The Docosatriene Protectin D1 Is Produced by TH2 Skewing and Promotes Human T Cell Apoptosis via Lipid Raft Clustering
Docosahexaenoic acid, a major ω-3 fatty acid in human brain, synapses, retina, and other neural tissues, displays beneficial actions in neuronal development, cancer, and inflammatory diseases by mechanisms that remain to be elucidated. In this study we found, using lipid mediator informatics employing liquid chromatography-tandem mass spectrometry, that (10,17S)-docosatriene/neuroprotectin D1, now termed protectin D1 (PD1), is generated from docosahexaenoic acid by T helper type 2-skewed peripheral blood mononuclear cells in a lipoxygenase-dependent manner. PD1 blocked T cell migration in vivo, inhibited tumor necrosis factor α and interferon-γ secretion, and promoted apoptosis mediated by raft clustering. These results demonstrated novel anti-inflammatory roles for PD1 in regulating events associated with inflammation and resolution. Docosahexaenoic acid, a major ω-3 fatty acid in human brain, synapses, retina, and other neural tissues, displays beneficial actions in neuronal development, cancer, and inflammatory diseases by mechanisms that remain to be elucidated. In this study we found, using lipid mediator informatics employing liquid chromatography-tandem mass spectrometry, that (10,17S)-docosatriene/neuroprotectin D1, now termed protectin D1 (PD1), is generated from docosahexaenoic acid by T helper type 2-skewed peripheral blood mononuclear cells in a lipoxygenase-dependent manner. PD1 blocked T cell migration in vivo, inhibited tumor necrosis factor α and interferon-γ secretion, and promoted apoptosis mediated by raft clustering. These results demonstrated novel anti-inflammatory roles for PD1 in regulating events associated with inflammation and resolution. Chemical mediators and autacoids, such as the local-acting lipid mediators derived from arachidonic acid, are well appreciated regulators of host defense, coagulation, inflammation, and cancer (1Gallin J.I. Snyderman R. Inflammation: Basic Principles and Clinical Correlates. Lippincott Williams & Wilkins, Philadelphia1999Google Scholar, 2Samuelsson B. Dahlen S.E. Lindgren J.A. Rouzer C.A. Serhan C.N. Science. 1987; 237: 1171-1176Crossref PubMed Scopus (1984) Google Scholar). The family of bioactive eicosanoids include leukotriene B4, for example, a major mediator of acute inflammation produced by neutrophils recently found to also regulate the recruitment of cytotoxic effector T cells to inflamed tissue (3Goodarzi K. Goodarzi M. Tager A.M. Luster A.D. von Andrian U.H. Nat. Immun. 2003; 4: 965-973Crossref Scopus (294) Google Scholar). These findings expand the role and actions of eicosanoids from innate to acquired immunity. Over the past 25 years, numerous studies have reported that ω-3 polyunsaturated fatty acids, administered as a dietary supplement, have therapeutic impact on human diseases such as atherosclerosis, arthritis, and asthma (4Serhan C.N. Clish C.B. Brannon J. Colgan S.P. Chiang N. Gronert K. J. Exp. Med. 2000; 192: 1197-1204Crossref PubMed Scopus (946) Google Scholar, 5Marchioli R. Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3741) Google Scholar, 6Billman G.E. Kang J.X. Leaf A. Circulation. 1999; 99: 2452-2457Crossref PubMed Scopus (393) Google Scholar, 7Robinson D.R. Xu L.L. Tateno S. Guo M. Colvin R.B. J. Lipid Res. 1993; 34: 1435-1444Abstract Full Text PDF PubMed Google Scholar, 8Calder P.C. Zurier R.B. Curr. Opin. Clin. Nutr. Metab. Care. 2001; 4: 115-121Crossref PubMed Scopus (160) Google Scholar). DHA, 4The abbreviations used are: DHAC22:6, docosahexaenoic acidATLaaspirin-triggered lipoxin A4 analogCTXcholera toxin(10,17S)-DT(10,17S)-docosatriene ((10,17S)-dihydroxydocosahexaenoic acid)(17S)-HDHA(17S)-hydroxydocosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid(18R)-THEPE(18R)-trihydroxyeicosapentaenoic acidIFNinterferonILinterleukinLC-MS-MSliquid chromatographytandem mass spectrometryLOlipoxygenasePBMCperipheral blood mononuclear cellsPMNpolymorphonuclear leukocytesPD1protectin D1NPD1neuroprotectin D1TUNELterminal deoxynucleotidyltransferase-mediated dUTP nick-labelingTHT helper typeTNFtumor necrosis factorFITCfluorescein isothiocyanatePEphycoerythrinsiRNAsmall interfering RNAPBSphosphate-buffered saline. a major ω-3 polyunsaturated fatty acid, is particularly prevalent in neuronal tissues, and its content in maternal breast milk correlates with both neural development end points and immune status in the fetus (9Hibbeln J.R. J. Affective Disord. 