The evolution of inflammatory mediators

Invertebrates do not display the level of sophistication in immune reactivity characteristic of mammals and other ‘higher’ vertebrates. Their great number and diversity of forms, however, reflect their evolutionary success and hence they must have effective mechanisms of defence to deal with parasites and pathogens and altered self tissues. Inflammation appears to be an important first line defence in all invertebrates and vertebrates. This brief review deals with the inflammatory responses of invertebrates and fish concentrating on the cell types involved and the mediators of inflammation, in particular, eicosanoids, cytokines and adhesion molecules.


Introduction
The nature of the invertebrate inflammatory response and the cell types involved It is ironic that one of the fathers of modern immunology, Elie Metchnikoff, carried out his Phagocytosis is a universal phenomenon most significant experiments in a non-mamma-within the animal kingdom that first functioned lian model, the starfish larva. While working in as a feeding mechanism in unicellular organisms the Mediterranean at the Straits of Messina he such as amoebae and was later employed as a implanted rose thorns into transparent starfish defensive mechanism to maintain the integrity of larvae in which he was able to observe the more complex multicellular organisms. 2 Phagocybehaviour of blood cells that surrounded the tic blood cells have been described in organisms 'foreign' implant. From this simple observation from anthrozoans through to the cephhe progressed to demonstrate the phagocytic alochordates 4 and urochordates 5 that are activity of these cells towards bacteria and subsebelieved to be the closest living relatives of the quently he applied this obseeeation made in an first vertebrates. 6 As shown in Fig. 1 early multiinvertebrate to explain the role of phagocytic cellular animals, whose modern day representaleucocytes in humans during inflammation. Later tives include sponges and coelenterates, gave rise in the 1920s the French scientist Metalnikov, a to more advanced forms with a body space pupil of Metchnikoff, marvelled at the phenom-referred to as a coelom. In most invertebrates enal ability of insect larvae to deal with injection the coelom is the main body cavity that is filled of pathogenic bacteria that would overwhelm the with fluid and cells termed coelomocytes. Not all natural defences of the mammalian immune animals have an extensive coelom and in insects, system. molluscs and urochordates for example, the From these early reports it can be seen that main body cavity is a haemocoel and hence the invertebrates and other 'lower' animals are cells are described as haemocytes rather than capable of mounting highly effective inflamma-coelomocytes. Some invertebrates, including tory responses that at least match the capacity annelid worms (see Fig. 1)have both haemocytes of any mammal. Indeed, invertebrates with in their blood vascular system and coelomocytes their lack of immune system comprising lymin the coelom. 2 Because all the main organs are phocytes and immunoglobulin, may therefore bathed in either coelomic fluid or blood, cells be more dependent on nonspecific defences are rapidly delivered to sites of damage or microsuch as inflammation to maintain their bial invasion making the inflammatory response integrity. This brief review aims to introduce the highly efficient. reader to the nature of the inflammatory response in invertebrates and 'lower' vertebrates Classification and characterization of inverteconcentrating on the nature of the cells involved brate "blood' cells involved in inflammation: For and the chemical mediators of this cellular a detailed appraisal of the structure and classifiresponse, cation 5 Whether in these animals the two classes of phagocytic Cells are part of a single maturation series, as in the case of mammalian monocytes and macrophages, or distinct cell types of different lineages, as with mammalian granulocytes and macrophages, is unknown. One approach that may resolve this question is to raise monoclonal antibodies to purified populations of leucocytes and use these as probes for ontogenetic studies. Such an approach has been made possible by the development of density gradient centrifugation techniques adapted for a range of invertebrate leucocytes (Fig. 2). To date monoclonalanti- 11 bodies have been produced against crustacean, molluscan, 2 insectan '4 and urochordate 5 leucocytes but they have not been employed to any great extent to study this problem of leucocyte interrelationships.
As well as the phagocytic leucocyte, mention should also be made of an additional cell type found mainly in arthropods (insects and crustaceans) that houses a range of mediators of inflammation in a similar way to the mast cell in mammals. Such cells are highly unstable and following wounding or contact with microbial material (e.g. LPS) they degranulate, releasing factors that influence the behaviour of phago-FIG. 2. Mytilus edulis basophilic (b) and eosinophilic (e) granulocytes before (A) and after (B and C) separation using density gradient centrifugation. Both the basophilic and eosinophilic granulocytes have been found to be phagocytic. 1 (Fig. 3). This 'mast cell analogue' of invertebrates is referred to as a granular cell in crustaceans and cystocyte, coagulocyte or granular cell in insects. 8 The nature of some of these mediators is described later in this review.
