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At least 19 recordsLinked to original sources
PubMed1989

[Leukotriene B4, leukotriene C4 and prostaglandin E2 in the serum, synovial fluid and synovium in patients with rheumatoid arthritis].

This study investigated the presence of arachidonic acid metabolites, (leukotriene B4, leukotriene C4 and prostaglandin E2) in the serum, synovial fluid and synovium of rheumatoid arthritis patients (RA). We obtained the serum, synovial fluid and synovium from 16 female patients with RA during knee operations. Leukotriene B4 (LTB4), leukotriene C4 (LTC4) and prostaglandin E2 (PGE2) were detected by RIA analysis. In the patients administered steroids, a positive correlation was found between the concentrations of LTB4 and PGE2 in the synovium. In the patients not administered steroids, significant correlations were found between the concentrations of LTB4 in the synovium and serum, and also between the concentrations of LTB4 and LTC4 in the synovium. The levels of immunoglobulins and LTB4 in the serum were determined and a significant correlation was found between the content of IgG and the concentration of LTB4. In the serum, the concentration of LTB4 was elevated in RA patients relative to the control normal subjects, and the difference was statistically significant. In conclusion, these data suggest that LTB4 in the serum reflects the concentration of LTB4 in the synovium.

Arthritis, Rheumatoid↗
PubMed1986

Effects of gold compounds on leukotriene B4, leukotriene C4 and prostaglandin E2 production by polymorphonuclear leukocytes.

The effects of auranofin (AF) and sodium aurothiomalate (GSTM) on the production of specific arachidonic acid metabolites by chemotactic tripeptide activated polymorphonuclear leukocytes has been investigated using radioimmunoassay techniques. AF insignificantly enhanced the production of leukotrienes B4 and C4 at a concentration of 0.5 microgram Au/ml. However, at increasing concentrations, this drug suppressed the production of these metabolites in a dose dependent manner. In contrast, GSTM did not affect the production of either leukotriene at the concentrations tested. Of particular interest, prostaglandin E2 production was not affected by either gold compound. Both leukotrienes and prostaglandins are metabolized from arachidonic acid and are potent mediators of inflammation. The inhibition of leukotriene production may be another mechanism by which AF manifests its antiinflammatory effects in patients with rheumatoid arthritis.

Adult↗
PubMed1987

Mouse bone marrow-derived mast cells cocultured with fibroblasts. Morphology and stimulation-induced release of histamine, leukotriene B4, leukotriene C4, and prostaglandin D2.

Mouse bone marrow-derived mast cells (BMMC), cultured for 2, 7, or 14 days in WEHI-3 conditioned medium in the absence or presence of mouse 3T3 fibroblasts, were examined morphologically and for their functional responses to IgE-Fc-mediated and calcium ionophore-mediated activation. The 7- and 14-day fibroblast-adherent and non-fibroblast-adherent populations of cocultured BMMC had more granules per cell and the granule contents were more electron dense than non-cocultured BMMC or BMMC cocultured for only 2 days. The adherent cocultured BMMC were usually located within multiple layers of fibroblasts, but did not form junctions with the fibroblasts. When activated immunologically, the adherent cocultured mast cells generally discharged their granules singly, but compound exocytosis was occasionally seen. Both the non-adherent cocultured BMMC and the BMMC that were cultured in the absence of fibroblasts were similar to one another in that they exocytosed 9 to 11% of their histamine when sensitized with anti-dinitrophenyl IgE and challenged with dinitrophenyl-bovine serum albumin and 27 to 29% of their histamine when challenged with calcium ionophore. In contrast, adherent cocultured BMMC exocytosed 27 and 61% of their histamine upon immunologic and calcium ionophore activation, respectively, representing a significant two- to three-fold increase relative to that obtained from the other populations of BMMC. When activated immunologically, BMMC cultured in WEHI-3 conditioned medium alone generated a mean of 12 ng of immunoreactive C-6-sulfidopeptide leukotrienes, 1.6 ng of leukotriene B4 (LTB4), and 1.0 ng of prostaglandin D2 (PGD2)/10(6) cells. The immunologic response of the nonadherent 7-day cocultured BMMC was similar. Fibroblast-adherent cocultured BMMC, on the other hand, generated 56 ng of immunoreactive C-6-sulfidopeptide leukotrienes, 6.4 ng of LTB4, and 5.6 ng of PGD2/10(6) mast cells, representing a significant increase for each product. When calcium ionophore was used as the agonist, the adherent cocultured mast cells also generated significantly more arachidonic acid metabolites than nonadherent cocultured BMMC or BMMC cultured in the absence of fibroblasts. Retention times on high performance liquid chromatography confirmed that the generated immunoreactive products were LTB4, PGD2, and LTC4. Thus, coculture of BMMC with fibroblasts induces an alteration in the composition of the secretory granules of the mast cells, as well as an augmentation of the activation-secretion response of the BMMC.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

