prostaglandins ( pg ) are a family of structurally related eicosanoids that have regulatory roles in normal physiological as well as pathological contexts .
cyclooxygenase enzymes catalyze the conversion of arachidonic acid to pgh2 , which is converted to other prostanoid species including pgd2 , pge2 , pgf2 , prostacyclin ( pgi2 ) , and thromboxane ( tx ) a2 by the action of specific synthases [ 13 ] .  
the synthesis of pgd2 from its precursor pgh2 is catalyzed by two pgd synthases ( pgdss ) .
prostaglandin d2 ( pgd2 ) is involved in a wide variety of neurophysiological functions , such as regulation of body temperature , hormone release , modulation of odor and pain responses , and regulation of the sleep - wake cycle in mammals .
pgd2 acts through two receptors ( dp1 and dp2 crth2 ) , whereas 15d - pgj2 can activate peroxisome proliferator - activated receptors or inhibit a range of proinflammatory signaling pathways , including nf-b [ 1 , 2 , 5 ] .   the importance of the role of pgd2 in the pathogenesis and resolution of inflammation and innate immune response is increasingly recognized [ 6 , 7 ] . however , the effect of pgd2 on inflammation is complex because pgd2 either promotes or suppresses inflammation depending on the inflammatory milieu .
this is further complicated by the fact that pgd2 undergoes nonenzymatic processes to generate 15d - pgj2 , an anti - inflammatory lipid .
therefore , the net effect may depend on the rate of production of distal products of pgd2 depending upon the disease process . here
, we review the biology and role of pgd synthases and pgd2 in inflammation and host immune response .
the arachidonate cyclooxygenase pathway can generate pgd2 by the functional linkage of a series of isoformic enzymes corresponding to phospholipase a2 , cyclooxygenase and pgds .
prostanoid formation occurs when cyclooxygenase oxygenates arachidonate converting it to pgg2 , which is then reduced to pgh2 .
pgh2 , in turn , is converted to five primary active metabolites , pgd2 , pge2 , pgf2 , pgi2 , or thromboxane a2 via distinct synthases such as pgd synthase and pge synthase [ 1 , 2 ] .
two pgd synthases have been identified , lipocalin ( l - pgds ) and hematopoietic ( h - pgds ) [ 4 , 810 ] .
l - pgds and h - pgds are quite different from each other biochemically in terms of their amino acid sequence , tertiary structure , evolutional origin , chromosomal and cellular localization , and tissue distribution and immunologically in terms of their functional relevance [ 10 , 11 ] .
hematopoietic pgd synthase ( h - pgds ) was previously known as the spleen - type pgds [ 9 , 12 ] or glutathione- ( gsh- ) requiring enzyme for the production of pgd2 in the peripheral tissues [ 12 , 13 ] .
h - pgds is characterized as a member of sigma class of glutathione s - transferase ( gst ) gene family   that catalyze the conjugation of gsh to an electrophilic substrate .
h - pgds is localized in antigen - presenting cells and mast cells of a variety of tissues and is involved in the activation and differentiation of mast cells .
h - pgds isomerizes pgh2 to pgd2 selectively and effectively , whereas other gst isozymes catalyze the conversion of pgh2 nonselectively to produce pgd2 , pge2 , and pgf2. the high specificity of h - pgds for the production of pgd2 is attributed to the unique architecture of the catalytic pocket .
the deep and wide catalytic cavity of h - pgds is striking in comparison with the narrow shallow cavities of other gsts .
the unique 3 d architecture of the cleft leads to the putative substrate binding mode and its catalytic mechanism , responsible for the specific isomerization from pgh2 to pgd2 .
h - pgds contributes to the production of the d and j series of prostanoids in the immune system and is involved in allergic inflammatory response .