The inflammatory processes of invertebrates: There are two main processes characteristic of the inflammatory response of invertebrates. The first is phagocytosis and essentially this defence reaction is very similar to its mammalian counterpart with the exception of the recognition process. 8 The mechanisms involved in the intracellular killing of phagocytosed material within invertebrate phagocytes involves various oxygen /-617 radicals formed during the respiratory burst, NO generation 8'9 and hydrolytic enzymes including lysozyme. 2 The second defence reaction is one of encapsulation which bears some superficial similarity to granuloma formation in mammals. The encapsulation response is found during integumental wound healing, parasite invasion and bacterial challenge. In this latter case it is normally referred to as nodule formation or nodulation. Both nodule formation and encapsulation are biphasic processes in arthropods where these events have been researched extensively. 8 The first stage involves the degranulation of unstable cells to release various proinflammatory factors (Fig. 3). The final .stage involves the ensheathment of this mass of cells by phagocytes, effectively walling-off invading parasites and microbial agents (Fig. 4A). During wound healing the first stage plugs the wound, hence limiting blood loss, and the proceeding ensheathment strengthens this haemostatic response and provides a framework for the regeneration of integumental tissues (Fig. 4B).
Mediators of inflammation in nocyte-stimulating hormone, met-enkephalin and substance P antagonize the effect of TNFin invertebrates Mytilus in which the expression of a neutral Cytokine-like molecules: There is much evidence endopeptidase 24.11 appears to be involved. for the existence of pro-inflammatory cytokine-Furthermore, generation of biogenic amines (epilike molecules in both protostome and deuternephrine, dopamine and norepinephrine) by ostome invertebrates (Fig. l). Prendergast and molluscan haemocytes is significantly reduced Liu 1 were the first to show that the starfish, following stimulation with corticotrophin-releas-Asterias forbesi, contains a cytokine-like factor in ing factor by preincubation of these cells with rthe 'blood' which stimulates monocyte chemo-IL-, IL-l[3, TNFor TNF-[3. These, and other taxis and macrophage activation in mammals, experiments, suggest that a link exists between Additionally, this 8 kDa molecule, appropriately the neuroendocrine and immune systems of named sea star factor (SSF), initiates an inflaminvertebrates involving cytokines in a similar matory-like response in A forbesi where coelo-(homologous?) way to the situation in mammals. mocytes aggregate and ensheath pellets of In summary, there is much evidence to suggest polymer incorporating SSF implanted in the that cytokines equivalent to their mammalian coelom. A further 29.5 kDa IL-l-like molecule counterparts exist in invertebrates. A certain has also been isolated from starfish by Beck and degree of caution should be expressed, however, Habicht whose biological activity can be inhibin a too liberal interpretation of these results as ited by polyclonal antisera to mammalian IL-1 we do not have available any sequence data to implying some evolutionary sequence conservagive insight into structural relationships between tion of this molecule. IL-I and IL-lj3-1ike moleinvertebrate and mammalian cytokines. The cules have also been found in the urochordate, finding of apparent TNFimmunoreactive mate-Syela clava. 24 This group of animals is of parti-rial associated with molluscan haemocytes, using cular interest as they are closely related to the a polyclonal antibody to human TNF-0t illustrates ancestors of the first vertebrates and hence may the problems with such an alproach to identifiTprovide clues to the immunological complexity ing cytokines in invertebrates.In the study they of pre-vertebrates. One fraction of >10 kDa found that this polyclonal antibody reacted obtained from the haemolymph of S. clava by strongly with a 53 kDa molecule and weakly with gel filtration and chromatofocusing chromatoa 120 kDa molecule associated with these cells graphy, stimulated the mitogenic proliferation of that is unlike the 17 kDa mammalian TNF-0t. both Syela haemocytes and murine thymocytes, Such findings serve to remind us that antibodies while the fraction containing IL-la-like activity raised against human cytokines may react with only had such activity with the murine cell unrelated molecules in animals widely separated type. 24'25 Further studies have shown that a 17.5 by many millions of years of evolution. Alter-kDa protein from Syela with IL-1 activity also natively, invertebrate cytokine-like activity may acts as an opsonin and chemoattractant in this reside in molecules with very different structures animal. 26'27 to those in their mammalian counterparts. Only Much attention has focused on the presence when we have purified and sequenced several and activity of cytokines in molluscs that as a invertebrate cytokine activities will answers to group belong to the protostome lineage (see such questions become available. Fig. 1). Not only have a variety of cytokines been located immunoc_ochemically in the haemocytes The prophenoloxidase-activating system: The of some molluscs 28 but lipopolysaccharide stimu-melanization response found in the haemocytic lation of the haemocytes from the bivalve capsules and nodules formed in response to mollusc, Mytilus edulis, causes the release of foreign agents is a common feature in arthro-s5 TNF and/or IL-l-like factors from these cells. 