The effect of leukotriene B4, leukotriene C4, zymosan activated serum, histamine, tabanid extract and N-formyl-methionyl-leucyl-phenylalanine on the in vitro migration of equine eosinophils.

The migration of equine eosinophils under agarose in response to inflammatory mediators, an arthropod extract and a synthetic peptide was examined. A chemotactic index (CI) was calculated by determining the ratio of the distance of eosinophil migration towards the chemoattractant to the distance migrated towards a buffer. Differences between the CI of those eosinophils exposed to chemoattractants and those exposed only to buffer were assessed by an analysis of variance. All agents except leukotriene C4 and the buffer induced statistically significant directional migration of eosinophils. Leukotriene B4 (LTB4) was the most effective chemotaxin for equine eosinophils. Migration of eosinophils stimulated by 10(-9) M LTB4 exceeded that induced by concentrations of histamine six orders of magnitude greater. The response of equine eosinophils to inflammatory mediators was similar to the reported behavior of human eosinophils. The ability of tabanid extract to attract equine eosinophils suggests that arthropod induced tissue eosinophilia many not depend entirely upon immunological mechanisms. The peptide, N-formyl-methionyl-leucyl-phenylalanine attracted equine eosinophils at 10(-4) M and 10(-3) M, concentrations that exceed those reported to be stimulatory for eosinophils of other species. The results of this study indicate that equine eosinophils are capable of migrating towards diverse stimuli, of which LTB4 was the most effective. It is plausible that LTB4 figures prominently in equine inflammation, particularly in lesions dominated by eosinophils.

Animals↗
PubMed1986

Leukotriene B3, leukotriene B4 and leukotriene B5; binding to leukotriene B4 receptors on rat and human leukocyte membranes.

Specific high-affinity binding sites for [3H]-leukotriene B4 have been identified on membrane preparations from rat and human leukocytes. The rat and human leukocyte membrane preparations show linearity of binding with increasing protein concentration, saturable binding and rapid dissociation of binding by excess unlabelled leukotriene B4. Dissociation constants of 0.5 to 2.5 nM and maximum binding of 5000 fmoles/mg protein were obtained for [3H] leukotriene B4 binding to these preparations. Displacement of [3H]-leukotriene B4 by leukotriene B4 was compared with displacement by leukotriene B3 and leukotriene B5 which differ from leukotriene B4 only by the absence of a double bond at carbon 14 or the presence of an additional double bond at carbon 17, respectively. Leukotriene B3 was shown to be equipotent to leukotriene B4 in ability to displace [3H]-leukotriene B4 from both rat and human leukocyte membranes while leukotriene B5 was 20-50 fold less potent. The relative potencies for the displacement of [3H]-leukotriene B4 by leukotrienes B3, B4 and B5 on rat and human leukocyte membranes were shown to correlate well with their potencies for the induction of the aggregation of rat leukocytes and the chemokinesis of human leukocytes.

Animals↗
PubMed1984

Human T-lymphocyte subset specificity of the regulatory effects of leukotriene B4.

