Lipoxin B4 regulates human monocyte/neutrophil adherence and motility: Design of stable lipoxin B4 analogs with increased biologic activity

Jane F. Maddox, Sean P. Colgan, Clary B. Clish, Nicos A. Petasis, Valery V. Fokin, Charles N. Serhan

Результат исследований: Материалы для журналаСтатьярецензирование

83 Цитирования (Scopus)

Аннотация

Lipoxins are biologically active products of arachidonic acid that are formed via cell-cell interactions, particularly those involving leukocytes. Lipoxin A4 and lipoxin B4 (LXB4), within similar concentration ranges, each inhibit human neutrophil, activate monocyte adherence and motility, and are rapidly converted by initial dehydrogenation to other inactive metabolites by human monocytes. Here, we exposed LXB4 to isolated recombinant 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) and found that it was a good substrate for the enzyme (K(m)=6.9 μM); we identified the major product as 5-oxo-LXB4 via physical methods including liquid chromatography/tandem mass spectrometry. This is the first evidence of 15- PGDH converting a substrate hydroxyl group at a position other than the ω-6 carbon. Based on these observations, several LXB4 analogs were designed and prepared by total organic synthesis to test as stable mimetics: 5(S)-methyl- LXB4-me, 5(R)methyl-LXB4-me, and 15-epi-LXB4-me (the aspirin-triggered form of LXB4). Both 5(S)-methyl-LXB4-me and 5(R)-methyl-LXB4-me were resistant to rapid conversion. In addition, actions of the stable analogs were evaluated separately with human monocytic cells and neutrophils, and 5(S)-methyl-LXB4-me was more potent (nM range) than LXB4 for both cell types. In contrast, 5(R)-methyl-LXB4-me was potent in inhibiting neutrophil transmigration across endothelial monolayers, but did not stimulate monocyte adherence. These results indicate that LXB4 analogs can be designed to resist rapid transformation and retain bioactivity with both monocytes and neutrophils. Moreover, they suggest that LXB4 stable analogs are useful tools to selectively evaluate the modes of actions of LXB4 with different tissues.

Язык оригиналаАнглийский
Страницы (с-по)487-494
Число страниц8
ЖурналFASEB Journal
Том12
Номер выпуска6
СостояниеОпубликовано - 1998
Опубликовано для внешнего пользованияДа

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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