29 pods (insects and crustaceans).' Over twenty Mytilus blood cells also respond to rlL-la and years ago this association between melanin and rTNF-a by changes in their adhesive behaviour inflammation was suggested to reflect a killing and IL-1 also stimulates the chemotactic activity mechanism caused by the generation of toxic of these cells. 1 The specificity of the reaction of quinones intermediate in the formation of Mytilus haemocytes to mammalian cytokines is melanin. 6 Since this observation, the biochemalso suggested by the inhibitory activity of polyistry of the cascade that yields melanin has been clonal antibodies to either rlL-10t or TNF-a. subject to detailed examination (see References Mention should also be made of experiments 8, 35 and 37 for reviews). Central to this system that appear to demonstrate a link between the is the enzyme phenoloxidase (EC 1.14.18.1) invertebrate neuroendocrine and immune found inside haemocytes or in the plasma as a systems that involves cytokine-like factors. Mela-proenzyme (prophenoloxidase). This system is initially activated by microbial products, such as chidonic or eicosapentaenoic acids (both sub-LPS or glucans, leading to cleavage of prophenostrates for eicosanoid generation). These fatty loxidase by serine protease activity. The end acid 'rescue' experiments reversed the effect of result of this pathway is the generation of a dexamethasone showing the specificity of the range of opsonic and haemostatic factors that activity of this PEA 2 inhibitor. Similarly, a range of influence the behaviour of other blood cells lipoxygenase and cyclooxygenase inhibitors also during inflammatory responses such as nodule reduced the number of nodules formed in formation, encapsulation and phagocytosis, response to bacterial challenge. 42 Hence, there is Although the prophenoloxidase activating system clear evidence for a role of eicosanoids in this has been likened to the vertebrate complement inflammatory response although it remains to be system, v the nature of some of the biologically determined which products are involved and the active factors generated and their mode of gen-mechanism of their action is also unknown. There eration is still unclear, are several stages of nodule formation during which eicosanoids could participate. The initial Eicosanoids: As eicosanoids, in particular leukostage involves the degranulation of unstable cells triene (LT) B4, have been reported to play a to release pre-formed mediators (e.g. lectins) central role in inflammation in mammals it is not together with the biosynthesis of additional surprising that attempts have been made to assess factors (e.g. prophenoloxidase-derived products the potential of these compounds as mediators of and pro-inflammatory eicosanoids?) (Fig. 3) 44 In this latter example, the integrin-like erate 15-HETE as their major product, with PGE2, molecule has been found to contain the char-PGD2, PGFiu and PGA2 as the main cyclooxacteristic RGD sequence (Arg-Gly-Asp) that ygenase-derived products. 41 In both cases, inhibirepresents the functional binding site to its tion of presumptive lipoxy-genase and cyclo-ligand(s). 44'45 The P. leniusculus adhesion moleoxygenase-derived product generation can be cule is a 76 kDa protein that causes degranula- 40 41 achieved with specific inhibitors. tion of crayfish granular blood cells 44'46 thereby Recently reported experiments have given causing the activation of the prophenoloxidase insight into the possible role of eicosanoids as system (see Fig.3) which in turn promotes inflammatory mediators in insects. These studies encapsulation activity. 47 A similar factor has also used nodule formation as the assay system where been found in another crustacean, the crab, Carinsect larvae of the tobacco hornworm (M. cinus maenas. 48 This 80 kDa protein found in sexta) were injected with bacteria (Serratia mar-the granular haemocytes acts as an opsonin cescens) and the size and number of nodules enhancing the phagocy.ic ability of hyaline blood formed in the haemocoel in response to this cells of this animal. 8 This protein, and its particulate insult determined. 42 They found that equivalent in other species, may be the opsonic prior injection of the phospholipase A2 (PLA2) principle generated by the prophenoloxidase inhibitor, dexamethasone, caused a dose-depensystem in insects and crustaceans during the dent inhibition of the nodule formation response degranulation response in unstable granule-conto S. marcescens. As PEA 2 is required for the taining haemocytes. Further evidence for the role provision of free fatty acid precursors for eic0sa-of integrins in the defence reactions of invertenoid biosynthesis, some insects were also brates comes from recent interesting studies injected with dexamethasone together with ara-where Sepharose beads were conjugated to the peptide, RGDS, and then incubated with haemocytes from the moth, Pseudoplusia includens. 49 Beads conjugated to this peptide were encapsulated by these blood cells while beads without peptide or beads with RGES were not ensheathed. Furthermore, soluble RGDS, but not RGES, inhibited this encapsulation response.
