Oxidoreductases in lipoxin A4 metabolic inactivation -: A novel role for 15-oxoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation
Oxidoreductases in lipoxin A4 metabolic inactivation -: A novel role for 15-oxoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehydrogenase in inflammation
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DOI：
10.1074/jbc.m002863200
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发表时间：
2000-08-18
影响因子：
4.8
通讯作者：
Serhan, CN
中科院分区：
文献类型：
--
作者：
Clish, CB;Levy, BD;Serhan, CN
脂氧素（LX）是在局部炎症环境中起作用以抑制嗜中性粒细胞募集并促进消退的自体素。15-羟基前列腺素脱氢酶（15-PGDH）和15-氧代前列腺素13-还原酶（也称为白三烯B-4 12-羟基脱氢酶（PGR/LTB 4 DH））是两种酶活性，因其在前列腺素和LTB 4代谢中的作用而受到重视。在这里，我们确定这些氧化还原酶是否也催化脂氧素A（4）（LXA（4））的转化，并评估这些LXA（4）代谢产物的活性。通过将LXA（4）与15-PGDH和NAD（+）孵育产生15-Oxo-LXA（4），用于其进一步转化的研究。PCR/LTB 4DH催化15-氧代-LXA（4）的NADH依赖性还原以产生13，14-二氢-15-氧代-LXA（4）。以NADH为辅因子，15-PGDH作为15-羰基还原酶，催化13，14-二氢-15-氧代-LXA（4）转化为13，14-二氢-LXA（4）。暴露于天然LXA（4）、15-oxo-LXA（4）或13，14-dihydro-LXA（4）的人多形核白细胞（PMN）不产生超氧阴离子。在LXA（4）和代谢稳定的LXA（4）类似物有效抑制白三烯B-4诱导的超氧阴离子产生的浓度下，其他代谢产物没有活性。15-氧代-LXA（4）和13，14-二氢-LXA（4）都不能有效地与H-3标记的LXA（4）竞争与重组LXA（4）受体（ALXR）的特异性结合。此外，将重组PGR/LTB 4DH引入小鼠渗出性炎症模型中可使PMN数量增加约2倍，表明该酶参与调节PMN运输。这些结果确定了LXA（4）进一步代谢产物的结构，并表明LXA（4）转化为氧代和二氢产物代表了炎症中LXA（4）失活的一种模式。此外，他们认为这些类花生酸氧化还原酶具有多方面的作用，控制参与炎症调节的特定类花生酸的水平。
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.