PAF Receptors Peter M. Henson* Department of Pediatrics, National Jewish Medical Research Center, 1400 Jackson Street, Room D-508, Denver, CO 80206-2761, USA * corresponding author tel: 303-398-1380, fax: 303-398-1381, e-mail:
[email protected] DOI: 10.1006/rwcy.2000.23003.
SUMMARY Platelet-activating factor (PAF) reacts with a specific seven transmembrane, G protein-linked receptor with two promoter splice forms showing tissue-specific regulation and for which a knockout mouse has recently been created. The receptor is widely expressed on hematopoietic cells, endothelial cells, keratinocytes, and cells of the central nervous system. A huge number of receptor antagonists have been synthesized and many are being explored in vitro, in animal models, and in a variety of clinical trials. In addition, the complexity of the PAF story is increased by the observation that in the majority of cells that synthesize it, most of the PAF remains within the cell, leading to speculation that it plays an intracellular role, perhaps even on an intracellular receptor, in addition to its role as extracellular communication molecule.
BACKGROUND
Discovery Following a large body of work on PAF receptors determined by a variety of binding assays, a candidate plasma membrane receptor from the guinea pig was cloned in 1991 by expression cloning in Xenopus eggs (Honda et al., 1991), followed soon after by its human counterpart (Nakamura et al., 1991; Ye et al., 1991; Kunz et al., 1992; Chase et al., 1993).
Structure The receptor is a seven transmembrane, heterotrimeric G protein-linked receptor (see Figure 2).
Main activities and pathophysiological roles As discussed in the PAF chapter, much of the PAF that is synthesized does not gain access to the extracellular environment. The presence of PAF within synthesizing cells as well as the recent interest in oxidized phospholipids and questions about the roles of intracellular acetylhydrolases, have rekindled research into the intracellular effects of this family of molecules. While there little direct evidence to date for such effects and even less information on specific receptors or signaling pathways, a number of intriguing (although speculative) possibilities and questions might be considered. Oxidized phospholipids would be expected to have potential toxic effects within cells leading to the propagation of redox alterations and alteration in normal membrane structure and function. Potent catabolic enzymes may have developed to counteract such effects. These acetylhydrolases (as well as the action of phospholipases A2) generate lysophosphatides, themselves potentially toxic because of their amphipathic properties. The transacylase and acetyltransferase involved in PAF biosynthesis could therefore further protect the cell, ultimately making use of an abundant ingredient, acetyl-CoA. The extremely wide distribution of such pathways (including plants, fungi, and bacteria) might be in keeping with such a concept. Additional activities of these molecules might originally have derived from this need for inactivation but now could include effects on intracellular receptors and signaling pathways. No such receptor has yet been definitively described although there were some early reports of such molecules at the 1998 PAF and Related Lipid Mediators Meeting in New Orleans. It has been suggested that the antagonist BN-50730
2184 Peter M. Henson may be effective against possible intracellular PAF receptors (Bazan et al., 1997) and its use has also raised the possibility of such effects in a number of neuronal systems. This is indeed an area that needs more investigation.
GENE
Accession numbers GenBank: Human: S52624, D10202, D31736, U11032 Mouse: D50872 Rat: U04740 Guinea pig: X56736
from leukocytes and brain; one is upregulated by glucocorticoids, the other by retinoids, etc. On the other hand, pharmacological studies have consistently suggested a more complex system with the likelihood of more than one receptor (see, for example, Hwang, 1988, 1991; Kato et al., 1994; LeVan et al., 1997; Voelkel et al., 1986). At this point, if another membrane receptor is found, it will probably be quite different from the cloned version since attempts to find genes related to the cloned PAFR have been uniformly unsuccessful. Glycosylation of the receptor is required for its expression (Garcia Rodriguez et al., 1995a). An intron in the 50 untranslated region of the human gene has also been described (Chase et al., 1993).
PROTEIN
Sequence
Description of protein
See Figure 1.
