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Oxidoreductases in Lipoxin A4 Metabolic Inactivation
Open accessAbstract
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.
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Cited by
Serhan, C. N., Hong, S., Gronert, K., Colgan, S. P., Devchand, P. R., Mirick, G., & Moussignac, R.-L. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020760 · Cited by 1,650
Self-citationLipid mediator class switching during acute inflammation: signals in resolution
Levy, B. D., Clish, C. B., Schmidt, B., Gronert, K., & Serhan, C. N. (2001) · Nature Immunology · doi:10.1038/89759 · Cited by 1,453
Self-citationResolvins in inflammation: emergence of the pro-resolving superfamily of mediators
Serhan, C. N., & Levy, B. D. (2018) · Journal of Clinical Investigation · doi:10.1172/jci97943 · Cited by 1,344
Self-citationHong, S., Gronert, K., Devchand, P. R., Moussignac, R.-L., & Serhan, C. N. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300218200 · Cited by 1,000
Self-citationResolvins and protectins in inflammation resolution
Serhan, C. N., & Petasis, N. A. (2011) · Chemical Reviews · doi:10.1021/cr100396c · Cited by 996
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Metadata
- Authors
- Clish, C. B., Levy, B. D., Chiang, N., Tai, H.-H., & Serhan, C. N.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-08
- Volume
- 275
- Issue
- 33
- Pages
- 25372-25380
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1964147273
- Cited by
- 184
- References
- 0
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
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