Other research attempted to evaluate the role of monocytes as essential sources of PGE 2 inflammatory mediators in Chagas disease patients. In this trial, peripheral blood mononuclear cells (PBMCs) before and after depletion of monocytes from patients with Chagas disease and from noninfected individuals were evaluated. It was found that partial depletion of adherent cells decreased production of PGE 2 slightly in patients with Chagas disease. Thus, monocytes seem to be important for modulation of immune responses in Chagas disease by inflammatory mediators and by regulating the processes of inflammation and antigen presentation [101] .

It was shown that T. brucei produces PGs in plasma and cerebrospinal fluid, producing fever, headache, immunosuppression, deep muscle hyperesthesia, miscarriage, ovarian dysfunction, and sleepiness. PGF 2a was the major prostanoid produced by T. brucei trypanosome lysates (TbPGFS). Phylogenetic analysis and molecular properties demonstrated that TbPGFS is completely distinct from mammalian PGF synthases. The researchers also found that TbPGFS mRNA expression and TbPGFS activity were high in the early logarithmic growth phase and low during the stationary phase [102] . It was reported that TbPGFS catalyzes the NADPH-dependent reduction of 9,11-endoperoxide PGH 2 to PGF 2a , and leads to elevation of PGF 2 concentration during African trypanosomiasis [103] . Prostanoids produced by African trypanosomes such as PGD 2 , PGE 2 , and PGF 2a probably interfere with the host's physiological response. However, addition of PGD 2 to cultured trypanosomes led to a significant inhibition of its growth, whereas PGE 2 or PGF 2a did not have the same effect. Trypanosomal PGD 2 induces an apoptosis-like programmed cell death (PCD) including maintenance of plasma membrane integrity, phosphatidylserine exposure, loss of mitochondrial membrane potential, nuclear chromatin condensation, and DNA degradation [104] . Having found that PGD 2 induces PCD of T. brucei in the bloodstream, Figaralla et al. [105] attempted to investigate further whether it is PGD 2 or its J series of metabolites that are the main cause. They concluded that PGJ 2 and ∆ 12 PGJ 2 metabolites of PGD2 in serum increased intracellular reactive oxygen species and enhanced PCD of trypanosomes.

Plasmodium species

As with T. cruzi, in malaria, pathogenesis and symptoms are mediated by prostanoids and COX-2-derived PGs, which are the important proinflammatory mediators of the host-immune response. Bicyclo-PGE 2 and COX-2 proteins were found to be lower in children with mild and severe malaria in comparison with healthy children. Accordingly, it was deduced that, in healthy children exposed to malaria, elevated PGE 2 may protect them against the infection and that decrease in PGE 2 induced by IL-10 during acute malaria may increase susceptibility to severe disease [106] . An attempted study of the effect of suppressing circulating bicyclo-PGE 2 in malaria-infected children and those with additional bacteremia or HIV infections revealed its significant association with reduced hemoglobin levels. The authors concluded that bicyclo-PGE 2 may be considered as a marker and as a mediator of pathogenesis in malaria [107] .

Study of PG in patients recovering from P. falciparum infection revealed three groups of classified prostanoid groups. Group 1 was composed of four subgroups; group 2 was composed of three subgroups that were unrelated to symptoms during the recovery process; and group 3 TXB 2 was increased per chance due to platelet regeneration and recovery, whereas 8-epi PGF was decreased possibly because of high oxidative stress [108] . Furthermore, decreased COX-2/PGE 2 levels were found to be significantly associated with increase in IL-10 anti-inflammatory cytokine, responsible for expression of COX-2 gene products. Also suppression of COX-2/PGE 2 is caused by the ingestion of ferriprotoporphyrin by blood mononuclear cells. Thus, the acquirement of hemozoin by blood mononuclear cells in malaria accounts for suppression of PGE 2 by inhibiting molecular de novo COX-2 transcripts [109] .