Chromosome location and linkages Only one gene has been identified (on chromosomes 1 and 4 in human or mouse respectively), although alternative splice forms are seen with an identical coding region but differing upstream. 50 sequences and different transcription initiation sites (Mutoh et al., 1993; Shimizu and Mutoh, 1997). One is found in most cells and tissues, the other is selectively absent
The receptor appears to be a relatively standard seven transmembrane, heterotrimeric G protein-linked receptor (Mutoh et al., 1993; Shimizu and Mutoh, 1997) comprising 342 amino acids (in human). The cysteines at positions 90 and 173 form a disulfide bond and Cys95 also seems important ± mutation of these alters membrane expression and function (Le Gouill et al., 1997). Mutation of Leu231 to Arg led to a constituitively active receptor with higher binding affinity for PAF, whereas conversion of the adjacent
Figure 1 Deduced sequences of rat, guinea pig, human, and mouse PAF receptor. From Nakamura et al. (1991), Bito et al. (1994), Honda et al. (1991), Ishii et al. (1996). RA: GP: HU: MU:
MEQNGSPRVDSEFRYTLFPIVYSVIFVLG VVANGYVLWVFATLYPSKKLNEIKIFMVNLTVADLLFLMTLPLWIVYYSNE NELNSSSRVDSEFRYTLFPIVYSIIFVLGIIANGYVLWVFARLYPSKKLNEIKIFMVNLTVADLLFLITLPLWIVYYSNQ MEPHDSSHMDSEFRYTLFPIVYSIIFVLGVIANGYVLWVFARLYPCKKFNEIKIFMVNLTMADMLFLITLPLWIVYYQNQ MEHNGSFRVDSEFRYTLFPIVYSVIFILGVVANGYVLWVFANLYPSKKLNEIKIFMVNLTMADLLFLITLPLWIVYYYNE GDWIVHKFLCNLAGCLFFINTYCSVAFLGVITYNRYQAVAYPIKTAQATTRKRGITLSLVIWISIAATASYFLATDSTNV GNWFLPKFLCNLAGCLFFINTYCSVAFLGVITYNRFQAVKYPIKTAQATTRKRGIALSLVIWVAIVAAASYFLVMDSTNV GNWILPKFLCNVAGCLFFINTYCSVAFLGVITYNRFQAVTRPIKYAQANTRKRGISLSLVIWVAIVGAASYFLILDSTNT GATILPNFLCNVAGCLFFINTYCSVAFLGVITYNRYQAVAYPIKTAQATTRKRGISLSLIIWVSIVATASYFLATDSTNL VPKKDGSGNITRCFEHYEPYSVPILVV HIFITSCFELVFFLIFYCNMVIIHTLLTRPVRQQRKPEVKRRA LWMVCTVLAV VSNKAGSGNITRCFEHYEKGSKPVLIIHICIVLGFFIVFLLILFCNLVIIHTLLRQPVKQQRNAEVRRRALWMVCTVLAV VPDSAGSGNVTRCFEHYEKGSVPVLIIHIFIVFSFFLVFLIILFCNLVIIRTLLMQPVQQQRNAEVKRRALWMVCTVLAV VPNKDGSGNITRCFEHYEPYSVPILVVHVFIAFCFFLVFFLIFYCNLVIIHTLLTQPMRQQRKAGVKRRALWMVCTVLAV FVICFVPHHVVQLPWTLAELGYQ-TNFHQAINDAHQITLCLLSTNCVLDPVIYCFLTKKFRKHLSEKFYSMRSSRKCSRA FVICFVPHHMVQLPWTLAELGMWPSSNHQAINDAHQVTLCLLSTNCVLDPVIYCFLTKKFRKHLSEKLNIMRSSQKCSRV FIICFVPHHVVQLPWTLAELGFQDSKFHQAINDAHQVTLCLLSTNCVLDPVIYCFLTKKFRKHLTEKFYSMRSSRKCSRA FIICFVPHHVVNLPWTLAGLGTQ-TNFHQAINDAHQITLCLLSTNCVLDPVIYCFLTKKFRKHLSEKFYSMRSSRKCSRA TSDTCTEVMMPANQTPVLPLKN TTDTGTEMAIPINHTPVNPIKN TTLTVTEVVVPFNQIPGNSLKN TSDTCTEVIVPANQTPIVSLKN
PAF Receptors 2185 Ala230 to Glu had the opposite effect (Parent et al., 1996), suggesting an important influence of this region of the third intracellular loop on configuration. An N-glycosylation site is present on the second extracellular loop and appears important for membrane expression but not for function (Garcia Rodriguez et al., 1995b).