Leukotriene B4, but not (12S)-leukotriene B4, coupled to fluorescein-labeled human serum albumin interacts specifically with human T lymphocytes, as assessed by fluorescence-activated flow cytometry. Approximately 11% of blood T lymphocytes bind the fluorescent conjugate of leukotriene B4. The leukotriene B4-reactive T lymphocytes are distributed between the suppressor-cytotoxic (14%) and helper-inducer (8%) subsets, which were identified concurrently by phycoerythrin-labeled monoclonal antibodies to subset-specific antigens. Leukotriene B4, but not (12S)-leukotriene B4 or leukotriene C4, enhances significantly the proliferation of mitogen-stimulated purified suppressor-cytotoxic T lymphocytes, at concentrations of 10(-12) M to 10(-6) M, and inhibits significantly the proliferation of mitogen-stimulated purified helper-inducer T lymphocytes, at concentrations of 10(-8) M to 10(-6) M, as assessed by the uptake of [3H]thymidine. The net effect of leukotriene B4 on blood T lymphocytes is immunosuppression, which may be expressed in some human hypersensitivity and inflammatory diseases.

Antibodies, Monoclonal↗
PubMed1996

Gas chromatographic/mass spectrometric analysis of oxo and chain-shortened leukotriene B4 metabolites. Leukotriene B4 metabolism in Ito cells.

Analysis by gas chromatography/mass spectrometry (GC/MS) of derivatized metabolites formed following incubation of leukotriene B4 (LTB4) incubation with Ito cells extends previous knowledge concerning fragmentation mechanisms for derivatized hydroxy-substituted unsaturated fatty acids. LTB4 was metabolized by rat Ito cells, a hepatic perisinusoidal stellate cell, by the delta 10- and delta 14-reductase pathways, resulting in the formation of 10,11-dihydro-LTB4 and 10,11,14,15-tetrahydro-LTB4. Formation of the intermediate metabolites, 12-oxo-10,11-dihydro-LTB4 and 12-oxo-10,11,14,15-tetrahydro-LTB4, was also observed. GC/electron impact (EI) MS analysis of the 12-oxo metabolites, derivatized as the pentafluorobenzyl ester/ trimethylsilyl ether compounds, resulted in unique fragmentations indicative of the oxo substituent and double bond positions. Further metabolism of 10,11-dihydro-LTB4 and 10,11,14,15-tetrahydro-LTB4 by carboxy terminus beta-oxidation resulted in chain-shortened monohydroxy metabolites. Possible intermediates in this metabolism, which resulted in loss of the original C-5 hydroxy substituent from LTB4, were identified as 2,4,6-conjugated triene-containing C-18 metabolites. The absence of a double bond allylic to the trimethylsiloxy ether in derivatized 10,11,14,15-tetrahydro LTB4 metabolites strikingly reduced the abundance of alpha-cleavage ions observed in the EI mass spectra of these compounds, thus suggesting the importance of formation of an allylic stabilized radical in such alpha-cleavage reactions. Lacking a favorable alpha-cleavage reaction, GC/EIMS analysis of 10-hydroxy-2,4,6-octadecatrienoic acid resulted in the formation of m/z 91, which may arise via cyclization of the conjugated triene moiety. In addition, GC/MS analysis of derivatized metabolites containing the 2,4,6 conjugated triene moiety resulted in a unique fragment ion in the electron capture ionization mass spectra that also may arise via cyclization of the conjugated triene with formation of m/z 121.

Animals↗
PubMed1996

Leukotriene A4 hydrolase, mutation of tyrosine 378 allows conversion of leukotriene A4 into an isomer of leukotriene B4.

