MPO deficiency

ABSTRACT: Taurine (2-aminoethane sulphonic acid), a ubiquitous beta-amino acid is conditionally essential in man. It is not utilized in protein synthesis but found free or in some simple peptides. Derived from methionine and cysteine metabolism, taurine is known to play a pivotal role in numerous physiological functions. Some of the roles with which taurine has been associated include osmoregulation, antioxidation, detoxification and stimulation of glycolysis and glycogenesis. Intracellular taurine is maintained at high concentrations in a variety of cell types and alteration of cell taurine levels is difficult. The role of taurine within the cell appears to be determined by the cell type. Recent research has determined a regulatory role for taurinechloramine,

the product formed by the reaction between taurine and neutrophil derived hypochlorous acid on macrophage function. Plasma taurine levels are also high, although decreases are observed in response to surgical injury and numerous pathological conditions including cancer and sepsis. Supplementary taurine replenishes decreased plasma taurine. Although commonly used as a dietary supplement in the Far East, the potential advantages of dietary taurine supplementation have not as yet been fully recognized in the Western World; this is an area which could prove to be beneficial in the clinical arena. (Journal of Parenteral and Enteral Nutrition 22:42-48, 1998)

Taurine is as old as mankind itself, although only discovered in 1827 by Tiedmann and Gmelin in ox bile. Its conservation through evolutionary change from the most primitive life forms to its presence in almost every tissue in humans confers on taurine an importance in the hierarchy of physiological status. In humans, taurine is frequently the highest concentrated free amino acid encountered in numerous cell types. It is not metabolized nor utilized for protein synthesis, yet taurine has been preserved since the beginning of humankind. Of course, some would argue that it is nothing more than a simple amino acid, innocuous and not interfering with cellular function, so why evolve processes to eliminate it. However, there are now many including the authors who believe that taurine not only plays a central role in numerous and varied biological functions but that probably only a fraction of the taurine story is currently known. In the last two decades research interest in taurine has reached new dimensions as groups worldwide strive to unravel its biological mysteries.

During the last 10 years many excellent reviews have been published and symposia dedicated to advances in the study of taurine. The purpose of this article is not to give a comprehensive account of all the physiological processes and pharmacologic actions in which taurine is now known to play a role but to focus specifically on the cells involved in host defense and the role of taurine in modulating both effector and target cell activities.

Taurine is a naturally occurring beta-amino acid derived from methionine and cysteine metabolism (Fig. 1) and differing from other amino acids by replacement of the COOH group with a SO,H group.1.A water-soluble colorless compound with undissociable side groups, which exists as a zwitterion even at physiological pH, taurine is not incorporated into proteins but is found either free or in some simple peptides.2 The sulfonic acid group confers on taurine greater acidity than other amino acids having a functional carboxylic group.3 Cysteinesulfinic acid decarboxylase ((CSAD) the enzyme that catalyzes the conversion of cysteinesulfmic acid to hypotaurine, the inunediate precursor that is oxidized spontaneously to taurine) is a pyridoxal phosphate-requiring enzyme, and therefore vitamin Bd^sub 6^ deficiency can lead to a reduction in endogenous taurine.1 There are a number of possible routes of synthesis, principle among which are (1) the oxidation of cysteine to cysteine sulfmic acid and subsequently to cysteic acid, which is decarboxylated to taurine, and (2) oxidation of cysteine to cysteine sulfinic acid with subsequent decarboxylation to hypotaurine, which is oxidized to taurine.1 The choice of route is not without consequence because hypotaurine is a competitive inhibitor of taurine uptake into cells, whereas cysteic acid has no effect on taurine transport.5 Although taurine is synthesized primarily in the liver and brain,6 high levels have been found in several tissues including the heart,7 retina,8 and gut.9

