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Titolo:
Oxidoreductases in lipoxin A(4) metabolic inactivation - A novel role for 15-oxoprostaglandin 13-reductase/leukotriene B-4 12-hydroxydehydrogenase ininflammation
Autore:
Clish, CB; Levy, BD; Chiang, N; Tai, HH; Serhan, CN;
Indirizzi:
Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, Boston, MA 02115 USA Brigham & Womens Hosp Boston MA USA 02115 us Injury, Boston, MA 02115 USA Harvard Univ, Sch Med, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 vard Univ, Sch Med, Boston, MA 02115 USA Univ Kentucky, Coll Pharm, Div Pharmaceut Sci, Lexington, KY 40536 USA Univ Kentucky Lexington KY USA 40536 rmaceut Sci, Lexington, KY 40536 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 33, volume: 275, anno: 2000,
pagine: 25372 - 25380
SICI:
0021-9258(20000818)275:33<25372:OILAMI>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
LEUKOTRIENE B-4; STABLE ANALOGS; CDNA CLONING; IDENTIFICATION; PURIFICATION; EXPRESSION; CONVERSION; RECEPTOR; ENZYMES; CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Serhan, CN Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, 75 Francis St, Boston, MA 02115 USA Brigham & Womens Hosp 75 Francis St Boston MA USA 02115 115 USA
Citazione:
C.B. Clish et al., "Oxidoreductases in lipoxin A(4) metabolic inactivation - A novel role for 15-oxoprostaglandin 13-reductase/leukotriene B-4 12-hydroxydehydrogenase ininflammation", J BIOL CHEM, 275(33), 2000, pp. 25372-25380

Abstract

The lipoxins (LX) are autacoids that act within a local inflammatory milieu to dampen neutrophil recruitment and promote resolution. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) and 15-oxoprostaglandin 13-reductase, also termed leukotriene B-4 12-hydroxydehydrogenase (PGR/LTB4DH), are two enzymatic activities appreciated for their roles in the metabolism of prostaglandins and LTB4. Here, we determined whether these oxidoreductases also catalyze the conversion of lipoxin A(4) (LXA(4)) and assessed the activities of these LXA(4) metabolites. 15-Oxo-LXA(4) was generated by incubating LXA(4) with 15-PGDH and NAD(+) for studies of its further conversion. PGR/LTB4DH catalyzed the NADH-dependent reduction of 15-oxo-LXA(4) to yield 13,14-dihydro-15-loxo-LXA(4). With NADH as a cofactor, 15-PGDH acted as a 15-carbonyl reductase and catalyzed the conversion of 13,14-dihydro-15-oxo-LXA(4) to 13,14-dihydro-LXA(4). Human polymorphonuclear leukocytes (PMN) exposed to native LXA(4), 15-oxo-LXA(4), or 13,14-dihydro-LXA(4) did not produce superoxide anions. At concentrations where LXA(4) and a metabolically stable LXA(4) analog potently inhibited leukotriene B-4-induced superoxide anion generation, the further metabolites were devoid of activity. Neither 15-oxo-LXA(4) nor 13,14-dihydro-LXA(4) effectively competed with H-3-labeled LXA(4) for specific binding to recombinant LXA(4) receptor (ALXR). In addition, introducing recombinant PGR/LTB4DH into a murine exudative model of inflammation increased PMN number by similar to 2-fold, suggesting that this enzyme participates in the regulation of PMN trafficking. These results establish the structures of LXA(4) further metabolites and indicate that conversion of LXA(4) to oxo- and dihydro- products represents a mode of LXA(4) inactivation in inflammation. Moreover, they suggest that these eicosanoid oxidoreductases have multifaceted roles controlling the levels of specific eicosanoids involved in the regulation of inflammation.

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Documento generato il 01/06/20 alle ore 02:24:42