since h - pgds is present in mast cells , th2 cells , and other leukocytes , it is thought to be responsible for the bulk of pgd2 production during allergic responses [ 16 , 17 ] . in mouse models of asthma and allergic disease , h - pgds has a substantial proinflammatory effect , regulating many hallmark characteristics including eosinophilia , airway hyperreactivity , mucus production , and th2 cytokine levels . inhibitors of h - pgds
the compound , hql-79 , is characterized as a specific inhibitor of human h - pgds and has shown to exhibit a therapeutic effect when used in animal models of allergic disease and neuroinflammation .
thus , selective inhibitors of h - pgds may prove to be more useful to suppress allergic and inflammatory reactions rather than cox-1 or cox-2 inhibitors , such as aspirin , indomethacin , and coxibs because these cox inhibitors suppress the production of all prostaglandins in comparison to h - pgds inhibitors [ 2023 ] . while h - pgds is proinflammatory in allergic airway diseases , h - pgds has shown to be protective in other models of inflammation .
showed that h - pgds negatively regulates the severity and duration of delayed type hypersensitivity responses .
their data suggests that contrary to the role of h - pgds in driving th2-like responses in models of asthma , hpgds may act as an internal braking signal essential for bringing about the resolution of th1-driven delayed type hypersensitivity reactions .
using h - pgds knockout mice showed that h - pgds synthesizes 15d - pgj2 during mammalian defense responses and together with pgd2 , acting through the dp1 receptor , plays a central role in controlling the onset of acute inflammation and its resolution by balancing pro- versus anti - inflammatory cytokines .
these data highlight the anti - inflammatory and proresolution properties of cyclopentanone prostaglandins , pgd2 and dp1 receptors .
lipocalin - type pgds is gsh independent and is identical to beta trace protein , which was discovered in 1961 as a major protein of human cerebrospinal fluid [ 2628 ] . because it resembles lipophilic ligand carrier proteins it was named lipocalin - type pgd synthase .
l - pgds is a bifunctional protein , acting as a pgd2-producing enzyme as well as an intercellular transporter of retinoids or other lipophilic molecules .
it is the only enzyme among the members of the lipocalin gene family that binds small lipophilic substances like retinoic acid , bilirubin , and ganglioside .
structurally it is a monomer with a -barrel structure and a hydrophobic pocket and was initially identified as responsible for pgd2 production in the brain [ 10 , 19 , 30 ] . since then it has been shown that l - pgds is also expressed in other tissues including the heart , kidneys [ 31 , 32 ] , and lungs [ 33 , 34 ] .
l - pgds is secreted into various body fluids , such as csf , plasma , seminal plasma , and urine , and functions as both a pgd2-producing enzyme and an extracellular transporter of various lipophilic substances .
the l - pgds/-trace concentration in human serum fluctuates with circadian rhythmicity and exhibits a nocturnal increase and is best known because of its ability to induce sleep .
deletion of l - pgds leads to accelerated glucose intolerance and induces obesity , nephropathy , and aortic thickening [ 36 , 37 ] . in animal models of ischemia
lack of l - pgds confers susceptibility to injury in brain and heart [ 31 , 32 , 38 ] .
l - pgds also has an inhibitory effect on progression of lung , ovarian , and colorectal cancer and some forms of leukemia .
thus , it is evident that l - pgds has several key regulatory roles that extend beyond its function in the brain .
similar to h - pgds in models of allergic inflammation l - pgds has shown to be proinflammatory .
fujitani et al . reported that l - pgds transgenic mice exhibit strong allergic lung responses and eosinophilia   with enhanced allergic airway inflammation . in a model of chronic allergic dermatitis blockade of l - pgds with
an inhibitor led to significant attenuation of inflammatory response , which was also confirmed in crth2 knockout mice .
the proinflammatory role of l - pgds has also been suggested in human ulcerative colitis .
hokari et al . showed that the level of l - pgds mrna expression is increased in uc patients in parallel with disease activity . in a diabetic rat model ogawa et al .
showed that urinary excretion of l - pgds increased preceding diabetic nephropathy   and the levels of l - pgds could predict the progression of renal injury .