Because mammalian ability to synthesize taurine is limited, dietary intake plays an important role in maintaining body taurine pools. Dietary sources include meat, dairy products, poultry, fish, and infant feeding formulas, which contain taurine in quantities similar to that of breast milk (19.1 to 68.3 (mu)mol taurine/100 mL).10 In humans the principal excretory pathway is through the kidneys, with the amount of urinary taurine reflecting dietary intake.ll Renal transport of taurine adapts to perturbed taurine homeostasis.12 Plasma taurine decreases in response to lowprotein and low-sulfur amino acid diets in addition to decreased fractional taurine excretion and increased net uptake of taurine by renal cortex and isolated brush border membrane. Alterations in sulfur amino acid intake elicit renal adaptive responses that may serve in maintaining availability of taurine; these adaptive responses, which are expressed at the renal brush border surface, relate in part to changes in taurine content in the renal cortex.11 An elevation in plasma taurine occurs in chronic renal failure, which may be related to the kidneys' role in maintaining sulfur balance in humans. A secondary secretory mechanism is through bile acid secretion, although this represents an insignificant amount compared with the whole-body pool.l3 Plasma levels are known to decrease in response to surgical in,jury14 and numerous pathological conditions including cancer,15 trauma,16 and sepsis.17

Although known for 150 years, taurine was until the 1970s widely viewed by researchers as an innocuous end product of methionine and cysteine metabolism that played no major physiological role, even though ubiquitous and present in relatively high concentrations. Research interest in taurine began in earnest in 1975 with elucidation of a role for taurine as an essential amino acid in the cat, where deficiency leads to retinal degradation and eventual blindness.18 Since then, research to elucidate additional mechanisms through which taurine mediates its biological effects is gathering momentum as interest in this amino acid expands. To date the list of biological activities with which taurine has been associated is impressive and includes antioxidation,19, 20 membrane stabilization,21 detoxification,22 neuromodulation,23 and regulation of calcium homeostasis.24 Depletion during early life is detrimental to normal functional integrity of the retina; in addition, central nervous system abnormalities and growth depression in young animals, as well as abnormal electroretinograms in children and auditory brain stemevoked responses in premature infants are known.25 Fetal total body content of taurine increases until term, particularly in the last 4 weeks of pregnancy. Because CSAD activity is low in developing human liver and brain, preterm neonates are at risk of deficiency and exogenous taurine is essential for the premature postpartum infant.26

There is now an abundance of evidence implicating taurine in regulation of calcium homeostasis. Taurine is one of the most abundant amino acids in mammalian heart.7 High levels within the heart are maintained by active transmembrane transport by a specific carrier. Taurine has been shown to be an effective treatment for congestive heart failure27 and to protect against the deleterious effects of reactive oxygen species (ROS) during reperfusion after an ischemic period.28 There is an impressive array of evidence associating the cardioprotective effects of taurine against Ca^sup 2+^-mediated cell damage. Cardiac reperfusion with Ca^sup 2+^ after a short period of Ca^sup 2+^-free perfusion results in irreversible myocardial damage a phenomenon known as the calcium paradox.29 Studies by Kramer et al30 reported decreased myocardial taurine levels in rat hearts subjected to the calcium paradox. In these studies taurine prevented loss of mechanical function resulting from the calcium paradox while also preventing the large decrease in sarcolemma adenosine triphosphatase (ATPase) activities with the concomitant increase in sarcolemma Ca^sup 2+^ binding associated with this model. Similar findings have been reported by others; Takahashi et al24 proposed that taurine plays an important role in membrane stabilization during the calcium paradox. Taurine also has been associated with elevated ATP-dependent Ca^sup 2+^ uptake and ^sup 45^Ca^sup 2+^ turnover in the disc membranes of frog retina, an effect specific for taurine.31

Although associated with many physiological functions, pathological conditions and pharmacologic actions, there is as yet relatively little known about taurine from a physiological and biochemical point of view in relation to mechanisms through which this amino acid may exert its influence. When the mechanisms through which taurine functions are clarified, the future prospects for the use of taurine in the clinical setting are indeed exciting.

TAURINE AND THE NEUTROPHIL

Cats fed a prolonged taurine-deficient diet become leukopenic and demonstrate a shift in the percentage of polymorphonuclear and mononuclear leukocytes, with an increase in the absolute mononuclear cell count. Phagocyte function is decreased as indicated by chemiluminescence responses, and a decrease in phagocytosis of Staphylococcus epidermis in taurine-deficient cats compared with cats fed the same diet supplemented with taurine is observed.32