2002; 69: 15-29Crossref PubMed Scopus (395) Google Scholar, 10Moriguchi T. Salem Jr., N. J. Neurochem. 2003; 87: 297-309Crossref PubMed Scopus (173) Google Scholar). DHA is also essential for proper T cell development in neonates (11Field C.J. Clandinin M.T. Van Aerde J.E. Lipids. 2001; 36: 1025-1032Crossref PubMed Scopus (67) Google Scholar) and regulates T cell functions, with a polarizing preference toward the TH2 phenotype as well as promotion of apoptosis in TH1-polarized CD4+ T cells (12Arrington J.L. Chapkin R.S. Switzer K.C. Morris J.S. McMurray D.N. Clin. Exp. Immunol. 2001; 125: 499-507Crossref PubMed Scopus (74) Google Scholar, 13Switzer K.C. Fan Y.Y. Wang N. McMurray D.N. Chapkin R.S. J. Lipid Res. 2004; 45: 1482-1492Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Consequently, TH2 cells are potent suppressors of inflammatory and autoimmune disorders, particularly in the central nervous system (14Kuchroo V.K. Das M.P. Brown J.A. Ranger A.M. Zamvil S.S. Sobel R.A. Weiner H.L. Nabavi N. Glimcher L.H. Cell. 1995; 80: 707-718Abstract Full Text PDF PubMed Scopus (1647) Google Scholar). However, the molecular mechanisms of the diverse actions of DHA in each of these vital systems still remain to be elucidated. C22:6, docosahexaenoic acid aspirin-triggered lipoxin A4 analog cholera toxin (10,17S)-docosatriene ((10,17S)-dihydroxydocosahexaenoic acid) (17S)-hydroxydocosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid (18R)-trihydroxyeicosapentaenoic acid interferon interleukin liquid chromatographytandem mass spectrometry lipoxygenase peripheral blood mononuclear cells polymorphonuclear leukocytes protectin D1 neuroprotectin D1 terminal deoxynucleotidyltransferase-mediated dUTP nick-labeling T helper type tumor necrosis factor fluorescein isothiocyanate phycoerythrin small interfering RNA phosphate-buffered saline. Along these lines, the question of whether DHA is a precursor to novel potent lipid mediators was of interest. This laboratory recently identified several novel 17-hydroxyl-containing bioactive chemical mediators derived from DHA that were termed docosatrienes and 17S series resolvins (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar, 16Marcheselli V.L. Hong S. Lukiw W.J. Hua Tian X. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. Bazan N.G. J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (678) Google Scholar). Neuroprotectin D1 ((10,17S)-dihydroxydocosatriene; NPD1) appears to be a major bioactive effector from this novel series of docosatrienes that possesses a conjugated triene system with alcohol groups at the 10 and 17 carbon positions as distinguishing features (17Serhan C.N. Hong S. Gronert K. Colgan S.P. Devchand P.R. Mirick G. Moussignac R.L. J. Exp. Med. 2002; 196: 1025-1037Crossref PubMed Scopus (1349) Google Scholar). At picogram to nanogram levels, NPD1 reduces the infiltration of polymorphonuclear cells (PMN) into both peritoneal exudates and murine ischemic brain (i.e. experimental stroke), resulting in both anti-inflammation and neuroprotection (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar, 16Marcheselli V.L. Hong S. Lukiw W.J. Hua Tian X. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. Bazan N.G. J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (678) Google Scholar). NPD1 was also found recently to inhibit oxidative stress-induced apoptosis of human retinal pigment cells V.L. Serhan C.N. Bazan N.G. S. 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A. 2004; PubMed Scopus Google Scholar). this possesses a of and actions and is to neuronal we protectin D1 in of its of and in systems other neural PD1 T cell apoptosis the of lipid were as DHA, and from DHA from and from and and and and from and from and from from and from and were by and by as in C.N. A. Colgan S.P. J.L. 1995; 34: PubMed Scopus Google and C.N. Clish C.B. Brannon J. Colgan S.P. Chiang N. Gronert K. J. Exp. Med. 2000; 192: 1197-1204Crossref PubMed Scopus (946) Google Scholar, PD1 was by and as (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar). of and T were from the blood of by as in A. Chiang N. M. Serhan C.N. J. Immunol. 