ment as a phospholipid from the outer membrane leaflet and probably only partitioned into the aqueous environment on a carrier such as albumin. It has been estimated that plasma albumin has four binding sites for PAF (probably of different affinities) and suggested that PAF is usually presented to its receptor on this protein (Clay et al., 1990). An alternative source of PAF activity for interaction with target cells may be the shedding of PAF-containing membrane vesicles from the synthesizing cells (Patel et al., 1992), perhaps providing an explanation for early studies of PAF activity in the absence of an albumin carrier. As indicated, there are still a significant number of discrepancies in our understanding of PAF-receptor interactions. Addition of PAF to cells results in nonreceptormediated association/insertion into the outer membrane leaflet (e.g. Bratton et al., 1992). From there it can be flipped to the inner leaflet by the action of the phospholipid scramblase. What is not clear is whether, in either of these configurations, it can interact with the PAF receptor or whether such binding can only occur when it is presented in solution (i.e. on a carrier) and/or whether it can interact with the receptor on one cell when presented in the membrane of another. It should be noted that PAF can also be internalized through interaction with its receptor (Gerard and Gerard, 1994), making it
Relevant homologies and species differences The differences between the PAF receptor in the three species from which it has been cloned are subtle (see Figure 1). The mouse and rat protein has one less amino acid than human or guinea pig. Figure 2 illustrates these differences in the context of the distribution across the membrane.
Affinity for ligand(s) PAF is an amphiphilic phospholipid. Accordingly, its mode of interaction with a surface receptor might be expected to be complex. At concentrations above micromolar in aqueous solution (without a carrier) it is likely to form micelles. When `secreted' by cells it is thought to be presented to the extracellular environ-
Figure 2 PAF receptor showing amino acids common between human, mouse, rat, and guinea pig. Adapted from Shimizu and Mutoh (1997). Extracellular D
W
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E F R Y
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Y I V I V P V L Y L P S T I F F L L L G D A A T N G L Y N V M L V W F V I F K A I L E Y N P K K F
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Cytoplasmic 342 (341)
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P L T L C L Q S T H T C P H N V F F V L V P F I D C F V F I Y A V I F C L T C I V C N T M V V K C K W S I Q Q L K R R I S A F S R R T T P R R K L M L V H D L T W
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C G L F F N I Y T S C A V L F G I V T Y N
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2186 Peter M. Henson imperative to distinguish these pathways in any studies of uptake. An intriguing observation that may have little to do with PAF or its analogs directly is the suggestion that Streptococcus pneumoniae can bind to cells, including epithelial cells, via the PAF receptor, utilizing the phosphorylcholine on the bacterial teichoic acid (Cundell et al., 1995).
Cell types and tissues expressing the receptor The PAF receptor and/or PAF binding has been found throughout the body, including the central nervous system on many different cell types, including neutrophils, eosinophils, basophils, mononuclear phagocytes, some lymphocytes, mast cells, endothelial cells (Domingo et al., 1994; Predescu et al., 1996; Sasaki et al., 1996), and keratinocytes (Shimada et al., 1998a). It can be seen associated with an endosomal compartment within endothelial cells (Ihida et al., 1999) but this could represent endocytosed receptor. Transcripts for the receptor are present from very early in embryogenesis (Stojanov and O'Neill, 1999) and are also present on spermatozoa (Reinhardt et al., 1999).
Regulation of receptor expression The human PAF receptor appears to be transcribed by two distinct promoters, each of which has distinct transcriptional initiation sites (Mutoh et al., 1993). These exons are alternatively spliced to a third that contains the total open reading frame, thus generating two different transcripts. Transcript 1 has consensus sequences (three) for NFB and SP-1, and the initiator (Inr) sequence (see also Pang et al., 1995, and see GenBank accession number U11032). Transcript 2 also contains consensus sequences for AP-1, AP-2, and SP-1. Both transcripts were reported in heart, lung, spleen, and kidney, whereas only transcript 1 was found in granulocytes and brain. A variety of cytokines have been reported to upregulate PAF receptor expression. Thus increased PAFR mRNA expression was seen in eosinophils from patients with asthma and was upregulated by exposure to IL-3, IL-5, and GM-CSF (Kishimoto et al., 1996a, 1996b, 1997). In endothelial cells, mechanical stress also increases mRNA expression (Okahara et al., 1998; Chaqour et al., 1999). PAF itself has been reported to do the same (Wang et al.,
1997). All of these have been suggested to act through NFB, three binding sites for which are seen in the promoter between ÿ571 and ÿ459 bp (Mutoh et al., 1994). On the other hand, PAF itself has also been suggested to downregulate PAF receptor mRNA expression (Nakao et al., 1997) and oxidized LDL has been reported to do likewise (Stengel et al., 1997). How this occurs is not yet clear but the contrasting observations certainly raise the possibility of complex, possibly multifactorial regulation. By a presumably different mechanism, the receptor is upregulated by TGF 2 acting as a consequence of a protein synthetic step on a response element in the PAFR promoter between ÿ44 and ÿ17 bp (Yang et al., 1997).