Seventy-six percent of the free amino acid content of human granulocytes is taurine.33 Although taurine concentrations in human plasma, platelets, lymphocytes, and erythrocytes were shown to be significantly reduced after long-term parenteral nutrition without taurine supplementation,34 neutrophil taurine levels were not affected. Other investigators reported similar results with the exception that neutrophil taurine was decreased but not markedly.35 Huxtable2 suggested that stringent control of cellular taurine levels may augment physiological competence. Neutrophils contain myeloperoxidase (MPO), a heme-containing cationic protein of molecular weight 144,000(36)belonging to the class of oxidoreductases (EC 1.11.1.7). The electron acceptor substrate for this enzyme is solely hydrogen peroxide, whereas the donor substrates are different reductants, including halides (with the exception of fluoride). The first report of the physiological activity of MPO was in 1968 whenZgliczynskiet al37 reported that MPO catalyzes amino acid deamination and decarboxylation in the presence of Hd^sub 2^O^sub 2^ and chloride ions (C1-).

Taurine was found to be a competitive inhibitor of this reaction.38

Taurine is known to influence neutrophil function both in vitro39, 40 and in vivo.41, 42 Dietary hyperlipidemic rats are more susceptible to infection because modulation of the lipid phase of phagocytic membranes affects phagocytosis. However, rats fed high-lipid diets supplemented with taurine have neutrophil bactericidal capacity restored. This effect was proposed to indicate an important role for taurine in the mechanism of host defense through neutrophil function.42 MPO is a pivotal component of the inflammatory cell respiratory burst pathway producing hypochlorous acid (HOC1), a powerful oxidizing agent able to cause tissue damage by directly oxidizing carbohydrates, nucleic acids, peptide linkages, and amino acids.43 MPO inactivation occurs during the course of chlorination of taurine; however, increasing concentrations of exogenous taurine attenuate inactivation. The optimum pH range for MPO chlorination of taurine is 5.0 to 5.5 and within this range there is little inactivation. Above pH 5.5 taurinechloramine production decreases with a concomitant increase in MPO inactivation. These observations were proposed to suggest a protective effect of taurine on cellular function.44 (Fig. 2). Preliminary work in our laboratory has shown that taurine delays neutrophil apoptosis, the physiological consequence being that neutrophil functional viability is prolonged within the circulation.

Modulation of neutrophil function by taurine in vitro has been shown in studies in which exogenous taurine significantly reduced luminol-dependent chemiluminescence with a corresponding increase in MPO activity and decrease in leukotriene B^sub 1^ production.39 Chemiluminescence measures ROS including H^sub 2^O^sub 2^,O^sub 2^ and HOC1 generated by inflammatory cells after initiation of the respiratory burst. Singlet oxygen (^sup 1^O^sub 2^ does not participate in the oxidation of luminol by HOCI and H^sub 2^O^sub 2,.46 Attenuated chemiluminescence response with taurine has been proposed to be mediated through its ability to scavenge HOCl.39 Reduced chemiluminescence may be due to the following: (1) loss of further production of ROS from HOC1 catabolism by sequestration of HOCI by taurine to form taurinechloramine, (2) loss of HOCl itself, and (3) more rapid metabolism of H^sub 2^O^sub 2^ due to enhanced MPO activity.

TAURINE AND THE MACROPHAGE

Recent studies have presented interesting results concerning the effects of taurine on macrophage function. Generation of nitric oxide (NO) and tumor necrosis factor a (TNFalpha) are established markers of macrophage activation, and production of both agents by the macrophage is enhanced by lipopolysaccharide (LPS) and interferon a (IFNgamma).47, 48 Studies in our laboratory have demonstrated that the antilipopolysaccharide agent taurolidine has immunoregulatory properties that are mediated by taurine.49 Taurolidine, which is a tauramide derivative, is bactericidal5 in addition to acting as an LPSblocking agent.51 Administration of taurolidine to CD1 mice significantly increased TNFalpha production in peritoneal macrophages. There was a concomitant increase in superoxide anion (O^sub 2^^sup -^ ) and NO production, and phagocytosis also was enhanced. Similar effects were observed after supplementation of culture medium in vitro although NO levels were reduced. The effects of taurine on macrophage function also were assessed in our laboratory and we reported significant increases in O^sub 2^ and TNFalpha levels. We proposed that in addition to its bactericidal and antilipopolysaccharide properties, taurolidine primes peritoneal macrophages for enhanced antimicrobial activity and that these effects appear to be mediated by taurine. It was interesting to note in our studies that pretreatment with taurolidine significantly reduced NO produced by peritoneal macrophages in response to coculture with LPS and IFNgamma. Parallel in vivo studies showed similar findings. Taurolidine may play a role as an irreversible inhibitor of inducible nitric oxide synthase (iNOS) in peritoneal macrophages, although the mechanisms through which taurolidine exerts its influence on this pathway require further clarification. On dual stimulation with LPS and IFNgamma the addition of taurine significantly decreased NO production. Stimulation with LPS alone with supplemented taurine upregulated NO levels, an effect not observed when IFNgamma was used as a sole stimulus. These data suggest that taurine can function as a costimulatory signal with LPS but not with IFNgamma for induction of the iNOS pathway. Clarification of the mechanism(s) through which taurine functions in combination with LPS for NO generation may prove to be beneficial in the development of novel strategies to modulate NO production. Previous findings by another group52 have shown that taurine alone did not influence the production of either NO or TNFalpha in the mouse macrophage cell line RAW 264.7. However, the chlorinated derivative taurinechloramine attenuated both NO and TNFalpha production by these cells.