2003; PubMed Scopus Google Scholar). T cells were by for on a to the The cells were and on a human & to the and were for The of these T cells was were to a TH2 phenotype by with and with and and of was to both and TH2 cells were with the were on and by in the of the cells were and by and and by cell were used as The cells were used for by and of in human TH2 were of and RNA was with RNA was for using the system was by of with for human and using the were by and were by The were used to and human type and was by the and and of was by cells and the to by to and with human were on and with DHA 10 In other were with of a of and for and were for with of the the cells were with and as in the the cells were and of the cells were for of using with and was used as a The cells were with DHA as The was and with liquid The were with for and to as in Hong (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar). In of lipid mediators was to the of and other using a liquid mass with a and a that the the The of of was as of with of with was using with as (17Serhan C.N. Hong S. Gronert K. Colgan S.P. Devchand P.R. Mirick G. Moussignac R.L. J. Exp. Med. 2002; 196: 1025-1037Crossref PubMed Scopus (1349) Google Scholar). were with and with of DHA, and with of into the the were and the peritoneal were for of of T and cells in the the cells were with and and and and by In the peritoneal were and in for The peritoneal was and were with and T and produced by human T cells were as in A. Chiang N. M. Serhan C.N. J. Immunol. 2003; PubMed Scopus Google Scholar). human peripheral blood T cells were with of PD1 for at and in with and for The were from the and for and content by a The for was as of by of by of by of by T of human peripheral blood T cells was using the In is a terminal deoxynucleotidyltransferase-mediated dUTP nick-labeling as in B. Wang X. J. 2002; PubMed Scopus Google Scholar). T cells were with PD1 for at In the cells were with to with PD1 The cells were on with in terminal and with terminal and for at the were with with and and a Lipid cells were on with for The cells were with PD1 DHA In the cells were with with PD1 the cells were and The cells were with with and with of The cells were and for with in was with were with a with a with a the of were in a The of cells with of and and the of cells in the cell in at were as S.E. are as S.E. The of the in and groups was using of for by was used to of was PD1 by on and of using we whether PD1 from DHA the of a major that appears to be in the of DHA to PD1 (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google is by such as interleukin and in M. J. Serhan C.N. J. Clin. 1993; PubMed Scopus Google peripheral blood J. Biol. Chem. Full Text PDF PubMed Google and cells R. M. A. A. B. S. A. 2001; PubMed Scopus Google Scholar). of TH2 with DHA, to the of the series and PD1 were identified as major as well as of was identified from its at and and and and its and the of a conjugated in the with a at is produced by from its the major of with DHA (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google that be by of to identified in these by its in its These results are with the of NPD1 (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar, 16Marcheselli V.L. Hong S. Lukiw W.J. Hua Tian X. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. Bazan N.G. J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (678) Google Scholar, V.L. Serhan C.N. Bazan N.G. S. A. 2004; PubMed Scopus Google its several at and demonstrated the of the 10 and 17 carbon at and and and and The of this in a at with at and a of with the conjugated triene in PD1 (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar). The of NPD1 (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar, 16Marcheselli V.L. Hong S. Lukiw W.J. Hua Tian X. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. Serhan C.N. Bazan N.G. J. Biol. Chem. 2003; 278: 43807-43817Abstract Full Text Full Text PDF PubMed Scopus (678) Google Scholar, C.N. Hong S. Gronert K. Colgan S.P. Devchand P.R. Mirick G. Moussignac R.L. J. Exp. Med. 2002; 196: 1025-1037Crossref PubMed Scopus (1349) Google Scholar, V.L. Serhan C.N. Bazan N.G. S. 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PubMed Scopus Google Scholar) was in at the the toward and TH2 the of produced by the cells was found that in the and of the cells produced and In in the TH2 and of the cells produced and these the toward TH2 these results that that DHA to PD1 in PD1 in mediators generated the of inflammation, such as and infiltration into inflamed (4Serhan C.N. Clish C.B. Brannon J. Colgan S.P. Chiang N. Gronert K. J. Exp. Med. 2000; 192: 1197-1204Crossref PubMed Scopus (946) Google Scholar, C.N. A. Colgan S.P. J.L. 1995; 34: PubMed Scopus Google Scholar). whether PD1 reduces inflammatory we by of in of PD1 is a leukocytes into the peritoneal The of to of by and inflammatory cells by the cell and infiltration was and tissue the of and infiltration were in the of that of cells from the peritoneal with for T cells and for and by that its precursor DHA, at and T and cell in the exudates and These results in to infiltration (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google PD1 regulates the migration of inflammatory leukocytes and particularly PD1 from T results that are of the of we the impact of PD1 on the of by human peripheral blood T cells in the of inflammation and is by other lipid mediators of such as A. Chiang N. M. Serhan C.N. J. Immunol. 