SIGNAL TRANSDUCTION
Cytoplasmic signaling cascades Signaling While the PAF receptor may be considered a relatively conventional member of the large seven transmembrane, heterotrimeric G protein-coupled receptor family, it may show differences from other chemoattractant or inflammatory mediator receptors in its presumed G protein usage, e.g. partial pertussis insensitivity (Hwang, 1988; Barzaghi et al., 1989; Yue et al., 1992; Honda et al., 1994), implying use of multiple G proteins (Ali et al., 1994). Its signaling pathways have been investigated in a number of cells with native receptor (e.g. neutrophils, eosinophils, or platelets) and after transfection into cells not normally expressing this molecule (see Boulay et al., 1997; Honda et al., 1994; Shimizu and Mutoh, 1997). On the other hand, a number of differences have been noted between fMLP and PAF signaling in neutrophils (e.g. Kadiri et al., 1990; M'Rabet et al., 1999), including relative selectivity towards p38 among the MAP kinases for the PAF receptor (Nick et al., 1997). Eicosanoid production often accompanies the generation of PAF, both in vitro and in vivo. The first step in biosynthesis of eicosanoids is the action of cPLA2 on the arachidonyl moiety esterified in membrane phospholipids. A proportion of this available substrate is in phosphatidylcholine (PC) and some of this, in turn, alkyl arachidonyl PC. Synthetic coupling of the two mediator classes would, therefore, be expected since substrate (arachidonate or lyso-PAF) for both synthetic pathways is generated simultaneously. In addition, however, PAF can activate cPLA2 in target cells via upstream signal pathways, including activation of the MAP kinase
PAF Receptors 2187 ERK (Hirabayashi et al., 1998), which could in turn lead to both more eicosanoids and more PAF.
Priming In neutrophils, and particularly eosinophils, PAF is directly chemotactic in vitro and also induces the related alterations in cell shape driven by cortical assembly of F-actin. On the other hand, with respect to other cell responses the PAF receptor often generates an incomplete signal, requiring additional cofactor stimulation for effective responses. In neutrophils this process was described as priming (Guthrie et al., 1984) and was first shown with LPS as a `priming' agent. However, PAF stimulation is the prime example of this effect (e.g. Gay, 1993). For example, by itself, it does not initiate the oxidative burst but rather induces alterations in the cell responsiveness such that other stimuli, including other chemoattractants as well as FcR ligation or even phorbol ester activation are all enhanced as a consequence (e.g. Bass et al., 1988; Kitchen et al., 1996). Other PAF-primable responses include eicosanoid production (Bauldry et al., 1991; Shindo et al., 1996, 1997), actin assembly (Shalit et al., 1987), secretion (Partrick et al., 1997; Vercellotti et al., 1988), etc. The mechanisms for this priming phenomenon are still not known but it does not seem to involve upregulation or significant alteration of the receptors for the triggering stimuli. One intriguing observation in this regard is that priming stimuli, especially PAF, are particularly effective at activating the p38 subfamily of MAP kinases (Nick et al., 1997) although its relationship to priming has still to be determined. (Note that PAF can also stimulate cells primed with other agents (e.g. Brunner et al., 1991), i.e. the processes are often reciprocal.) The suggested importance of priming is that stimuli such as PAF are presumed to initiate inflammatory cell accumulation but, by themselves, not to stimulate the cells further, thus minimizing potential damage to the vessel wall during the migration. Once in the tissues however, the primed cells would be hyperresponsive to additional triggering stimuli such as other inflammatory mediators, bacteria, immune complexes, etc. This is not to imply that PAF is only, or even primarily, a proinflammatory mediator since, as discussed below, it acts on many other cells and systems and, in vivo, may have equally or more important roles in a number of physiologic processes. Rather, the point here is that PAF receptor signaling probably intersects significantly with other signaling pathways ± a concept that may be of critical importance in consideration of some of its other potential roles, such as in
the neurologic or vascular systems, cell growth and differentiation, etc. Receptor Desensitization From studies in inflammatory cells again, it has long been appreciated that PAF responses are often even more transient that those seen with other inflammatory mediators and chemokines, i.e. the receptor seems to be particularly susceptible to desensitization. In fact, this process was earlier used to show PAF action in vivo in a model of IgE-mediated anaphylactic shock wherein the rapid and transient thrombocytopenia was suggested to be PAF-dependent because the platelets that returned to the circulation after 60 minutes had become selectively unresponsive to PAF (Henson and Pinckard, 1977). The PAF receptor can be directly phosphorylated (Ali et al., 1994), probably by a PKC, PKA, and a receptor kinase, leading to homotypic desensitization (Takano et al., 1994). The serine/threonine phosphorylation seems to enhance receptor internalization and thereby plays an additional role in desensitization (Ishii et al., 1998a). A further mechanism for desensitization has been described in which PKA-driven phosphorylation of PLC 3 is suggested to lead to unresponsiveness of that enzyme, and because of its relatively selective usage by the PAF receptor, unresponsiveness of the cell to PAF (Ali et al., 1997, 1998). The potential importance of rapid and effective downregulation is the transience of PAF responses, perhaps related to the potency of the mediator and strength of its effects.