Leukotriene A4 hydrolase catalyzes the final step in the biosynthesis of the proinflammatory compound leukotriene B4, a reaction which is accompanied by suicide inactivation of the enzyme by leukotriene A4. We have recently reported that Tyr-378 is a major structural determinant for suicide inactivation and that mutation of Tyr-378 into Phe or Gln protects leukotriene A4 hydrolase from this catalytic restriction (Mueller, M. J., Blomster, M., Opperman, U. C. T., Jörnvall, H., Samuelsson, B., and Haeggström, J. Z. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 5931-5935). In the present study, we show that both [Y378F]- and [Y378Q]leukotriene A4 hydrolase converts leukotriene A4 not only into leukotriene B4 but also into a second, previously unknown, product of the enzyme. From biophysical analyses and comparison with a synthetic standard, the structure of this product was determined to 5S,12R-dihydroxy-6,10-trans-8, 14-cis-eicosatetraenoic acid, i.e. Delta6-trans-Delta8-cis-leukotriene B4. The relative formation of Delta6-trans-Delta8-cis-leukotriene B4 versus leukotriene B4 by [Y378F]- and [Y378Q]leukotriene A4 hydrolase, was 18% and 32%, respectively. For [Y378F]leukotriene A4 hydrolase, the turnover of leukotriene A4 into leukotriene B4 or Delta6-trans-Delta8-cis-leukotriene B4 was calculated to 2.5 s-1 which is almost three times the kcat value of the wild type enzyme. Taken together, these findings indicate that Tyr-378 is located at the active site where it assists in the formation of the correct double-bond geometry in the product leukotriene B4.

Binding Sites↗
PubMed1984

Superoxide production of human polymorphonuclear leukocytes stimulated by leukotriene B4.

Leukotriene B4 stimulated a transient production of superoxide anions (O2-) by human polymorphonuclear leukocytes which continued for only about 1 min. The production was dependent on Ca2+ in the suspending medium and no production was observed without the addition of calcium. The concentrations of leukotriene B4 and calcium for the half-maximal production were about 1 microM and 200 microM, respectively. 8-(N,N,-Diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8), an intracellular calcium antagonist, did not inhibit the O2- production stimulated by leukotriene B4 in the presence of calcium, while N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a calmodulin inhibitor, did. When leukotriene B4 was added to the cells treated with cytochalasin B, the production of O2- was biphasic: an initial rapid phase, followed by a slow one. The slow phase was also dependent on Ca2+ concentrations but it could be induced even without the addition of Ca2+ to the medium. The cells treated with both cytochalasin B and TMB-8 in Ca2+-free medium showed a negligible production of superoxide on addition of leukotriene B4, but the production appeared upon addition of CaCl2. These findings suggest that the superoxide production stimulated by leukotriene B4 is associated with the influx of Ca2+.

Animals↗
PubMed1984

Production of intraepidermal microabscesses by topical application of leukotriene B4.

Leukotriene B4 is a highly potent leukocyte chemotactic compound. It has been identified in chamber fluid and scale from psoriatic skin lesions, in which epidermal neutrophil infiltration is reported to be one of the earliest pathologic events. The ability of leukotriene B4 to reproduce the inflammatory events of psoriasis, by topical application to the skin of normal human volunteers, was thus studied. Persistent visible inflammatory reactions were elicited by application of amounts of leukotriene B4 as low as 5 ng, and the maximum diameters of the reactions were dose-related up to at least 500 ng. The visible reactions appeared 12-24 h after initial application of leukotriene B4, and persisted for several days, leaving brownish pigmentation and scaling at 7 days. Histologic examination showed intraepidermal neutrophil microabscesses at 24 h, but these had resolved by 48 h. A mixed, perivascular neutrophil and mononuclear cell infiltrate was seen in the dermis at 24 h, becoming predominantly mononuclear after 24 h. Nonspecific chemical irritant contact dermatitis was excluded by the absence of reactions to high doses of two chemically similar metabolites of arachidonic acid which lack significant in vitro chemokinetic activity. These experiments provide further evidence for the role of leukotriene B4 in the pathogenesis of psoriasis, and may lead to the development of an experimental model of the inflammatory events in psoriasis, and of a simple in vivo test of neutrophil function.

Abscess↗
PubMed1998

Leukotriene B4.

