Published online 16 October 2000.
© The Rockefeller University Press, 0022-1007/2000/10/1197/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 8, October 16, 2000 1197-1204
Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and Transcellular Processing
Charles N. Serhana,
Clary B. Clisha,
Jessica Brannona,
Sean P. Colgana,
Nan Chianga, and
Karsten Gronerta
a Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
Director, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.617-278-6957617-732-8822
Aspirin therapy inhibits prostaglandin biosynthesis without directly acting on lipoxygenases, yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive lipoxins (LXs) epimeric at carbon 15 (15-epi-LX, also termed aspirin-triggered LX [ATL]). Here, we report that inflammatory exudates from mice treated with
-3 polyunsaturated fatty acid and aspirin (ASA) generate a novel array of bioactive lipid signals. Human endothelial cells with upregulated COX-2 treated with ASA converted C20:5
-3 to 18R-hydroxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15R-LX5 and 5,12,18R-triHEPE. These new compounds proved to be potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue > 5,12,18R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HEPE and 15R-HEPE generation with recombinant COX-2 as well as
-5 and
-9 oxygenations of other fatty acids that act on hematologic cells. These findings establish new transcellular routes for producing arrays of bioactive lipid mediators via COX-2–nonsteroidal antiinflammatory drug–dependent oxygenations and cell–cell interactions that impact microinflammation. The generation of these and related compounds provides a novel mechanism(s) for the therapeutic benefits of
-3 dietary supplementation, which may be important in inflammation, neoplasia, and vascular diseases.
Key Words: dietary PUFA eicosanoids leukocytes cardiovascular disease
Presented in part at the 11th International Conference on Advances in Prostaglandin and Leukotriene Research, plenary session June 5, 2000, Florence, Italy.
© 2000 The Rockefeller University Press

CiteULike
Complore
Connotea
Del.icio.us
Digg
Facebook
Reddit
Technorati
Twitter What's this?
This article has been cited by other articles:
-
Ohira, T., Arita, M., Omori, K., Recchiuti, A., Van Dyke, T. E., Serhan, C. N.
(2010). Resolvin E1 Receptor Activation Signals Phosphorylation and Phagocytosis. J. Biol. Chem.
285: 3451-3461
[Abstract]
[Full Text]
-
Seki, H., Fukunaga, K., Arita, M., Arai, H., Nakanishi, H., Taguchi, R., Miyasho, T., Takamiya, R., Asano, K., Ishizaka, A., Takeda, J., Levy, B. D.
(2010). The Anti-Inflammatory and Proresolving Mediator Resolvin E1 Protects Mice from Bacterial Pneumonia and Acute Lung Injury. J. Immunol.
184: 836-843
[Abstract]
[Full Text]
-
Dornelles, F. N., Santos, D. S., Van Dyke, T. E., Calixto, J. B., Batista, E. L. Jr., Campos, M. M.
(2009). In Vivo Up-Regulation of Kinin B1 Receptors after Treatment with Porphyromonas gingivalis Lipopolysaccharide in Rat Paw. J. Pharmacol. Exp. Ther.
330: 756-763
[Abstract]
[Full Text]
-
Tian, H., Lu, Y., Sherwood, A. M., Hongqian, D., Hong, S.
(2009). Resolvins E1 and D1 in Choroid-Retinal Endothelial Cells and Leukocytes: Biosynthesis and Mechanisms of Anti-inflammatory Actions. IOVS
50: 3613-3620
[Abstract]
[Full Text]
-
Dangi, B., Obeng, M., Nauroth, J. M., Teymourlouei, M., Needham, M., Raman, K., Arterburn, L. M.
(2009). Biogenic Synthesis, Purification, and Chemical Characterization of Anti-inflammatory Resolvins Derived from Docosapentaenoic Acid (DPAn-6). J. Biol. Chem.
284: 14744-14759
[Abstract]
[Full Text]
-
Roberts, L. J. II, Milne, G. L.