l - pgds in the urine is being investigated as a diagnostic biomarker of acute kidney injury and inflammation associated with diabetes , hypertension , and drug - induced nephropathy . because l - pgds has a smaller molecular weight than serum albumin
it may be expected to appear in the urine even before albuminuria and hence prove as a more sensitive marker for early detection of renal injury .
we have studied the role of l - pgds in lps - induced inflammation and shown that l - pgds is induced in vitro in macrophages [ 33 , 34 ] and in vivo in the lung in response to lps and p. aeruginosa .
our study showed that h - pgds was constitutively expressed in vitro in macrophages whereas l - pgds is induced in a time - dependent manner in response to lps or pa103 . similarly in vivo studies in mice showed that the expression of l - pgd synthase was induced in response to lps and pa103 .
however , the immunomodulatory effects of l - pgds are less well studied . in a mouse model of p.
aeruginosa infection we have shown that l - pgds mice have impaired host defenses whereas overexpression of l - pgds is protective in p. aeruginosa - induced pneumonia suggesting a pivotal role for l - pgds in innate immune response .
pgs are a group of 20-carbon polyunsaturated fatty acids containing a unique 5-carbon ring structure .
prostaglandins are all produced from arachidonic acid ( c20:4 fatty acid ) via their common intermediate , pgh2 , and are a family of structurally related eicosanoids that not only have an important role in homeostasis but also contribute to the pathology of numerous inflammatory diseases .
each prostanoid is then produced from pgh2 by its specific terminal pg synthase such as pgd synthase in the case of pgd2 .
pgd2 is an acidic lipid mediator derived from arachidonic acid by sequential action of cyclooxygenase and pgd2 synthases .
both h- and l - pgd synthase enzymes may form pgd2  in vitro , but it is not fully understood which pgds enzyme predominates under varied conditions in vivo .
pgd2 for a long time was considered as a minor and biologically inactive prostaglandin . in the 1980s , however , pgd2 was found to be the most abundant prostaglandin in the brains of rats   and other mammals including humans , thus suggesting that it may have an important function in the central nervous system ( cns ) .
the physiological functions of pgd2 have now been extensively defined and include regulation of sleep and body temperature , olfactory function , hormone release , and nociception in the central nervous system .
it is released from mast cells as an allergic and inflammatory mediator   and is responsible for the symptoms in mastocytosis patients , such as flushing , diarrhea , tachycardia , dyspnea , and deep sleep .
pgd2 is further converted to 9 , 11-pgf2 , a stereoisomer of pgf2 , which exerts various pharmacological actions different from those induced by pgf2. pgd2 is also readily dehydrated in vitro and in vivo   to produce prostaglandins of the j series , such as pgj2 , -pgj2 , and 15-deoxy--pgj2 .
15-deoxy--pgj2 has been identified as an endogenous ligand for a nuclear receptor ( peroxisome proliferator - activated receptor  ) , and it promotes adipocyte differentiation [ 5 , 6 ] .
pgd 2 has been implicated in the initiation and progression of inflammation . in mouse models of asthma and allergic disease
, pgd2 has a substantial proinflammatory effect , regulating many hallmark characteristics including eosinophilia , airway hyperreactivity , mucus production , and th2 cytokine levels [ 40 , 47 ] .
moreover , inhibition of pgd 2 synthesis and pgd 2 signaling blockade has a suppressive effect on neuroinflammation in mouse models of krabbe 's disease .
the injection of pgd 2 into the skin has been shown to result in erythema , edema , induration , and leukocyte infiltration .
pgd 2 and other vasodilator prostaglandins may also contribute to inflammation by increasing local blood flow .  
in contrast to these proinflammatory effects , pgd 2 and its cyclopentenone prostaglandin derivatives also have anti - inflammatory properties , with functions in resolution of inflammation .
there is considerable interest in the importance of pgd2 and its distal products in the mediation and resolution of inflammation [ 3 , 57 ] .