These results imply that encapsulation involves an adhesion molecule with the characteristic RGD recognition motif.
Insight into a further potential adhesion molecule and its function in inflammation comes from the use of a monoclonal antibody raised against the haemocytes of the wax moth, Galleria mellonella. 5 This antibody reacts with an approx. 100 kDa molecule found associated with the unstable granular haemocytes that play a role in the first stage of nodule formation. 8 Blocking the action of the protein with this monoclonal antibody causes a reduction in the adhesion of wax moth haemocytes to glass substrates and nodule formation in vivo. 49 Unfortunately, the structure of the 100 kDa protein remains to be determined and so no sequence comparisons with other adhesion molecules can be made.
The nature of the inflammatory response in "lower" vertebrates and the cell types involved The most significant stage in the evolution of the immune system came about with the appearance of the first vertebrates. These were probably the first animals with 'true' lymphocytes, with the ability to respond by clonal selectivity upon challenge. Furthermore, these animals would have had the ability to synthesize 'true' immunoglobulins (i.e. molecules with variable regions) that specifically interact with non-or altered-self materials. The modern day ancestors of these first vertebrates are fish (Fig. 1). The earliest vertebrates were jawless (agnathous) fish and the only animals to retain this feature are lampreys and hagfishes, thought to be the ancestors of some of the early vertebrates. All other fish are jawed and these include the two main divisions of cartilaginous (e.g. sharks, rays) and bony forms (e.g. trout, carp etc.). Hence fish are a useful group to examine in this review on the phylogeny of inflammation and the following sections highlight the changes brought about in the inflammatory response with their evolution from invertebrate ancestors.
of mammalian blood, i.e. granulocytes and monocytes/macrophages, also evolved at this stage. Hence all vertebrates have remarkably similar leucocyte types reflecting a close association and a common ancestry. The only possible exception may be mast cells, although some fish have cells in the stratum compactum of the alimentary canal (Fig. 5), the dermis, gills and swimbladder with similar structural and functional properties to mammalian mast cells. 51'52 Mast cells have been clearly identified in all other vertebrates.
An area of some controversy is that of granulocyte heterogeneity in fish. Some species of fish have been reported to have neutrophilic, eosinophilic and basophilic granulocytes in peripheral blood, yet others may only have a single morphological type. Even more curious is the observation that at different stages in the life cycle of the same species there may be different types of granulocytes present. An example of this is in the lamprey (Lampetra fluviatilis) where both neutrophilic and eosinophilic granulocytes are found in the larval stage yet in the adult only the former cell type is present in the blood stream (Fig. 6). 5 In cartilaginous fish there may also be several different morphological types of eosinophilic granulocytes in the same species (Fig. 6), some of which appear to function in a manner equivalent to mammalian neutrophils.  Two main conclusions can be drawn from these findings. Firstly, the staining characteristics of fish granulocytes (i.e. eosinophilic, basophilic etc.) do not Leucocyte ypes involved in inflammation: Not only did the lymphocyte probably make its first appearance during the evolution of the vertebrates but the other leucocyte types characteristic always mirror functional diversity and secondly, that there is no common evolutionary trend in granulocyte heterogeneity within the different types of fish.