(2009). Isoprostanes. J. Lipid Res.
50: S219-S223
[Abstract]
[Full Text]
-
Serhan, C. N., Yang, R., Martinod, K., Kasuga, K., Pillai, P. S., Porter, T. F., Oh, S. F., Spite, M.
(2009). Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. JEM
206: 15-23
[Abstract]
[Full Text]
-
Vassiliou, E. K., Kesler, O. M., Tadros, J. H., Ganea, D.
(2008). Bone Marrow-Derived Dendritic Cells Generated in the Presence of Resolvin E1 Induce Apoptosis of Activated CD4+ T Cells. J. Immunol.
181: 4534-4544
[Abstract]
[Full Text]
-
Merched, A. J., Ko, K., Gotlinger, K. H., Serhan, C. N., Chan, L.
(2008). Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J.
22: 3595-3606
[Abstract]
[Full Text]
-
Dona, M., Fredman, G., Schwab, J. M., Chiang, N., Arita, M., Goodarzi, A., Cheng, G., von Andrian, U. H., Serhan, C. N.
(2008). Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets. Blood
112: 848-855
[Abstract]
[Full Text]
-
Milne, G. L., Yin, H., Morrow, J. D.
(2008). Human Biochemistry of the Isoprostane Pathway. J. Biol. Chem.
283: 15533-15537
[Full Text]
-
Brooks, J. D., Milne, G. L., Yin, H., Sanchez, S. C., Porter, N. A., Morrow, J. D.
(2008). Formation of Highly Reactive Cyclopentenone Isoprostane Compounds (A3/J3-Isoprostanes) in Vivo from Eicosapentaenoic Acid. J. Biol. Chem.
283: 12043-12055
[Abstract]
[Full Text]
-
Hong, S., Porter, T. F., Lu, Y., Oh, S. F., Pillai, P. S., Serhan, C. N.
(2008). Resolvin E1 Metabolome in Local Inactivation during Inflammation-Resolution. J. Immunol.
180: 3512-3519
[Abstract]
[Full Text]
-
Hinz, B., Cheremina, O., Brune, K.
(2008). Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J.
22: 383-390
[Abstract]
[Full Text]
-
Kalsotra, A., Du, L., Wang, Y., Ladd, P. A., Kikuta, Y., Duvic, M., Boyd, A. S., Keeney, D. S., Strobel, H. W.
(2008). Inflammation resolved by retinoid X receptor-mediated inactivation of leukotriene signaling pathways. FASEB J.
22: 538-547
[Abstract]
[Full Text]
-
Hasturk, H., Kantarci, A., Goguet-Surmenian, E., Blackwood, A., Andry, C., Serhan, C. N., Van Dyke, T. E.
(2007). Resolvin E1 Regulates Inflammation at the Cellular and Tissue Level and Restores Tissue Homeostasis In Vivo. J. Immunol.
179: 7021-7029
[Abstract]
[Full Text]
-
Haworth, O., Levy, B. D.
(2007). Endogenous lipid mediators in the resolution of airway inflammation. Eur Respir J
30: 980-992
[Abstract]
[Full Text]
-
Yin, H., Brooks, J. D., Gao, L., Porter, N. A., Morrow, J. D.
(2007). Identification of Novel Autoxidation Products of the {omega}-3 Fatty Acid Eicosapentaenoic Acid in Vitro and in Vivo. J. Biol. Chem.
282: 29890-29901
[Abstract]
[Full Text]
-
Campbell, E. L., Louis, N. A., Tomassetti, S. E., Canny, G. O., Arita, M., Serhan, C. N., Colgan, S. P.
(2007). Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution. FASEB J.
21: 3162-3170
[Abstract]
[Full Text]
-
Sun, Y.-P., Oh, S. F., Uddin, J., Yang, R., Gotlinger, K., Campbell, E., Colgan, S. P., Petasis, N. A., Serhan, C. N.