Leukotriene B4 is a pro-inflammatory mediator synthesised in myeloid cells from arachidonic acid. Synthesis is catalysed by 5-lipoxygenase and leukotriene A4 hydrolase and is increased by inflammatory mediators including endotoxin, complement fragments, tumor necrosis factor and interleukins. A nuclear membrane protein, 5-lipoxygenase activating protein, is an essential co-factor for 5-lipoxygenase. Leukotriene B4 induces recruitment and activation of neutrophils, monocytes and eosinophils. It also stimulates the production of a number of proinflammatory cytokines and mediators indicating an ability to augment and prolong tissue inflammation. Elevated levels of leukotriene B4 have been found in a number of inflammatory diseases and levels are related to disease activity in some of these. Initial data from pharmacological inhibition studies support a role for leukotriene B4 in the pathogenesis of neutrophil mediated tissue damage, and treatments which reduce its production or block its effects may prove beneficial in neutrophil mediated inflammatory diseases.

Arachidonate 5-Lipoxygenase↗
PubMed1990

Endothelial cells can synthesize leukotriene B4.

Leukotriene B4 (LTB4) from vascular endothelium may play a key role in the genesis of atherosclerotic lesions. However, the ability of this tissue to synthesize LTB4 is controversial. To resolve this issue arachidonic acid metabolism was characterized in cultures of confluent monolayers of a rabbit aortic endothelial cell line by use of both high-pressure liquid chromatography and radioimmunoassay. Cells were grown to confluence in Dulbecco's modified Eagle's medium/Ham's F12 with 5% fetal bovine serum. Lipoxygenase activity was studied by placing the cells in Hank's balanced salt solution with 2 mumol/L indomethacin. After 30 minutes preincubation with indomethacin cells were exposed to either arachidonic acid (10 mumol/L) or arachidonic acid labeled with radioactive carbon (14C) (1 microCi; SA 58 mCi/mmol) and then stimulated with 9.5 mumol/L calcium ionophore A23187 for 55 minutes. Studies of the cyclooxygenase activity were performed without preincubating with indomethacin. Samples were prepared for high-pressure liquid chromatography by evaporation to dryness under a vacuum and resuspending in 2 ml of 1:1 methanol/water. Tritium-labeled standards were added before loading the 14C-labeled samples on the column. Radiolabeled arachidonic acid metabolites were separated by high-pressure liquid chromatography and detected by means of a dual channel flow-through radiodetector that monitors both 14C and 3H. Based on coelution with authentic standards three lipoxygenase metabolites of arachidonic acid have been identified: LTB4, 12- and 5-hydroxyeicosatetraneoic acid. Leukotriene B4 was further characterized by ultraviolet spectral analysis and inhibition studies with use of nordihydroguaiaretic acid. Quantitation was facilitated by commercially available radioimmunoassay kits. An average of 600 pg LTB4/10(6) cells was measured from separate experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Avian osteoclast cells are stimulated to resorb calcified matrices by and possess receptors for leukotriene B4.

Leukotriene B4 (LTB4) is elevated in inflammatory conditions and appears to be a potential mediator of inflammation. We have recently shown that this 5-lipoxygenase metabolite of arachidonic acid stimulates bone resorption in vitro and in vivo. In order to determine the mechanism whereby LTB4 causes bone resorption, avian osteoclasts were examined for the effects of LTB4 and for the presence of LTB4 receptors. Isolated avian osteoclast mononuclear precursor cells, which fuse in culture to form multinucleated cells, were chosen for receptor binding studies because this population is a morphologically similar source of osteoclasts, and large numbers of these cells can be obtained from egg-laying hens. Binding of LTB4 and activation would support the hypothesis of a direct effect of this compound on osteoclasts. LTB4 stimulated isolated avian osteoclasts to form resorption lacunae on calcified matrices and to increase their content of tartrate-resistant acid phosphatase (TRAP), a marker of activated osteoclasts. Receptor binding studies were performed at day 1, when the cells were mononuclear, at day 4, when mononuclear precursors were actively fusing, and at day 7, when fusion has slowed. Scatchard analysis of saturation binding data showed two classes of binding sites, a high- and low-affinity binding site with dissociation constants (KD) of 0.2-0.4 nM and 5. 6-24 nM. Association studies showed rapid binding of LTB4 to the cells within 10 minutes. These data show that LTB4 accelerates fusion and activates highly enriched populations of avian osteoclasts and that LTB4 receptors are present in this cell population.