Another report confirms that malarial pigment and malarial parasite products ingested by blood mononuclear cells induce suppression of PGE 2 through suppression of COX-2. It was noted that enhanced malarial anemia is associated with suppression of PGE 2 allowing overproduction of Tumor Necrosis Factor (TNFα) [110] . The relation of free heme and the suppression of anti-inflammatory mediators such as PGE 2 in human vivax malaria have been investigated. Patients with severe disease with higher hemolysis had lower plasma concentrations of PGE 2 than those with mild disease. This was attributed to the increased concentrations of plasma PGE 2 that occurred in severely sick patients undergoing treatment. Therefore, it was deduced that the binding of heme to CD14 monocytes, induced partial impairment of PGE 2 production. The researchers assumed that these results may generally explain the mechanisms of hemolytic diseases and represent a basis for future studies on therapeutic approaches [111] . On the other hand, PGD 2 , which is a potential factor derived from P. falciparum within erythrocytes, may be involved in the pathogenesis of cerebral malaria by inducing heme oxygenase-1 expression releasing iron, carbon monoxide, and biliverdin/bilirubin, and may influence iron supply to the P. falciparum parasites [112] . Another report also showed that in children with cerebral malaria and severe anemia there is significant reduction of PGE 2 in plasma and urine and COX-2 transcripts, with significant positive association between hemoglobin and both plasma and urinary PGE 2 . Additional analyses demonstrated the progressive decrease of plasma and urinary PGE 2 and COX-2 transcripts with the increase in concentration of malarial pigment in monocytes. It was concluded that reduced COX-2-derived PGE 2 decreased erythropoietic responses in children with severe malaria [113] .

Filarial species

In 2000, the ability of the filarial parasite O. volvulus to compete with serum albumin for procurement of the AA precursor of prostanoids was evaluated. Results showed that the worm's secretory protein (OvS1) bound AA with a five-fold greater affinity than that of the main host's fatty acid carrier protein [114] . A later study reported that O. volvulus carries extracellular GST (Ov-GST1), which is a glutathione-dependent PGD synthase, in its outer hypodermal lamellae and in parts of the cuticle. This Ov-GST1 produces PGD2 directly at the parasite-host interface [115] . In another report it was hypothesized that the large amount of AA surrounding the parasite may promote the uptake of fatty acid important for PG synthesis. The researchers conceded that the mechanisms controlling inflammatory processes in onchocerciasis facilitate the survival of the parasite, leading to chronic infection. They explained that the synthesized PGE 2 promoted the production of IgE and IgG1 in mice [116] , corresponding to human IgG4 [116] , and that both antibody types, which are characteristic of Th2-type immune responses, are characteristic of onchocerciasis [116] .

An immunohistological study to depict the site of PGE 2 in adult male and female O. volvulus showed significant localization in the hypodermis and weak expression in the epithelia of the intestine, uterus, and male genital tract, while the muscles stained PGE 2 negative. Less-pronounced PGE 2 staining was observed in some dermal microfilariae. It was concluded that PGE 2 released from live or dead filaria worms could affect the host´s immune response and metabolism in favor of the filarial parasite [26] .

In 2008, it was shown that the GST of Ov-GST1 carries a signal peptide that is cleaved off during maturation of the worm. This glycoprotein enzyme is probably involved in the production of parasite-derived prostanoids that control the host's effector responses, and thus it may be considered a target for chemotherapy and vaccine development [117] .

A more recent study on the onchocercoma showed that PGE 2 occurred significantly in infiltrating inflammatory cells. Sequential sectioning revealed the additional presence of TGF-β with PGE 2 . The authors indicated that the concomitant infiltration of PGE 2 and TGF-β immunoregulative mediator in host cells may control the inflammatory responses favoring the survival of the filarial worms [118] .

