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Assignments of D1/Protectin D1 and Its Anti-Inflammatory Actions of Neuroprotectin D1/Protectin D1 and Its Natural Stereoisomers: Assignments of Dihydroxy-Containing Docosatrienes This information is current as of September 25, 2021. Charles N. Serhan, Katherine Gotlinger, Song Hong, Yan Lu, Jeffrey Siegelman, Tamara Baer, Rong Yang, Sean P. Colgan and Nicos A. Petasis J Immunol 2006; 176:1848-1859; ; doi: 10.4049/jimmunol.176.3.1848 Downloaded from http://www.jimmunol.org/content/176/3/1848 References This article cites 44 articles, 20 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/176/3/1848.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts Errata An erratum has been published regarding this article. Please see next page or: /content/176/6/3843.2.full.pdf The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Anti-Inflammatory Actions of Neuroprotectin D1/Protectin D1 and Its Natural Stereoisomers: Assignments of Dihydroxy-Containing Docosatrienes1 Charles N. Serhan,2* Katherine Gotlinger,* Song Hong,* Yan Lu,* Jeffrey Siegelman,* Tamara Baer,* Rong Yang,† Sean P. Colgan,* and Nicos A. Petasis† Protectin D1, neuroprotectin D1 when generated by neural cells, is a member of a new family of bioactive products generated from docosahexaenoic acid. The complete stereochemistry of protectin D1 (10,17S-docosatriene), namely, chirality of the carbon-10 alcohol and geometry of the conjugated triene, required for bioactivity remained to be assigned. To this end, protectin D1/ neuroprotectin D1 (PD1) generated by human neutrophils during murine peritonitis and by neural tissues was separated from natural isomers and subjected to liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Downloaded from Comparisons with six 10,17-dihydroxydocosatrienes prepared by total organic and biogenic synthesis showed that PD1 from human cells carrying potent bioactivity is 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Additional isomers identified included trace amounts of ⌬15-trans-PD1 (isomer III), 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid (isomer IV), and a double dioxygenation product 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid (isomer 18 18 I), present in exudates. O2 labeling showed that 10S,17S-diHDHA (isomer I) carried O in the carbon-10 position alcohol, indicating sequential lipoxygenation, whereas PD1 formation proceeded via an epoxide. PD1 at 10 nM attenuated (ϳ50%) human http://www.jimmunol.org/ neutrophil transmigration, whereas ⌬15-trans-PD1 was essentially inactive. PD1 was a potent regulator of polymorphonuclear leukocyte (PMN) infiltration (ϳ40% at 1 ng/mouse) in peritonitis. The rank order at 1- to 10-ng dose was PD1 Ϸ PD1 methyl ester ϾϾ ⌬15-trans-PD1 > 10S,17S-diHDHA (isomer I). 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid (isomer VI) proved > PD1 in blocking PMN infiltration, but was not a major product of leukocytes. PD1 also reduced PMN infiltration after initiation (2 h) of inflammation and was additive with resolvin E1. These results indicate that PD1 is a potent stereoselective anti-inflammatory molecule. The Journal of Immunology, 2006, 176: 1848–1859. ecently, we uncovered potent new families of lipid-de- acid-derived prostaglandins and leukotrienes (LT)3 are potent by guest on September 25, 2021 rived mediators generated during resolution that are anti- proinflammatory mediators (9), whereas their cousins, the lipoxins R inflammatory, neuroprotective, and activate novel reso- (LX), biosynthesized from arachidonic acid, are potent anti- lution pathways (1–3). The resolution of inflammation is a central inflammatory and proresolving molecules (for reviews see Refs. component of host defense and the return of tissue to homeostasis 10–12). During the course of inflammation, arachidonate-derived (4). It is now well recognized that inflammation plays a key role in eicosanoids switch from prostaglandins and LTs within inflamma- many prevalent human diseases including cardiovascular diseases, tory exudates to LXs that, in turn, stop the recruitment of neutro- atherosclerosis, Alzheimer’s disease, and cancer (5–7). Although phils to the site. This switch in eicosanoid