Acid Phosphatase↗
PubMed1988

Biological properties of dihydro-leukotriene B4, an alternative leukotriene B4 metabolite.

Dihydro-leukotriene B4 (a 5,12-dihydroxy-eicosatrienoic acid) has been shown to be the primary metabolite of leukotriene B4 (LTB4) in a variety of cells other than human polymorphonuclear leukocytes (PMNLs). In this report we show that dihydro-LTB4 is significantly less active than LTB4 in different biological assay systems, i.e. leukocyte chemotaxis, chemokinesis, aggregation, adhesion to endothelium and superoxide anion production. This suggests that primary reduction constitutes a second so far unknown deactivation pathway for LTB4.

Cell Adhesion↗
PubMed1981

Biological activities of leukotriene B4.

Leukotriene B4 isomer III is released from polymorphonuclear leucocytes, monocytes, eosinophils and macrophages in vitro and has been detected and measured in human synovial fluid in vivo. Its most prominent biological activities are to induce the aggregation of and to stimulate the movement (chemokinesis and chemotaxis) of leucocytes in vitro and it acts as a cytotaxin in vivo. In addition, it increases vascular permeability in vivo when administered together with the vasodilator, PGE2.

Animals↗
PubMed1981

The lung parenchymal strip as a sensitive assay for leukotriene B4.

Leukotriene B4 (LTB4) (3 X 10(-11) to 1.5 X 10(-9) mole; 10 ng to 500 ng) contracted the guinea-pig lung parenchymal strips in a dose-dependent manner. The contractile effect of LTB4 was not affected by methysergide (0.2 microgram/ml), propranolol (3.0 microgram/ml), phenoxybenzamine (0.1 microgram/ml), atropine (0.1 microgram/ml), diphenhydramine (0.1 microgram/ml) and FPL-55712 (1.0 microgram/ml), but was nearly completely abolished by indomethacin (20 microgram/ml). It is concluded that the contraction of the parenchymal strip to LTB4 may constitute a simple, sensitive and selective bioassay which could be either used for the determination of LTB4 in biological material or for studies on structure-activity relationship.

Animals↗
PubMed1984

Enhancement of chemotactic factor-stimulated neutrophil oxidative metabolism by leukotriene B4.

Leukotriene B4 (LTB4) is a potent primary stimulator of neutrophil chemotaxis, aggregation, and degranulation and induces superoxide production at higher concentrations. In order to determine whether LTB4 modulates neutrophil responses to oxidative stimuli, human neutrophils (PMNs) were incubated with LTB4 prior to stimulation with f-Met-Leu-Phe (fMLP, 10(-7) mol/L), opsonized zymosan (OZ, 250 micrograms/mL), or phorbol myristate acetate (PMA, 32 nmol/L). Superoxide (O2-) production by stimulated PMNs was assessed by the superoxide dismutase-inhibitable reduction of cytochrome c. LTB4 alone did not stimulate O2- production in concentrations below 10(-7) mol/L and had no effect on the O2- assay. In the concentration range of 10(-12) to 10(-8) mol/L, LTB4 did not alter O2- release induced by OZ or PMA. In contrast, LTB4-treated cells demonstrated enhanced O2- production following exposure to fMLP, and in the presence of 10 nmol/LLTB4, generated 180% +/- 41% of O-2 quantities produced by control cells (n = 23). Enhancement was LTB4 dose-dependent, was maximal in the range of 1 to 10 nmol/L LTB4, was not reversed by removal of the lipid from the medium prior to fMLP stimulation, and was not dependent on the presence of Ca++ or Mg++ in the suspending medium. Chemiluminescence of fMLP-stimulated neutrophils was increased to 323% of controls in neutrophils preincubated with 10 nmol/L LTB4. Unlike augmentation of oxidative responses to fMLP seen with other degranulating stimuli, enhancement by LTB4 was not correlated with an increase in 3H-fMLP receptor binding. These results indicate that, in addition to its primary effects on neutrophil function, LTB4 modulates PMN oxidative responses to the chemotactic peptide and, thus, may amplify the release of oxygen metabolites at inflammatory foci.

Chemotactic Factors↗