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/LTB(4)DH), are two enzymatic activities appreciated for their roles in the metabolism of
prostaglandins and LTB(4). 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/LTB(4)DH catalyzed the
NADH-dependent reduction of 15-oxo-LXA(4) to yield 13,14-dihydro-15-oxo-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 (3)H-labeled LXA(4) for specific binding to recombinant LXA(4) receptor (ALXR). In addition, introducing recombinant PGR/LTB(4)DH into a murine exudative model of
inflammation increased PMN number by approximately 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.