Taurinechloramine was more efficiently transported into RAW 264.7 cells than taurine. Although the aims of the study conducted in our laboratory19 and that of Park et al52 were similar, the results are not comparable. There is an eightfold increase in the taurine concentration used by Watson et al,49 compared with that used by Park et al,51 whereas Park et al, used 10 times the concentration of LPS as a printing agent. In addition Park et al compiled their data using a cell line, in contrast with peritoneal cells isolated by Watson et al.49 Attenuated production of the inflammatory mediators NO and TNFalpha either directly by taurine or indirectly through taurinechloramine formation would further enhance the view that taurine is a pivotal component in host defense and that alteration in cellular levels may predispose to increased susceptibility to host tissue damage after activation of the inflammatory cells. Conflicting data concerning the ability of taurine to modulate macrophage activity indicate that further work is required in relation to taurine and this cell before definite answers are obtained.

TAURINE AND THE LYMPHOCYTE

Although taurine constitutes >50% of the free amino acid pool of lymphocytes, the role of lymphocyte taurine remains to be clarified. Lymphocytes have a high dependence on their Beta-amino acid transport system to transfer plasma taurine in order to maintain their high endogenous levels. Human lymphocyte-derived cultured lymphoblastoids have an active taurine transport system. Depletion of cellular taurine in cultured lymphoblastoid cells takes several days. However, levels can be replenished within a few minutes for cells cultured in serum or a taurine-supplemented medium. Increased cellular viability was also recorded with exogenous taurine. Maintenance of such high taurine levels through the development of a high-affinity transport system would suggest importance for taurine in these cells. Pasantes-Morales et al53 observed the efficacy of taurine in maintaining cellular viability of cultured lymphoblastoid cells after long periods of aerobic incubation in the presence of the peroxidative agents ferrous sulfate and ascorbate. Taurine protected against iron-ascorbate oxidative injury while maintaining cell shape and volume integrity. The protective nature of taurine on the lymphoblastoid cells was, however, not related to an antioxidant effect as may have been anticipated. The presence of taurine in the incubation medium, in conditions that preserved cell viability, failed to reduce lipid peroxidation compared with cells cultured in the absence of exogenous taurine. This suggested that the lymphoblastoid protective effect of taurine although not mediated through antioxidant activity may have been related to a membrane effect because membrane damage by lipid peroxidation often leads to loss of membrane integrity. Loss of membrane integrity results in increased permeability, with the resulting iron overload being the primary cause of cell death. In a previous study Pasantes-Morales et al22 suggested that the protective effect of taurine may have been related to its ability to mediate ion permeability. Further study, however, did not indicate ion permeability as the mechanism through which taurine exerted its protective influence because iron-ascorbate failed to increase sodium accumulation markedly, although uptake of ^sup 45^Ca^sup 2+^ was enhanced. This study concluded that the mechanism through which taurine modulates lymphoblastoid cell damage in the presence of iron-ascorbate may be through prevention of calcium influx.