(2007). Resolvin D1 and Its Aspirin-triggered 17R Epimer: STEREOCHEMICAL ASSIGNMENTS, ANTI-INFLAMMATORY PROPERTIES, AND ENZYMATIC INACTIVATION. J. Biol. Chem.
282: 9323-9334
[Abstract]
[Full Text]
-
Arita, M., Ohira, T., Sun, Y.-P., Elangovan, S., Chiang, N., Serhan, C. N.
(2007). Resolvin E1 Selectively Interacts with Leukotriene B4 Receptor BLT1 and ChemR23 to Regulate Inflammation. J. Immunol.
178: 3912-3917
[Abstract]
[Full Text]
-
Fiaccavento, R., Carotenuto, F., Minieri, M., Masuelli, L., Vecchini, A., Bei, R., Modesti, A., Binaglia, L., Fusco, A., Bertoli, A., Forte, G., Carosella, L., Di Nardo, P.
(2006). {alpha}-Linolenic Acid-Enriched Diet Prevents Myocardial Damage and Expands Longevity in Cardiomyopathic Hamsters. Am. J. Pathol.
169: 1913-1924
[Abstract]
[Full Text]
-
Gonzalez-Periz, A., Planaguma, A., Gronert, K., Miquel, R., Lopez-Parra, M., Titos, E., Horrillo, R., Ferre, N., Deulofeu, R., Arroyo, V., Rodes, J., Claria, J.
(2006). Docosahexaenoic acid (DHA) blunts liver injury by conversion to protective lipid mediators: protectin D1 and 17S-hydroxy-DHA. FASEB J.
20: 2537-2539
[Abstract]
[Full Text]
-
Duffield, J. S., Hong, S., Vaidya, V. S., Lu, Y., Fredman, G., Serhan, C. N., Bonventre, J. V.
(2006). Resolvin D Series and Protectin D1 Mitigate Acute Kidney Injury. J. Immunol.
177: 5902-5911
[Abstract]
[Full Text]
-
Arita, M., Oh, S. F., Chonan, T., Hong, S., Elangovan, S., Sun, Y.-P., Uddin, J., Petasis, N. A., Serhan, C. N.
(2006). Metabolic Inactivation of Resolvin E1 and Stabilization of Its Anti-inflammatory Actions. J. Biol. Chem.
281: 22847-22854
[Abstract]
[Full Text]
-
Calder, P. C
(2006). n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am. J. Clin. Nutr.
83: S1505-1519S
[Abstract]
[Full Text]
-
Gao, L., Yin, H., Milne, G. L., Porter, N. A., Morrow, J. D.
(2006). Formation of F-ring Isoprostane-like Compounds (F3-Isoprostanes) in Vivo from Eicosapentaenoic Acid. J. Biol. Chem.
281: 14092-14099
[Abstract]
[Full Text]
-
Serhan, C. N., Gotlinger, K., Hong, S., Lu, Y., Siegelman, J., Baer, T., Yang, R., Colgan, S. P., Petasis, N. A.
(2006). Anti-Inflammatory Actions of Neuroprotectin D1/Protectin D1 and Its Natural Stereoisomers: Assignments of Dihydroxy-Containing Docosatrienes. J. Immunol.
176: 1848-1859
[Abstract]
[Full Text]
-
Ariel, A., Li, P.-L., Wang, W., Tang, W.-X., Fredman, G., Hong, S., Gotlinger, K. H., Serhan, C. N.
(2005). The Docosatriene Protectin D1 Is Produced by TH2 Skewing and Promotes Human T Cell Apoptosis via Lipid Raft Clustering. J. Biol. Chem.
280: 43079-43086
[Abstract]
[Full Text]
-
Arita, M., Yoshida, M., Hong, S., Tjonahen, E., Glickman, J. N., Petasis, N. A., Blumberg, R. S., Serhan, C. N.