2003; PubMed Scopus Google Scholar). and were used to the by cells that to the of and by T PD1 in a the of both by and and At 10 PD1 the with and of and secretion, In the of PD1 the of both and was of was that of at and impact on was the cells were to PD1 T cells and by were by PD1 that PD1 was to T PD1 and by human T PD1 of T apoptosis to T cell J. Nat. 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Immun. 2000; Scopus Google that the are lipid raft the of PD1 on lipid raft and we the impact of and such as DHA, and DHA at of the of lipid raft from to was that with PD1 at as as is that the actions for DHA be for by its to PD1 by these a on the of lipid raft whether apoptosis is on lipid raft we human T cells with both and blocked apoptosis promoted cell results that PD1 is a potent of lipid raft by in these and that this the of a and apoptosis and In the we that a novel is produced by TH2 that this is by of in TH2 and is on also found that PD1 is a potent of T cell infiltration to peritoneal and of by human T and we found that PD1 T cell apoptosis the of lipid raft The of the recently identified as (15Hong S. Gronert K. Devchand P.R. Moussignac R.L. Serhan C.N. J. Biol. Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar) in neuronal systems as NPD1 V.L. Hong S. Lukiw W.J. Hua Tian X. Gronert K. Musto A. Hardy M. Gimenez J.M. Chiang N. 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Chem. 2003; 278: 14677-14687Abstract Full Text Full Text PDF PubMed Scopus (841) Google be produced by a neural TH2 cells that the Consequently, PD1 to the impact of TH2 cells on brain and produced by T cells are for of and the of inflammatory such as arthritis, inflammatory and other M. Nat. Immunol. 2002; PubMed Scopus Google Scholar, G. G. Curr. 2002; PubMed Google Scholar, A. Nat. Immunol. 2002; PubMed Scopus Google Scholar). The of these is in the of inflammation J. Immunol. 2003; PubMed Scopus Google Scholar, T. A. 2002; PubMed Scopus Google Scholar). PD1 inhibited the of both and by T cells by These results are in with a role for PD1 as a TH2 the of a major T cell of inflammation is associated with the apoptosis of cell J. Nat. Immunol. 2002; PubMed Scopus Google Scholar). that of human T cells with PD1 cell The results the that PD1 T cell a potent of T cell this the of T cells in the inflammatory and in the of studies have that cell is mediated by of and its on T cells J. Clin. 2000; PubMed Scopus Google Scholar). In the we found that PD1 T cell we whether PD1 apoptosis of T cells a to that of Lipid are to as the on cell are in and and to by K. PubMed Scopus Google Scholar). to the of a that to cell apoptosis Wang K. R. S. K. M. J.M. Res. 2002; PubMed Scopus Google Scholar, D.R. Immunol. 2003; PubMed Scopus Google Scholar). with lipid on T cell Wang K. R. S. K. M. J.M. Res. 2002; PubMed Scopus Google and in these cells are on its in lipid the that lipid raft cell apoptosis Wang K. R. S. K. M. J.M. Res. 2002; PubMed Scopus Google Scholar). PD1 of lipid on the T cell to to that by the actions of PD1 on this lipid raft on T cell are by by in demonstrated that by T cells was by to PD1 These results that PD1 as of a of the impact of DHA in a of from inflammatory and autoimmune to neural development and R. Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3741) Google Scholar, 7Robinson D.R. Xu L.L. Tateno S. Guo M. Colvin R.B. J. Lipid Res. 1993; 34: 1435-1444Abstract Full Text PDF PubMed Google Scholar, Jr., N. B. K. Lipids. 2001; 36: PubMed Scopus Google Scholar) the beneficial of DHA as a However, the of DHA actions is still in molecular The results demonstrated that a novel of is produced by a reduces T cell migration to inflamed in vivo, and reduces the of PD1 also promoted apoptosis in human T was associated with lipid raft clustering. PD1 is a potent of T cell inflammatory and a role in the and to fatty (i.e. and in regulating the of TH2 cells in the inflammation of the central nervous These findings to the development of therapeutic to T inflammation and for and for in