Oxidoreductases in Lipoxin A4 Metabolic Inactivation A NOVEL ROLE FOR 15-OXOPROSTAGLANDIN 13-REDUCTASE/LEUKOTRIENE B4 12-HYDROXYDEHYDROGENASE IN INFLAMMATION

摘要: The lipoxins (LX) are autacoids that act within a local inflammatory milieu to dampen neutrophil recruitment and promote resolution. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) 15-oxoprostaglandin 13-reductase, also termed leukotriene B4 12-hydroxydehydrogenase (PGR/LTB4DH), two enzymatic activities appreciated for their roles in the metabolism of prostaglandins LTB4. Here, we determined whether these oxidoreductases catalyze conversion lipoxin A4 (LXA4) assessed LXA4 metabolites. 15-Oxo-LXA4 was generated by incubating with 15-PGDH NAD+ studies its further conversion. PGR/LTB4DH catalyzed NADH-dependent reduction 15-oxo-LXA4 yield 13,14-dihydro-15-oxo-LXA4. With NADH as cofactor, acted 15-carbonyl reductase 13,14-dihydro-15-oxo-LXA4 13,14-dihydro-LXA4. Human polymorphonuclear leukocytes (PMN) exposed native LXA4, 15-oxo-LXA4, or 13,14-dihydro-LXA4 did not produce superoxide anions. At concentrations where metabolically stable analog potently inhibited B4-induced anion generation, metabolites were devoid activity. Neither 15-oxo-LXA4nor effectively competed with3H-labeled specific binding recombinant receptor (ALXR). In addition, introducing into murine exudative model inflammation increased PMN number ∼2-fold, suggesting this enzyme participates regulation trafficking. These results establish structures indicate oxo- dihydro- products represents mode inactivation inflammation. Moreover, they suggest eicosanoid have multifaceted controlling levels eicosanoids involved