Calcium stimulation of the 5-lipoxygenase from RBL-1 cells

Parker, Charles W.; Aykent, Serdar

doi:10.1016/0006-291x(82)92040-x

Cited by 62 publications

(20 citation statements)

References 7 publications

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“…Resident tissue macrophages are major sources of the LT (3)(4)(5). The plasma membrane of these cells is rich in esterified arachidonate that is released during membrane perturbation and is then available to Ca2+-dependent 5-lipoxygenase that regulates the formation of the LT (6,7). Traditional stimuli for LT production by macrophages in vitro include both soluble (calcium ionophore A23187, endotoxin, phorbol myristate acetate) and particulate (zymosan, immunocomplexes) stimuli; LT production in response to the latter has been related directly to the degree of phagocytosis (3)(4)(5).…”

Section: Each Of These Compounds Incorporated [3h]arachidonic Acidmentioning

confidence: 99%

Alteration of leukotriene release by macrophages ingesting Toxoplasma gondii.

Locksley¹,

Fankhauser²,

Henderson³

1985

Proc. Natl. Acad. Sci. U.S.A.

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Mouse resident peritoneal macrophages incubated with ionophore A23187 or opsonized zymosan released leukotrienes (LT) B4 and C4 (LTB4 and LTC4) and LTC4 and LTD4, respectively. In contrast, incubation with Toxoplasma gondii, an obligate intracellular protozoan, led to the formation of 11-, 12-, and 15-hydroxyicosatetraenoic acids (HETEs), together with an unidentified compound, designated compound X. Each of these compounds incorporated [3H]arachidonic acid from the macrophage during phagocytosis of T. gondi. Compound X migrated immediately prior to 15-HETE by reversephase HPLC and was distinct from authentic monoHETE, monohydroperoxyicosatetraenoic acid (mono-HPETE), and dihydroxyicosatetraenoic acid (diHETE) standards. The generation of compound X by macrophages correlated with the extent of phagocytosis of T. gondii and with intracellular survival of the organisms. Prior antibody-coating of T. gondii or activation of macrophages, either of which inhibited survival and replication of ingested organisms, was associated with production of LTD4 but not compound X. Killed organisms also stimulated LTD4 release only. Although T. gondii concentrated arachidonic acid, they did not metabolize the compound to identifiable lipoxygenase products. Preincubation of macrophages with the relative lipoxygenase inhibitors nordihydroguaiaretic acid or 5,8,11,14-icosatetraynoic acid inhibited the formation of compound X. The absence of leukotriene production by macrophages ingesting T. gondji may explain the relative lack of a neutrophil inflammatory response in diseases due to obligate intracellular organisms. Alternatively, compound X may have functional activities that might mediate some of the host responses to cellular parasitism.The leukotrienes (LT) have been identified as potentially important inflammatory mediators of host defense (1, 2). LTB4 is a potent neutrophil chemoattractant and stimulus for aggregation, degranulation, and adherence to endothelium. The sulfidopeptide leukotrienes LTC4, LTD4, and LTE4, which collectively constitute the slow-reacting substance of anaphylaxis (SRS), promote vasoconstriction and enhance permeability across the postcapillary venule. Resident tissue macrophages are major sources of the LT (3-5). The plasma membrane of these cells is rich in esterified arachidonate that is released during membrane perturbation and is then available to Ca2+-dependent 5-lipoxygenase that regulates the formation of the LT (6, 7). Traditional stimuli for LT production by macrophages in vitro include both soluble (calcium ionophore A23187, endotoxin, phorbol myristate acetate) and particulate (zymosan, immunocomplexes) stimuli; LT production in response to the latter has been related directly to the degree of phagocytosis (3-5).Resident tissue macrophages are the initial target of many obligate intracellular pathogens that infect man, but the capacity of viable organisms to trigger the release of inflammatory mediators from macrophages has not been systematically investigated. The pathogenic protozoa...

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Section: Each Of These Compounds Incorporated [3h]arachidonic Acidmentioning

confidence: 99%

Alteration of leukotriene release by macrophages ingesting Toxoplasma gondii.

Locksley¹,

Fankhauser²,

Henderson³

1985

Proc. Natl. Acad. Sci. U.S.A.

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“…Phosphorylations at Ser-271 by MAPKAP kinase 2 (Werz et al , 2000 ) and at Ser-663 by ERK2 ) have a stimulatory effect, whereas phosphorylation at Ser-523 by protein kinase A (PKA) inhibits the activity (Luo et al , 2004 ). In most reviews, 5-LO is mentioned as a monomeric enzyme (Rouzer and Samuelsson , 1985 ;R å dmark, 2002 ), nevertheless, it was previously shown that 5-LO from rat basophilic leukemia cells (RBL-1) forms dimers in the presence of calcium (Parker and Aykent , 1982 ). Recently, Shang et al analyzed dimerization and fl exibility of rabbit 12/15-LO and human 12-LO by small angle X-ray scattering (SAXS) (Shang et al , 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Dimerization of human 5-lipoxygenase

Häfner

Cernescu

Hofmann

et al. 2011

BCHM

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Human 5-lipoxygenase (5-LO) can form dimers as shown here via native gel electrophoresis, gel fi ltration chromatography and LILBID (laser induced liquid bead ion desorption) mass spectrometry. After glutathionylation of 5-LO by diamide/glutathione treatment, dimeric 5-LO was no longer detectable and 5-LO almost exclusively exists in the monomeric form which showed full catalytic activity. Incubation of 5-LO with diamide alone led to a disulfi debridged dimer and to oligomer formation which displays a strongly reduced catalytic activity. The bioinformatic analysis of the 5-LO surface for putative protein-protein interaction domains and molecular modeling of the dimer interface suggests a head to tail orientation of the dimer which also explains the localization of previously reported ATP binding sites. This interface domain was confi rmed by the observation that 5-LO dimer formation and inhibition of activity by diamide was largely prevented when four cysteines (C159S, C300S, C416S, C418S) in this domain were mutated to serines.

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“…The 5-lipoxygenase converts arachidonic acid (5,8,11,14-eicosatetraenoic acid) to 5S-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HPETE) (62). 5-lipoxygenase is a calcium-dependent cytosolic enzyme in cell-free preparations from RBL-1 rat basophilic leukemia cells, guinea pig PMN, and human PMN (63)(64)(65), and in the RBL-l preparations it is considered to manifest catalytic activity only as a calcium-dependent dimer (63). After extraction from guinea pig PMN, its preferential substrates are arachidonic acid and (5,8,11,14,17-cis)-eicosapentaenoic acid, which is preferentially present in fish fatty acid-enriched diets, but not such common fatty acids as linoleic (9,12-cis-octadecadienoic acid) and linolenic (9,12,15-cis-octadecatrienoic acid), which lack a 5,6-olefinic bond (64 5-HPETE is converted by a dehydrase to 5,6-trans-oxido-7,9-trans-1 1, 14-cis-eicosatetraenoic acid, (leukotriene A4, LTA4) (66) or is hydrolyzed to its alcohol, 5S-hydroxy-6-trans-8, 11,14-cis-eicosatetraenoic acid.…”

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confidence: 99%