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Lipoxin B 4 regulates human monocyte/neutrophil adherence and motility: design of stable lipoxin B 4 analogs with increased biologic activity
Author(s) -
Maddox Jane F.,
Colgan Sean P.,
Clish Clary B.,
Petasis Nicos A.,
Fokin Valery V.,
Serhan Charles N.
Publication year - 1998
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.12.6.487
Subject(s) - lipoxin , chemistry , monocyte , chemotaxis , arachidonic acid , lipid signaling , hydroxyeicosatetraenoic acid , substrate (aquarium) , stereochemistry , in vitro , biochemistry , enzyme , receptor , biology , immunology , ecology
Lipoxins are biologically active products of arachidonic acid that are formed via cell‐cell interactions, particularly those involving leukocytes. Lipoxin A 4 and lipoxin B 4 (LXB 4 ), 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 LXB 4 to isolated recombinant 15‐hydroxy‐prostaglandin dehydrogenase (15‐PGDH) and found that it was a good substrate for the enzyme (A m =6.9 μM); we identified the major product as 5‐oxo‐LXB 4 via physical methods including liquid chromatogra‐phy/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 LXB 4 analogs were designed and prepared by total organic synthesis to test as stable mimetics: 5( S )‐methyl‐LXB 4 ‐me, 5( R )‐methyl‐LXB 4 ‐me, and 15‐epi‐LXB 4 ‐me (the aspirin‐triggered form of LXB 4 ). Both 5( S )‐methyl‐LXB 4 ‐me and 5( R )‐methyl‐LXB 4 ‐me were resistant to rapid conversion. In addition, actions of the stable analogs were evaluated separately with human mono‐cytic cells and neutrophils, and 5( S )‐methyl‐LXB 4 ‐me was more potent (nM range) than LXB 4 for both cell types. In contrast, 5( R )‐methyl‐LXB 4 ‐me was potent in inhibiting neutrophil transmigration across endothelial monolayers, but did not stimulate monocyte adherence. These results indicate that LXB 4 analogs can be designed to resist rapid transformation and retain bioactivity with both monocytes and neutrophils. Moreover, they suggest that LXB 4 stable analogs are useful tools to selectively evaluate the modes of actions of LXB 4 with different tis‐sues.—Maddox, J. F., Colgan, S. P., Clish, C. B., Petasis, N. A., Fokin, V. V. Serhan, C. N., Lipoxin B 4 regulates human monocyte/neutrophil adherence and motility: design of stable lipoxin B 4 analogs with increased biologic activity. FASEB J . 12, 487–494 (1998)