The inflammatory response in fish: This has been 56 57 the subject of recent excellent reviews and hence this following section is only included to present some more recent findings and highlight topics of particular interest to the reader. There are many descriptions of inflammatory exudate formation in fish following experimental challenge or in naturally infected fish. Several similarities exist between the mammalian and piscine acute inflammatory responses. For example, the cellular involvement in inflammation in fish appears to be biphasic with an influx of granulocytes followed by a later arrival of monocytes/ macrophages. 5 Both cell types are also actively phagocytic. 57 Some key differences do exist, however, between the response in fish and mammals, in particular the dynamics and intensity of this reaction. Most studies have reported a protracted inflammatory response in fish where peak numbers of granulocytes and macrophages occur at about 1-2 days and 2-7 days respectively post-challenge. 5< In carp, the granulocytes that migrate to sites of inflammation originate from the head-kidney, 5 a haemopoietic 55 tissue equivalent to mammalian bone marrow, while the macrophages in exudates appear to originate from blood-derived monocytes. The site of monocytopoiesis in bony fish is usually the head-kidney and/or spleen. 55 Once at the site of inflammation, macrophages may become stimulated with increased phagocytic potential and enhanced antimicrobial activity. 59 As would be expected, the sequence of events during phagocytosis (chemotaxis, attachment, include the elevation in a number of macrophage ingestion and intracellular digestion) are essenactivities including phagocytosis, adherence and tially the same in fish as in mammals. 5v The spreading to substrates, respiratory burst and attachment of foreign material to both piscine bacterial killing, vx Recent studies have reported granulocytes and mononuclear phagocytes synergism between human rTNF-z and fishappears to be aided by immunoglobulin  and derived MAF in terms of respiratory burst activity complement fragments 6 at least in some cases, in fish macrophages, v This effect could be while subsequently the respiratory burst leads to inhibited by prior incubation of target macroan increase in oxygen radical generation. 5v'64 phages with monoclonal antibodies to the mam-There is also evidence for the production of NO malian receptor for' TNF-z. in fish phagocytes that is enhanced by exposure to microbial products. 65'66 Various hydrolytic Adhesion molecules: The explosion in our underenzymes are present in lysosomes and granules standing of the nature and function of adhesion in granulocytes and mononuclear phagocytes 6v molecules in the control of leucocyte migration and these presumably play a role in killing and during inflammation in mammals does not digestion of ingested microorganisms, appear to have stimulated the search for similar molecules in fish and other lower vertebrates.
Inflammatory mediators in fish Indeed, the only apparent report of a potential adhesion molecule in fish comes from a study on Cytokines: Mthough IL-l-like cytokines have been fish brain where 'foamy' macrophages were demonstrated in fish nothing is known about found to react with an antiserum to the 2 chain their potential involvement in inflammatory of human leucocyte integrins. 74 responses. IL-1 has been shown to be generated by monocytes in the catfish, Ictalurus puncta-Complement.. Although there is some evidence tus, and by macrophages and granulocytes for the existence of complement components from the carp, Cyprinus carpio. 69 In catfish, polyand associated factors in invertebrates, the evoluclonal antisera to human IL-lz and IL-1]3 revealed tion of the 'fully-functional' pathways of this immunopositive bands in Western blots of system appears to coincide with the appearance monocyte supernatants at 60, 43 and 30 kDa with of fishes. Hence, with the exception of possibly IL-lz antiserum, and 70 and 21 kDa with IL-1IB agnathous and cartilaginous fish, both classical antiserum. 7 In carp, polyclonal antiserum to and alternative pathways of complement activahuman rIL-lz reacted with a 22.3 kDa protein in tion exist in lower vertebrates. 75 There are Western blots of SDS-PAGE separated macro-several reports of both chemotactic/chemokiphage lysates while a 21.7 kDa band was revealed netic 76 and opsonic 77'78 activities for complement using antiserum against IL-I. 69 A further immu-factors in fish, showing that these are important noreactive 15 kDa band was found with both ILpro-inflammatory molecules in such animals. lz and IL-113 antisera. Importantly, these antisera to IL-10t and IL-1]3 ablated the biological activity Eicosanoids.. The eicosanoid-generating ability of of supernatants from stimulated carp macro-fish leucocytes has received a great deal of attenphages in the assays employed for IL-1 activity tion in the last decade. Most studies have conshowing that at least one of the three proteins centrated on the biosynthetic capacity for that interacted with the antibodies corresponds eicosanoid generation in macrophages. For to the active principle in these preparations. 