Recombinant interleukin-2 (rIL-2) immunotherapy is limited by microvascular endothelial cell-targeted injury. Previously, we demonstrated in vitro that taurine significantly attenuated rIL-2-induced endothelial cell injury, whereas the tumor cytotoxicity of lymphokine-activated killer (LAK) cells was enhanced, and established that this effect was Ca^sup 2+^ -dependent.54 This demonstrates the duality of the action of taurine through enhancement of effector cell activity against the tumor target while protecting the endothelium from the deleterious effects associated with rIL-2 immunotherapy. We also assessed the effect of taurine on Ca^sup 2+^-dependent granule exocytosis, which we determined by measuring cytotoxic granule protein (BLT esterase) activity. BLT esterase production by LAK cells after stimulation with the calcium agonists phorbol myristate acetate (PMA) and A23187 was elevated by taurine, whereas intracellular calcium antagonists TMB8 and EGTA (ethylenediaminetetraacetic acid) inhibited BLT esterase production. We concluded that taurine behaves as an attenuator of rIL-2-induced vascular inJury through a Ca^sup 2+^-dependent mechanism while also increasing cytotoxic granule levels in lymphocytes.'

ANTIOXIDANT PROPERTIES OF TAURINE

Increased ROS production is associated with decreased immune function, and reactive oxygen scavengers are known to attenuate the deleterious effects of these toxic intermediates on immune function in mice.55 Taurine has been proposed to act as both a direct and indirect antioxidant. Indirectly, taurine functions as a membrane stabilizer,56, 57 whereas as a direct antioxidant, taurine has been proposed to act through sequestration of HOC1.39,40 When used clinically as a prophylactant against reperfusion injury during myocardial revascularization,28the protective capacity of taurine was attributed to free radical scavenging. Subjects treated with placebo showed a significant increase in the number of severely damaged mitochondria after reperfusion whereas the number of damaged and necrotic myocytes also increased significantly in these subjects after infusion. No such damage to mitochondria or myocytes was observed in the taurinetreated subjects. The use of supplemental taurine as a physiological protective agent against lipid peroxidation was advocated by another study58 that demonstrated protection of hamster bronchioles from acute NO^sub 2^-induced alterations.

Gordon et al58 outlined the mechanism through which acute ROS tissue damage is believed to act. NO^sub 2^ and its highly ROS interact directly with plasma membranes of cell products, possibly via lipid peroxidation triggering a series of events that include the release of chemotactic factors and acute phase reactions responsible for the influx of neutrophils. Activation of neutrophils results in production of superoxide, free radicals, and H^sub 2^O^sub 2^, which cause further epithelial damage. Activated neutrophils also release proteolytic enzymes that have the capacity to alter alveolar interstitial components. It was proposed by Gordon et al58 that the protective activity of taurine may reside in its ability to become chlorinated in the presence of HOC1, thereby preventing the direct attack of this oxidant on cell membranes. Schuller-Levis et al59 suggested that taurine via formation of its chlorinated derivative protects the lung from oxidant injury at least in part by inhibiting production of the proinflammatory mediators, TNFalpha and nitrite.

Recently, we have shown that taurine protects against neutrophil-mediated pulmonary microvascular injury in an animal ischemia reperfusion model.60 Another group also has reported the protective effect of taurine on the heart from neutrophil-induced reperfusion injury in a guinea pig model.61 Isolated hearts were reperfused in a nonworking mode in the presence or absence of homologous neutrophils with or without taurine. Work was resumed 15 minutes later and percentage recovery of function was assessed after an additional 20 minutes. Reperfusion with neutrophils decreased the recovery of external heart work (EHW) to 30% compared with 76% observed in control hearts. In the taurine-treated hearts EHW recovery was 60%. Taurine markedly reduced luminol-dependent chemiluminescence elicited by activated neutrophils. The protective effects of taurine from neutrophil-mediated reperfusion injury in this model were proposed by Raschke et all to be mediated through the ability of taurine to function as an antioxidant.

Combination of taurine with niacin has been shown to be efficacious in protecting against interstitial pulmonary fibrosis (IPF) induced by the anticancer drug bleomycin (BL) in hamsters.62 The BL hamster model of IPF is an established model used to study the efficacy of novel putative antifibrotic agents. Increased lung lipid peroxidation is associated with IPF in this model, and Giri and Wang62 reported that in combination taurine (1% in drinking water) and niacin (250 mg/kg) administered intraperitoneally significantly reduced BL-induced lipid peroxidation products. Similar effects were observed in the same BL model of IPF in which the inducing agent was the antiarrhythmic drug amiodarone. Further studies by Wang et al,63 using this model, demonstrated that taurine combined with niacin suppressed BL-induced inflammation and almost completely abrogated pulmonary fibrosis. Treated animals had less inflammatory cell infiltration and less epithelial necrosis and collagen deposition compared with hamsters treated with BL alone. Wang et al63 concluded that combined treatment with taurine and niacin offers a novel therapeutic modality in the prevention of pulmonary fibrosis.