It was previously noted that microfilariae of W. bancrofti and B. malayi while circulating in the blood acquire polyunsaturated fatty acids, AA, and other fatty acids, and discharge PGE 2 on their surface [119] . Further, inhibition of aggregation of human platelets by microfilariae was evaluated in vitro. It was found that B. malayi microfilariae incubation with human platelets inhibited their aggregation, as well as TX generation and serotonin release. This inhibition did not require direct contact with the parasites and was found to be stimulated by thrombin, collagen, and AA. Decreased release of PGI 2 and PGE 2 and consequent inhibition of platelet aggregation occurred after treatment of microfilariae with COX inhibitors. These results confirmed the role of antiaggregatory prostanoids released by microfilariae in enhancing their survival [120] . Dirofilariasis in naturally infected cats showed significantly higher levels of PGE 2 and TXB 2 than in uninfected cats. This led the researchers to specify that dirofilariasis leads to the production of intravascular prostanoids, where PGE 2 in the early phase of infection may promote worm survival, whereas TXB 2 detected later may mediate inflammatory responses and thrombi formation [121] .

Schistosoma species

An early report in 1984 revealed the involvement of PGs during cercarial skin penetration due to stimulation of cercariae by skin and fatty acids. The researchers based their findings on the prevention of this response by COX inhibitors (ibuprofen and aspirin and 13-azaprostanoic acid) as powerful antagonists of the TX/endoperoxide receptor [122] .

In another early report, it was shown that macrophages from S. mansoni liver granulomas of mice could synthesize TXA 2 in larger amounts than PGE 2 and PGI 2 . Thus, TXA 2 appeared to be the major AA metabolite produced after stimulation of cells by either a phagocytic stimulus such as zymosan or by exogenous substrates AA and PGH 2 . It was concluded that TX synthase is responsible for the main arachidonate enzymatic activity in these cells [123] . In another study, the formation of PGE 2 by human PBMCs in schistosomiasis patients via the L-arginine-NO pathway concluded that NO too may be another important second signal stimulating PGE 2 production by immune complexes in PBMCs [124] . In a later report, after incubation with linoleic free fatty acid, which naturally occurs on the surface of the skin, S. mansoni cercariae were found to produce significant quantities of PGE 2 . COX-2 inhibitors failed to block this reaction, indicating that production of PGE 2 by the cercariae may be through a different biochemical pathway. In addition, the cercariae could induce PGE 2 and IL-10 from human and mouse cultured keratinocytes cells, which were not blocked by COX-2 inhibitors. In sharp contrast, the induction of PGE 2 or IL-10 from skin cells was significantly reduced after attenuation of cercariae by gamma irradiation. In the absence of IL-10 the schistosomula in the skin became surrounded by a noticeable cellular reaction that hindered migration through the skin. It was therefore postulated that the cercarial-induced PGE2 is involved in downregulation of host immune responses in the skin [125] . It was also found that the production of PGD 2 by S. mansoni interferes with migration of Langerhans cells TNFα through the adenylate cyclase-coupled PGD 2 receptor causing reduction of contact hypersensitivity responses. Accordingly, this inhibition of Langerhans cell migration may be another means for evasion of the host immune system by the parasites. Thus, PGD 2 too may have a major function in maintaining the cutaneous immune response against schistosomiasis [126] .

Another study found that PGE 2 secretion from mouse macrophage model cells was significantly promoted and IFN-γ-induced major histocompatibility complex (MHC II) expression was significantly suppressed by antigen prepared from normal cercariae as compared with antigen prepared from ultraviolet-radiation-attenuated cercariae [127] .

In addition, the activation of hepatic stellate cells, which particularly affects schistosome-induced hepatic fibrosis, could be inhibited by PGE 1 by alternating type I and III collagen. The researchers indicated that PGE 1 effectively protects the liver from fibrosis and that its combination with praziquantel therapy would effectively reverse ensuing fibrosis [128] .

Thanan et al. [129] used immunohistochemical analysis to study stem cell markers (Oct3/4 and CD44v6) and COX-2 expression in urinary bladder tissues from cystitis and cancer patients. The Oct3/4 stemness marker showed significantly higher immunoreactivity in S. haematobium-infected tissues than in normal tissues; whereas COX-2 located in the nuclei upregulated the two stemness markers in the presence of schistosomiasis-associated urinary cancer than in normal tissues. This proved enhancement of stem cell proliferation and differentiation through the production of PGE 2 , which in turn promotes inflammation of the urinary schistosomiasis.