gilroy et al . showed that in a model of experimental pleuritis pgd2 significantly attenuated inflammation . similarly in a model of experimental colitis cox-2-derived pgd2 , acting via the dp receptor , was shown to attenuate neutrophilic infiltration into colonic mucosa . in a human model of an acute inflammatory response induced by administration of lps , which evokes transient flu - like symptoms with pyrexia and a hemodynamic response , song et al .
have shown that tetranor pgdm increases markedly during this response and that pgj2 has antipyretic effects .
although several studies have investigated the role of pgd 2 in inflammation , the role of pgd2 in host immune response has been scantly studied .
an earlier study showed that pgd2 concentration , but not the pge2 or il-1 concentrations , is elevated in a time - dependent manner in the csf of patients with african sleeping sickness , caused by trypanosoma brucei .
these investigators have also shown that mouse astrocytes and fibroblasts in culture induce the production of pgd2 in response to t. brucei .
although the production of pgd2 was increased in vitro , the functional effects of pgd2 in this setting remain unclear . in a recent investigation zhao et al . showed that an age - related increase in pgd2 in mice led to diminished respiratory dendritic cell migration resulting in defects in virus - specific t - cell responses in vivo .
they further showed that administration of pgd2 antagonist reversed this defect resulting in migration of dendritic cells with enhancement of t - cell antivirus response with increased clearance and survival .
these data suggest that similar to allergic airway disease pgd2 may have immunosuppressive effects in viral infections . in a mouse model of p.
aeruginosa lung infection we have shown that inhibition of cox-2 improves survival in a lethal model of p. aeruginosa infection .
the bacterial clearance of p. aeruginosa was enhanced in cox-2 knockout mice whereas transgenic mice that overexpress cox-2 have an impaired bacterial clearance from the lungs .
our study showed that the immunomodulatory effects of inhibition of cox-2 are related to inhibition of pge2 .
we also examined the effects of administration of pgd2 in a model of p. aeruginosa lung infection .
mice that were given intratracheal pgd 2 showed an enhanced clearance of p. aeruginosa from the lungs .
these results were in agreement with our studies from l - pgds knockout and l - pgds overexpressing mice .
we have shown that pgd2 inhibits a key proinflammatory immunoglobulin cell surface receptor trem-1 in vitro in macrophages .
furthermore , we have shown that pgd2 induces the expression of nrf2 in a dp1 receptor - dependent manner .
these studies provide a new paradigm and highlight a key regulatory role of pgd2 in innate immune response to bacterial infections .
the role of pgds / pgd 2 in regulating inflammation in a variety of organ systems and disease process is burgeoning .
the inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host .
it is now evident that endogenous biochemical pathways such as pgds / pgd 2 get activated during defense reactions .
the effect of pgds / pgd2 on inflammation is complex because they can either promote or suppresses inflammation depending on the inflammatory milieu .  
table 1 provides a summary of the models of different effects of pgds / pgd2 .
interdiction of l - pgds , pgd2 , and dp receptors provides novel therapeutic approaches to modulate inflammation and innate immune responses .
 pgd2 is formed from arachidonic acid by successive enzyme reactions : oxygenation of arachidonic acid to pgh2 , a common precursor of various prostanoids , catalyzed by cyclooxygenase , and isomerization of pgh2 to pgd2 by pgd synthases ( pgdss ) . 
 pgd2 can be either pro- or anti - inflammatory depending on disease process and etiology . 
 the anti - inflammatory and immunomodulatory attributes of pgds / pgd2 provide opportunities for development of novel therapeutic approaches for resistant infections and refractory inflammatory diseases . 
 this paper highlights the role of pgd synthases and pgd2 in immune inflammatory response . 
1. Introduction
2. PGD Synthases
3. Hematopoietic PGD Synthase
4. Lipocalin-Type PGD Synthase
5. Prostaglandin D
6. Conclusions