(2005). Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc. Natl. Acad. Sci. USA
102: 7671-7676
[Abstract]
[Full Text]
-
Fukunaga, K., Kohli, P., Bonnans, C., Fredenburgh, L. E., Levy, B. D.
(2005). Cyclooxygenase 2 Plays a Pivotal Role in the Resolution of Acute Lung Injury. J. Immunol.
174: 5033-5039
[Abstract]
[Full Text]
-
Lu, Y., Hong, S., Tjonahen, E., Serhan, C. N.
(2005). Mediator-lipidomics: databases and search algorithms for PUFA-derived mediators. J. Lipid Res.
46: 790-802
[Abstract]
[Full Text]
-
Bannenberg, G. L., Chiang, N., Ariel, A., Arita, M., Tjonahen, E., Gotlinger, K. H., Hong, S., Serhan, C. N.
(2005). Molecular Circuits of Resolution: Formation and Actions of Resolvins and Protectins. J. Immunol.
174: 4345-4355
[Abstract]
[Full Text]
-
Flower, R. J., Perretti, M.
(2005). Controlling inflammation: a fat chance?. JEM
201: 671-674
[Abstract]
[Full Text]
-
Arita, M., Bianchini, F., Aliberti, J., Sher, A., Chiang, N., Hong, S., Yang, R., Petasis, N. A., Serhan, C. N.
(2005). Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. JEM
201: 713-722
[Abstract]
[Full Text]
-
Fernandez-Real, J.-M., Vendrell, J., Ricart, W.
(2005). Circulating Adiponectin and Plasma Fatty Acid Profile. Clin. Chem.
51: 603-609
[Abstract]
[Full Text]
-
Chiang, N., Bermudez, E. A., Ridker, P. M., Hurwitz, S., Serhan, C. N.
(2004). Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc. Natl. Acad. Sci. USA
101: 15178-15183
[Abstract]
[Full Text]
-
Mukherjee, P. K., Marcheselli, V. L., Serhan, C. N., Bazan, N. G.
(2004). From The Cover: Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc. Natl. Acad. Sci. USA
101: 8491-8496
[Abstract]
[Full Text]
-
Bazan, N. G.
(2003). Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J. Lipid Res.
44: 2221-2233
[Abstract]
[Full Text]
-
Marcheselli, V. L., Hong, S., Lukiw, W. J., Tian, X. H., Gronert, K., Musto, A., Hardy, M., Gimenez, J. M., Chiang, N., Serhan, C. N., Bazan, N. G.
(2003). Novel Docosanoids Inhibit Brain Ischemia-Reperfusion-mediated Leukocyte Infiltration and Pro-inflammatory Gene Expression. J. Biol. Chem.
278: 43807-43817
[Abstract]
[Full Text]
-
Hong, S., Gronert, K., Devchand, P. R., Moussignac, R.-L., Serhan, C. N.
(2003). Novel Docosatrienes and 17S-Resolvins Generated from Docosahexaenoic Acid in Murine Brain, Human Blood, and Glial Cells. AUTACOIDS IN ANTI-INFLAMMATION. J. Biol. Chem.
278: 14677-14687
[Abstract]
[Full Text]
-
Serhan, C. N., Hong, S., Gronert, K., Colgan, S. P., Devchand, P. R., Mirick, G., Moussignac, R.-L.
(2002). Resolvins: A Family of Bioactive Products of Omega-3 Fatty Acid Transformation Circuits Initiated by Aspirin Treatment that Counter Proinflammation Signals. JEM
196: 1025-1037
[Abstract]
[Full Text]
-
Hontecillas, R., Wannemeulher, M. J., Zimmerman, D. R., Hutto, D. L., Wilson, J. H., Ahn, D. U., Bassaganya-Riera, J.
(2002). Nutritional Regulation of Porcine Bacterial-Induced Colitis by Conjugated Linoleic Acid. J. Nutr.
132: 2019-2027
[Abstract]
[Full Text]