Fasciola species

As with the other parasites mentioned, prostanoids were found to affect the pathophysiological changes in fasciolosis by acting as a cytoprotective and anti-inflammatory agent [130] . It was observed that the reduction of prostanoid and increase in TXB 2 /PGI 2 levels occur similarly in both F. hepatica infection and alcoholic liver disease [131] .

It was explained that reduction of prostanoid produced by F. hepatica may be a result of inhibition of PL activity, enhanced catabolism, and/or negative feedback of prostanoid. Such a decrease in the level of PGE 2 may then predispose to Fasciola-associated hepatitis and fibrosis. Parasite-induced inflammatory vascular responses such as vasoconstriction or vasodilation may be due to PGs such as TXB 2 and PGF or PGI 2 and PGE, respectively. On the other hand, prostanoids of parasite origin may inhibit macrophages and T-cell and B-cell functions allowing its evasion of the host's immune system [132] . The pattern of plasma prostanoids was also studied during the course of acute and chronic fasciolosis in sheep. This revealed a reduction in plasma PGE 2 and a significant increase in TXB 2 over PGF 1 . The surmised indication was that the shift in ratio causes altered clotting of blood during fasciolosis as TXB 2 stimulates thrombocyte aggregation, whereas PGI 2 is anti-aggregatory. The suspected cause for reduced plasma PGE 2 was its probable enhanced catabolism or disturbed synthesis of PG in the liver. It was concluded that parasite-induced liver damage is the cause of prostanoid depletion in the plasma, and prostanoid levels correlate with the severity of liver injury and clinical signs of fasciolosis. Furthermore, it was deduced that parasite-derived prostanoids enable the flukes to develop and survive and at the same time enhance the associated fibrosis in the parasitized bile ducts [133] .

Assessment of the plasma levels of PGE 2 , 6-keto-PGF 1a , and TXB 2 in F. hepatica infections of water buffaloes was also attempted. Transient increase in plasma PGE 2 was noted in buffaloes with subclinical fasciolosis. However, throughout the study period, no statistically significant increase was recorded, indicating that the early phase of subclinical fasciolosis is not associated with changes in plasma PGE 2 levels. On the other hand, during chronic fasciolosis, TXB 2 values showed transient significantly lower values. Even then the detected moderate changes in plasma prostanoid patterns might still be responsible for tissue damage and/or inflammation with F. hepatica infection. The different PGE 2 responses in infected sheep and water buffaloes may be attributed to differences in the course of infection and in the host's resistance. In water buffaloes, the recorded low fluke burden indicated the unlikely direct involvement of the worm products in the host's prostanoid metabolism [134] .

In another study, it was found that F. hepatica secretes thioredoxin peroxidase, which recruits and activates macrophages by producing Th2 responses represented by high levels of IL-10 and PGE 2 and low levels of IL-12 [135] .

In 2012, an investigation showed that the Sigma class GST of F. hepatica (FhGST-S1) simulates PG synthase activity promoting the synthesis and release of PGD 2 and PGE 2 from host immune cells, dendritic cells, and macrophages by activation of Th2 cells. The synthesized PGs via FhGST-S1 establishes the infection within the host. PGs are apparently also involved in reproduction by contributing to the development of ova [136] .


  Concluding remarks Top


  1. Although information about the metabolism and function of prostanoids is still scarce, it is obvious that these mediators play a major role in the physiology of parasitic protozoa and helminths.
  2. These lipids are essential modulators of parasite infectivity and host pathology, irrespective of their source.
  3. The ability of parasites to synthesize and release prostanoids has obviously become useful and effective in modulating the host response in favor of the parasite.
  4. Prostanoids are involved in the regulation and interaction between innate and adaptive immunity. The role played by COX metabolites of AA in immunity is complex and may sometimes be contradictory.
  5. Recently attention has been directed toward the importance of prostanoids and their receptors in modulating adaptive immunity and inflammatory responses.
  6. Understanding the mechanism by which prostanoids modulate immune response may permit the development of new drug targets selective to each prostanoid receptor. Thus, new drugs for disease management and for inflammatory and immunological disorders may be developed.



  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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