profiles and biosynthesis much is known about the molecular basis of initiating signals and is driven, in part, by cyclooxygenase-derived prostaglandin E2 and prostaglandin D , which instruct the transcriptional regulation of proinflammatory chemical mediators in inflammation, it has only 2 enzymes involved in LX biosynthesis (13). Hence, the appearance recently become apparent that endogenous stop signals are critical of LXs within inflammatory exudates is concomitant with sponta- at early checkpoints within the temporal events of inflammation neous resolution of inflammation (13), and these chemical medi- (8). In this context, lipid mediators are of interest. The arachidonic ators are nonphlogistic stimulators of monocyte recruitment and macrophage phagocytosis of apoptotic polymorphonuclear leuko- cytes (PMN) (14, 15). Further studies on the endogenous mechanisms of anti- *Center for Experimental Therapeutics and Reperfusion Injury, Department of An- inflammation using a murine model of spontaneous resolution esthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and demonstrated, for the first time, that resolution is an active bio- Harvard Medical School, Boston, MA 02115; and †Department of Chemistry and the Loker Hydrocarbon Research Institute, University of Southern California, Los An- chemical process that involves the generation of specific new fam- geles, CA 90089 ilies of lipid mediators (for recent reviews, see Refs. 16 and 17). Received for publication June 10, 2005. Accepted for publication November 4, 2005. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 3 Abbreviations used in this paper: LT, leukotriene; LX, lipoxin; PMN, polymorpho- nuclear leukocyte; DHA, C22:6, docosahexaenoic acid; EPA, C20:5, eicosapenta- 1 This work was supported in part by National Institutes of Health Grants GM38765 enoic acid; NPD1, neuroprotectin D1; LO, lipoxygenase; PD1, protectin D1/neuro- and P50-DE016191. protectin D1; pt5LO, 5-LO from potato; LC, liquid chromatography; MS-MS, tandem 2 Address correspondence and reprint requests to Dr. Charles N. Serhan, Center for mass spectrometry; GC, gas chromatography; 17S-H(p)DHA, 17S-hydro(peroxy)- Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, DHA; NMR, nuclear magnetic resonance; 10S,17S-diHDHA, 10S,17S-dihydroxy-do- Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis Street, cosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid (the dioxygenation product); RvE1, re- Boston, MA 02115. E-mail address: [email protected] solvin E1, 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 1849 During spontaneous resolution, cell-cell interactions and transcel- Materials and Methods lular biosynthesis lead to the production of these new families of Materials potent bioactive lipid mediators from omega-3 essential fatty acid Zymosan A, soybean LO (fraction V), and calcium ionophore, A-23187, precursors, and were termed resolvins (resolution phase interaction were purchased from Sigma-Aldrich. DHA and 5-LO from potato (pt5LO) products derived from docosahexaenoic acid (DHA, C22:6) and were obtained from Cayman Chemical. Additional materials used in liquid eicosapentaenoic acid (EPA, C20:5)) and protectins (docosatrienes chromatography (LC)-UV-tandem mass spectrometry (MS-MS) analyses 18 derived from DHA; Refs. 1, 3, and 18 and recently reviewed in were obtained from vendors reported in Refs. 1 and 3. O2 isotope was Ref. 19). These novel di- and tri-hydroxy-containing products purchased from Cambridge Isotopes. from EPA and DHA that are generated by previously unrecognized Isolation, LC-MS-MS, and gas chromatography (GC)-MS enzymatic pathways display potent anti-inflammatory and analyses immunoregulatory actions in vitro and in vivo in murine models of acute inflammatory actions (1, 3, 18). Incubations were extracted with deuterium-labeled internal standard (pros- taglandin E2) (Cayman Chemicals) for LC-MS-MS analysis using a Finni- In 1929, the omega-3 polyunsaturated fatty acids were assigned gan LCQ LC ion trap tandem mass spectrometer equipped with a LUNA essential roles because their exclusion from the diet gave rise to a C18-2 (150 ϫ 2mm5␮m) column and a rapid
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