69 example, macrophages from the head-kidney of a Significant progress has been made in elucidat-number of species of fish have been found to ing macrophage activating cytokines in fish contain 5-and 12-1ipoxygenase activities that largely as a result of Secombes and co-workers result in the synthesis of leukotrienes and lipox-(see Reference 71 for review). Macrophage acti-ins from endogenous or exogenous arachidonic vating factor (MAF) can be generated by incubat-(20:4,n-6) and eicosapentaenoic (20:5,n-3) ing head-kidney leucocytes with T cell mitogens acids. [79][80][81][82] Challenge of macrophages from the and the cell type directly responsible in its gen-head-kidney of the rainbow trout, Oncorhynchus eration belongs to a population of surface Igmykiss, with microbial factors (LPS, glucans) or cell-like). Activity resides in 19 calcium ionophore results in the rapid synthesis lymphocytes (T 72 and 32 kDa fractions although the active princi-of both lipoxygenase and cyclooxygenase prodpie(s) have not been isolated and sequenced to ucts including 12-HETE, 12-HEPE, lipoxin (LX) date. 71 Several pieces of evidence suggest that A4, ERa 5, LTB4, LTB5 and PGE2. Although this MAF is a form of IFN-7 although the biological overall profile of products is similar to that found activity of fish MAF cannot be replaced by in mammalian macrophages it differs in the maghuman IFN-T. 71 The biological properties of MAF nitude of the amounts generated. The lipoxin generating capacity of rainbow trout macro-4soophages is about four to five times greater than reported in mammalian macrophages under the 00same conditions. 79 The greater amounts of lipoxin formed in some species of fish has led to 2700the rather simplistic suggestion that these compounds may be more important in fish than in " 1800 mammals] 9 Recently, an 18 kDa protein that appears to be the forerunner of 5-1ipoxygenase activating protein (FLAP), has been found in 00lysates of trout macrophages. 8 FLAP has been found to be essential for cellular leukotriene bio-0 synthesis in a range of mammalian leucocyte types. 84 Several of the main eicosanoids generated by fish leucocytes have been found to be involved in inflammatory responses in these animals. Evidence supporting this viewpoint comes from both in vivo and in vitro experiments. Intraper- 4-itoneal injection of microbial products, such as zymosan or adjuvant, into fish results in an influx of leucocytes into the main body cavity with the typical protracted dynamics already described. Aspiration of the exudate formed followed by "o 2quantification of eicosanoid levels by enzyme immunoassay has demonstrated significant increases in the amounts of LXA4, LTB 4 and PGE2 (Fig. 7A). 85 In rainbow trout infected with 0 proliferative kidney disease the causative agent, probably a myxosporean parasite, multiplies in the kidney, leading to a strong inflammatory mation, it could also be argued that it simply reflects the increase in leucocyte numbers in chemokinetic in nature could not be ascertained such tissues mediated by other factors such as with this method. Experiments have been carded complement. However, the finding that injection out to examine the migration-inducing activities of nordihydroguaiaretic acid, a lipoxygenase inhi-of LTB 4 and lipoxins for trout neutrophils using bitor, significantly reduces the number of macro-a Boyden chemotaxis chamber and checkerphages and granulocytes in the peritoneal cavity board assays. 89 These allow for differentiation of trout following challenge with the bacterium between chemokinesis and chemotaxis not possaeromonas salmonicida, implies an active role of ible in most other assays. IX& was found to be some eicosanoids in inflammation. 87 one to three times more potent at inducing As summarized in Table 1, eicosanoids modify migration of trout neutrophils than LTB4 at all and mediate a number of inflammatory processes concentrations tested (0.03 1 x 10 -5 M).
of fish as assessed with in vitro assays. For However, LTB4 was found to be a chemotactic example, LTB4 has been shown to cause the agent for trout neutrophils while LXA4 was only a migration of fish leucocytes in vitro. In the case chemokinetic factor. In mammals, LXA4 is regarof a cartilaginous fish, the lesser spotted dogfish, ded as an inhibitor of granulocyte migration in r n t 90 91 Scyliorhinus canicula, LTB 4 causes a dose-espo se o either FMLP or LTB4.
Similarly, dependent increase in the migration of eosino-IX& also inhibits 'human neutrophil transmigra- 92 93 philic granulocytes in a migration under agarose tion through epithelial and endothelial cells. 88 assay. Whether this reaction is chemotactic or These results suggest that in mammals, IX& At F Rowley inhibits several key events during inflammatory responses, while in fish it appears to be proinflammatory at least in the absence of other chemotactic agents. PGE2 is the only other eicosanoid to be studied in detail in terms of its potential involvement in the nonspecific cellular defences of fish (Table 1). It is rather paradoxical that PGE2 is a potent stimulator of the uptake of yeast particles by macrophages, 94 yet in the same cell type it inhibits both respiratory burst activity 95 and degranulation 5 that follow the ingestion process.