DOWNSTREAM GENE ACTIVATION Incomplete information.
BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY The enormous heterogeneity of the possible effects of PAF in vitro and ultimately in vivo makes it difficult (a) to summarize these in simple terms in one chapter and (b) to determine which of these possibilities is actually operative, or even more critical, important, in the whole animal. To determine a specific role for a potential mediator, such as PAF (and its analogs), in
2188 Peter M. Henson any given process, it would need to be present at the site and shown able to induce the response if introduced; the effect should be abrogated if the mediator is removed, blocked or absent and return when reintroduced. As indicated above, the availability of a number of PAF receptor antagonists has allowed various combinations of these criteria to be applied and has suggested the many potential actions. The presence and wide distribution of potent inactivating enzymes has also led to speculative roles for PAF in vivo and, in some cases, genetic variants of these enzymes have been shown to have disease associations. The field was reviewed in 1994 by Stewart (Stewart, 1994) but most of the more recent reviews have addressed specific areas of potential action. In this section we will discuss some of the likely areas of PAF effect, not with any expectation of completeness but rather to emphasize some specific points, concepts, and areas for future development. As a general example, the potential importance of oxidized phospholipids in atherosclerosis and the recognition that some of these have PAF-like activity opens up a number of important questions that are crying out for more detailed investigation. A receptor knockout mouse has recently been created with a phenotype that calls into question some of these wide-ranging effects ± at least as far as those mediated through this receptor are concerned (see below).
Unique biological effects of activating the receptors When added to isolated cells with functioning PAF receptors (e.g. neutrophils or eosinophils) the types of cellular responses that are seen are, in general, typical of rapid mediator action via seven transmembrane, G protein-coupled receptors. These include calcium mobilization, shape change (morphologic polarization), actin polymerization, chemokinesis and chemotaxis, priming for NADPH oxidase activation and eicosanoid production, adhesion, and integrin regulation. Platelet responses are also relatively standard, for example, potent aggregation and some release reaction. Interestingly, phosphatidylserine expression is not observed (Henson and Landes, 1976) and, as a consequence, procoagulant effects are minimal. There has been some suggestion that PAF is relatively selective as a proadhesive and chemotactic agent for eosinophils (Stewart, 1994; Wardlaw et al., 1986), but it certainly has similar activity against other leukocytes in vitro and its administration to animals does
not result in an exclusively eosinophilic response. On the other hand, the addition of IL-5 increases the eosinophil response selectively (e.g. Warringa et al., 1992), thus emphasizing the importance of mediator cooperation in selecting specific cells for activation. Longer term cellular responses in inflammatory cells have been less often investigated except for those classified under the rubric of `priming' responses, i.e. an enhancing function in cooperation with other stimuli. Even here there is much room for further investigation, for example in the de novo synthesis of new mediators, regulatory enzymes of the eicosanoid pathways, etc. A similar confusing story is seen when questions of PAF action in cell proliferation and maturation are raised. Reported effects include growth inhibition (Huang et al., 1999; Shimada et al., 1998b) and downregulation of myelopoesis (Dupuis et al., 1998) or, on the other hand, evidence of growth stimulation (Bennett and Birnboim, 1997; Rougier et al., 1997). It is presumed that responses will vary between cell types and, for the most part, will be mediated via secondary production or inhibition of regulatory molecules. PAF as a Cofactor and the Concept of Mediator Networks A common statement is that `PAF is a mediator of inflammation'. What is specifically meant by this is not always clear. The