Decreased plasma taurine levels after surgical injury14 and sepsis17 have been well established. Increased urinary taurine output however, does not fully account for postoperative plasma taurine decreases. We hypothesized that decreased plasma taurine may partially be accounted for by increased uptake by neutrophils to compensate for increased cellular activation after operation. To test this hypothesis, we recently have measured neutrophil taurine levels in a cohort of surgical patients and have reported increased intercellular levels in the immediate postoperative period.14 We believe that this further strengthens a major role for taurine in neutrophils. The efficacy of taurine as an antioxidant has dual biological benefits. Sequestration of ROS while protecting the effector cell from the inevitable deleterious effects of ROS overproduction also protects other cells. High levels of taurine therefore aid in the preservation of effector cell function while minimizing host tissue ROS-mediated damage.

TAURINE AND THE IMMUNE RESPONSE

Immune response impairment was studied in taurinedeficient mice by Lake et al.64 This group showed rapid taurine depletion in the lymphoid organs of 3- to 6-monthold carcinoma-bearing mice receiving drinking water supplemented with either of the taurine-uptake antagonists, Beta-alanine, or guanidinoethane sulfonate. The effect of taurine depletion on humoral responses to sheep red blood cell antigens assessed by plaque-forming assays indicated a significant taurine effect on the plaque-forming ability; however, taurine depletion had no adverse effect on the viability of spleen cells harvested. To assess the proportion of lymphocytes bearing specific surface markers in the lymphoid organs, the antigenic markers, Lyt 2 and L3T4, were quantified for T cells by flow cytometry, whereas for the B cells the mu- heavy-chain antigen mu-HC was measured. There was no difference in the frequency distribution in the lymphocyte subtypes in the lymphoid organs. It was concluded by Lake et al64 that their results suggested that taurine depletion mediates attenuated immune responses and that immune deficiencies may arise as a consequence of suppressed cell function, although cell viability is not affected. They did, however, suggest a second possibility: that the responsiveness of a second cell type not evaluated in their study may have been altered by taurine depletion.

There is evidence to suggest a positive correlation between age-dependent depression in immune function and elevated morbidity and mortality.65, 66 Age-mediated decline in immune function has been shown for both cell-mediated and humoral immune responses. The effect of taurine on age-associated decline in immune function has been the subject of much interest in recent years in an effort to elucidate the role of the high levels of this free amino acid in immunologically active cells. The effect of taurine on an age-associated decrease in T- and B-cell proliferation in mice was investigated after stimulation with ionomycin and the Protein Kinase C (PKC) activator PMA.67 T cells were more susceptible to an age-related decline in proliferative ability than B cells. Taurine upregulation of T-cell proliferation at suboptimal concentrations of ionomycin was more pronounced in old T cells than in young cells, an effect not accounted for by an agemediated augmentation in taurine transport, because the rate of uptake was similar for all cells. It was interesting to note that intracellular calcium concentration ([Ca^sup 2+^) was significantly lower in the older T cells after costimulation with ionomycin and PMA. Taurine mediated an increase in [Ca^sup 2+^] in the older cells to levels found in younger T cells. This indicated that under stimulation, taurine improved the proliferative response of old T cells by the restoration of the increment of [Ca^sup 2+^].

Schuller-Levis and Sturman68 reported on the activation of alveolar leukocytes from cats fed taurine-free diets. Alveolar cell taurine concentration decreased 25% to 60% in animals maintained on taurine-deficient diets. In addition taurine deficiency mediated a neutropenia in alveolar lavage cells. Functional activity of alveolar-lavaged cells was influenced strongly by taurine. In all cases of deficiency the levels of the ROS Hd^sub 2^,0^sub 2^ and ^sub 0^ were highly elevated. Nonspecific chemiluminescence measurement showed a significantly shorter time required to attain peak responses in the taurine-deficient cells. Monoclonal antibodies were used to identify expression of specific granulocyte/macrophage markers and class II major histocompatibility complex (MHC) antigens on lung macrophages. There were no differences in the percentage of alveolarlavage cell expression of the granulocyte/macrophage markers; however, there was a pronounced taurine effect on the expression of the class II antigens. Animals supplemented with taurine expressed these antigens on 42% of these cells, whereas the deficient group had 72% expression. Macrophage-mediated activation of T cells is class II-dependent and is expressed in high levels on activated neutrophils.68 The conclusion to be drawn from this study is that taurine acts as a central modulator of granulocyte/ macrophage reactivity through its antioxidant ability in addition to playing a chaperoning role in relation to MHC class II antigen expression.

Conclusions

During the past two decades taurine has generate a vast degree of interest among researchers. Although skeptics remain convinced that this "innocuous compound" is an evolutionary artifact without which we would continue to prosper, there can be few researchers investigating taurine who remain to be convinced of its importance in the pathological, physiological, and pharmacologic hierarchy. The next decade or two promise to be very exciting and rewarding because much ground work is now completed and opens up the possibility that further research may provide answers to the many questions related to the ubiquity and functional diversity of taurine. Perhaps one of the most intriguing question future research may answer is clarification of the role of taurine in immune response modulation. There are now sufficient research data to suggest that taurine is closely related to immune function. Although the nature of this relationship is as yet not fully clear, its elucidation presents an array of possibilities for manipulation in a variety of pathological conditions. Extensive experimental data confirm that taurine is an amino acid of considerable biological significance. When one considers the biological functions with which taurine is now associated, it seems illogical that it is not more widely used clinically. The benefits of taurine administration as an immunostimulatory agent are not difficult to enumerate. In addition to efficacy as a pharmacologic agent, the usefulness of a compound in the clinical arena is dependent on toxic side effects. It is widely accepted by regulatory authorities worldwide that administration of taurine to humans is safe even at high doses. Taurine has been administered in the clinical setting previously and is now a component of many neonatal food regimes. Biological inability to utilize taurine for protein synthesis ensures that supplementary taurine will not be shunted into metabolic pathways, which would diminish concentrations available for specific functions for which it was intended. An inevitable consideration with any medical treatment is the cost; economics play a major role in decision-making because finite resources must be administered equitably to offer most benefits to most people. Taurine is readily available and ease of production minimizes cost.

We have demonstrated previously that in the human chronic inflammatory condition psoriasis," neutrophil taurine levels are significantly lower than normal. If further research proves this to be a general phenomenon of chronic inflammation, then supplementary taurine may attenuate inflammatory cell-mediated tissue injury while affording protection to the effector cell in these conditions. Decreased plasma taurine in sepsis and trauma and after surgery is well established. We recommend that taurine could be used where endogenous levels of taurine are low, such as in the situations mentioned here. Preoperative supplementation may protect against postoperative plasma taurine decrease. In addition taurine supplementation in people whose familial history indicates that chronic inflammatory conditions such as psoriasis or inflammatory bowel diseases may arise in later life could prove beneficial in attenuating inflammatory cell activity and therefore disease severity. Another area in which promotion of taurine supplementation could prove beneficial would be cardiac care units. The evidence linking taurine to beneficial effects in the heart is strong, and this is an area where supplementation could be especially beneficial.

Although much remains to be clarified regarding taurine's physiological functions and pharmacologic actions, evidence to date implicates taurine as an important biological agent. The importance of taurine as a dietary supplement was first realized by the Japanese in 1949 who began to sell taurine extracted from octopus as a "cure all" medicine. Imaginative and dynamic marketing strategies in the Western world in recent decades have contributed significantly to the vast consumption of vitamins and vitamin-based formulations. In the Far East taurinesupplemented drinks have been available for some time, an innovation now encountered in the United States and Europe. Perhaps with increased awareness of the putative benefits of clinically administered taurine, manufacturers will direct marketing strategies toward taurine in a manner similar to those for vitamin and mineral supplements, which could prove lucrative to the pharmaceutical industry and beneficial to the well-being of the general population.

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Royal College of Surgeons in Ireland, Department of Surgery, Beaumont Hospital, Dublin, Ireland

Received for publication, February 29, 1996.

Accepted for publication, July 14, 1997.

Correspondence: Philip P. Stapleton, PhD, Cornell University Medical College, P.O. Box 177,1300 York Avenue, New York, NY 10021.

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