presence of PAF receptors on inflammatory cells (including platelets) as well as on the endothelium provides for an action on these cells via the cell responses listed above. In artificial systems PAF can be shown to induce chemotaxis, transendothelial migration (e.g. Casale et al., 1993) and, in conjunction with other stimuli, production and secretion of oxidants, other lipid mediators and proinflammatory mediator proteins. In a significant number of circumstances in vivo, the observed PAF effect is actually mediated by one of these downstream. products, often an eicosanoid ± i.e. PAF is an intermediary, perhaps contributing an amplification step to the overall proinflammatory signal. A potential theme that might be considered for PAF action is that it is, for the most part, a cofactor. Its role as a priming agent for neutrophil oxidant production is well established. Taking this as a model then, the ability of signaling pathways initiated through the PAF receptor to integrate with signaling from other, often more cell-specific, receptors could serve to explain many of the proposed PAF actions. For example, its role as an eosinophil chemoattractant may involve interaction with the relatively eosinophil-selective agent IL-5. Similarly with monocytes
PAF Receptors 2189 in the presence of endothelial P-selectin (Zimmerman et al., 1996). The idea of selective recognition resulting from integrated networks rather than exclusively cell- and ligand-specific receptors is gaining general ground (see, for example, the latest concepts of selectivity in odorant recognition (Mombaerts, 1999)). Similar processes could apply in inflammation where the complex network of mediators may drive specific, directed, and sequential cell responses by the integrated action of numerous, intrinsically generally acting, mediators on a given cell type. A cofactor role for PAF would mean that its antagonism could dampen down many specific responses (as seen in the studies with antagonists) but also that specific essential actions would be very hard to pin down. It would also explain the relative absence of phenotype in the knockout mice, in which compensatory mechanisms within the network would be particularly prone to take over.
Phenotypes of receptor knockouts and receptor overexpression mice Such mice developed normally and, when adult, showed no obvious physical or physiologic abnormalities (Ishii et al., 1998b). The animals reproduced normally despite a suggested role for PAF in reproduction. Interestingly, the mean arterial blood pressure was unchanged in the PAFRÿ/ÿ mice which is not easily consistent with a role for PAF in normal vasomotor tone, although confirmation of this would require more detailed investigation. There is a longstanding suggestion that PAF is involved in anaphylactic shock and endotoxic shock. In keeping with the former, intravascular antigen administration to sensitized PAFRÿ/ÿ animals did indeed result in markedly diminished shock and also the concomitant bronchial constriction and airways resistance. By contrast, endotoxin effects in knockout mice were indistinguishable from the control PAFR/ animals. Since a wide variety of PAF receptor antagonists have been shown to be capable of reducing or abolishing endotoxic shock, this finding was indeed a surprise. Even more so since PAF receptor overexpressing mice showed increased susceptibility to LPS (Ishii et al., 1997). Admittedly, many of the pharmacological studies with PAF in endotoxin shock were performed in rats and there are marked species differences in LPS responses. Additionally, possible compensatory mechanisms are well known to have the ability to confound conclusions drawn from knockout mice. Despite the caveats, at first glance we may have to reassess our concepts of PAF action
and/or reconsider the issue of alternative receptors or modes of action for this group of molecules. Finally, there are many areas of pathophysiology in which PAF has been invoked that have not yet been tested rigorously in PAFRÿ/ÿ mice, in particular, acute and chronic inflammation, platelet effects, neurophysiological processes, and responses mediated through putative intracellular PAF effects. To date then, the receptor knockout animals show alterations only in IgE-mediated responses ± anaphylaxis and bronchoconstriction.
THERAPEUTIC UTILITY
Effects of inhibitors (antibodies) to receptors Over 50 compounds have been described with PAF receptor antagonist activity (see Hwang, 1994; Koltai et al., 1994; Negro Alvarez et al., 1997, for example). They range widely in chemical composition and have often been synthesized on a semi-rational basis (Lamotte-Brasseur et al., 1991; Lamouri et al., 1993; Heymans et al., 1997). Some are structurally related to PAF but many are not. Some are of natural origin, including a variety of compounds extracted from the evolutionarily ancient tree, Gingko biloba, but most are synthetic. Of importance for antagonism of a phospholipid mediator, some are lipophilic (CV62091) but others, including the widely used WEB2086, are hydrophilic and presumably do not enter the lipid bilayer, but rather act on the receptor from the aqueous phase. A representative, but by no means exhaustive, sample of these antagonists is listed in Table 1, each with a relatively recent reference as a potential access to its bibliography. In most cases the antagonists have been shown to act in one or more of the myriad in vivo models wherein PAF has been felt to play a part. In fact, it is from these studies of antagonist effect that, for the most part, the complexity and breadth of potential PAF actions have been derived. In many cases the specificity for PAF (and related phospholipids) is quite remarkable and with newer generation compounds, the activity has increased significantly. Because of the plethora of receptor antagonists, little emphasis has been placed on PAF synthesis inhibitors. Not surprisingly from the cPLA2 knockout data, inhibitors of this enzyme do reduce PAF production in stimulated cells and drugs have been described that block both PAF and leukotriene production at this step (e.g. Farina et al., 1994). However, in the light of new evidence for multiple
2190 Peter M. Henson Table 1 Some of the compounds described with PAF receptor antagonist activity Source
Name/number
Reference
Ginkolides
Heller et al., 1998; Lamouri et al., 1993; Simon et al., 1987
Kadsurenone
Ko et al., 1992; Shen et al., 1985
Gliotoxins
Okamoto et al., 1986a, 1986b; Yoshida et al., 1988; Tanaka et al., 1995
Natural compounds
FR-900452 FR-49175 Synthetic compounds Structurally related to PAF
Structurally unrelated to PAF
CV-3988
Adachi et al., 1997; Dupuis et al., 1998; Khoury and Langleben, 1996; Okano et al., 1995
SR-27417
Bernat et al., 1992; Herbert, 1992; Kravchenko et al., 1995
ONO-6240
Toyofuku et al., 1986; Terashita et al., 1987; Ando et al., 1990
RO-19-3704
Wallace et al., 1987; Lagente et al., 1988; Mounier et al., 1993
E-5880
Nakatani et al., 1996; Ono et al., 1996; Takada et al., 1998
RP-48740
Ferreira et al., 1991; Lefort et al., 1988; Weissman et al., 1993
RP-59227
Zhang and Decker, 1994; Auchampach et al., 1998
WEB-2086
Liu et al., 1998; Latorre et al., 1999; Mori et al., 1999; Okayama et al., 1999; Rainsford, 1999
WEB-2170 BN-50730
Singh et al., 1997; Bazan, 1998
TCV-309
Kawamura et al., 1994; Ide et al., 1995; Adachi et al., 1997; Izuoka et al., 1998;
YM-264
Arima et al., 1995; Nagaoka et al., 1997
A-85783, ABT-299
Albert et al., 1996; Kruse-Elliott et al., 1996; Travers et al., 1998
Adapted from Heller et al. (1998).
pathways (and even nonenzymatic mechanisms) for generation of PAF-like molecules, disinterest in this approach seems even more reasonable. Despite all the receptor inhibitors, there is to date no example of an effective therapeutic role for any of these drugs. A few clinical trials have been reported in, for example, asthma (Hozawa et al., 1995; Evans et al., 1997), arthritis (Hilliquin et al., 1995, 1998), sepsis (Dhainaut et al., 1994, 1998; Froon et al., 1996), and psoriasis (Elbers et al., 1994), with equivocal results. This has led to some disillusionment on the part of the pharmaceutical industry. Part of the problem may be the misconception that any one mediator, PAF in particular, plays such a key role that its blockade will, in and of itself, prevent a given disease process. For reasons of historical accident, the early history of the PAF field may have given a disproportionate emphasis to its role as mediator
of allergic reactions and asthma (resulting in many complex schemes with PAF and/or leukotrienes as major participants in these processes). Had the molecule been developed out of its possible role in modulation of the vascular system, or in the category of ether lipid antitumor agents a different emphasis might have ensued. More realistically, PAF is an accessory molecule, playing key but not necessarily sole, roles in a variety of complex mediator networks from inflammation to parturition, neuronal function to vascular motor tone. On the other hand, there is also a perception among some investigators that the reason for the problems with early clinical trials is not only the possible choice of disease processes to examine but, more importantly, the relatively low efficacy of the first-generation antagonists. Some of the later compounds are reputedly in early trials and may show promise in the future.
PAF Receptors 2191
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