Inflammation is a response that protects tissues affected by foreign pathogens or physical trauma. Inflammation is initiated through the carefully orchestrated movement of inflammatory cells (neutrophils, monocytes/macrophages, and lymphocytes) following the initial cellular insult. The trafficking of these cells to the inflammatory nidus is regulated by numerous cell surface receptors and ligands, along with the release of chemokines, cytokines, vasoactive amines, and bioactive lipid mediators. Lipid mediators, primarily comprised of sphingolipids and eicosanoid derivatives, were once thought to be just inert members of the bilipid cell membrane, but are now known to play a decisive role not only in proinflammatory cell movement but also paradoxically in its resolution as well.

Eicosanoid lipids are derived from the activity of phospholipase A2 on the 20-carbon membrane phospholipid arachidonic acid (AA).2 Multiple divergent metabolic pathways use AA as their substrate. One pathway metabolizes AA via the lipoxygenase pathway to leukotrienes (LTs) and lipoxins. A second major pathway forms the PGs and thromboxanes from AA via the cyclooxygenase pathway. The prostanoids and lipoxins will not be discussed in this review, because they have been the subjects of numerous recent reviews (1, 2, 3, 4). The sphingolipids, derived from sphingomyelin, include ceramide and its derivatives, sphingosine, and sphingosine 1-phosphate (S1P), and the novel immunomodulatory sphingosine analog 2-amino-2[2-(4-octylphenyl)ethyl]-1–3-propanediol hydrochloride (FTY720), which has recently been reported to serve as an agonist for leukocyte migration with potential clinical applications (5). This review focuses on the biosynthetic pathways, cellular distribution, receptors, and mechanisms of action of, as well as the interactions among, the LT and sphingolipid bioactive mediators, particularly in reference to their role in leukocyte trafficking.

LTs are a family of eicosanoid lipid mediators derived from the metabolism of AA. First described in 1937 as the slow-reacting substances of anaphylaxis, these compounds are now known as the cysteinyl LTs (cysLTs) LTC4, LTD4, and LTE4 (6). Synthesis of LTs can be divided into two pathways: one to create cysLTs and another to create LTB4 (Fig. 1). Both pathways share the common intermediate, the short-lived epoxide LTA4. AA is oxygenated by 5-lipoxygenase (5-LO) to form hydroperoxide 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetranoic acid, which is subsequently dehydrated, yielding LTA4 (7).

FIGURE 1.

LT biosynthetic pathway. Receptors for LTs are in parentheses.

FIGURE 1.

LT biosynthetic pathway. Receptors for LTs are in parentheses.

Close modal

5-LO is a 72- to 80-kDa monomeric soluble protein containing one nonheme iron believed necessary for catalysis (8, 9). Active mainly in myeloid cells, including monocytes, B lymphocytes, granulocytes, and mast cells, 5-LO requires Ca2+ and is stimulated by ATP, phosphatidylcholine, and lipid hydroperoxides (reviewed in Refs.10 and 11). The Ca2+ stimulation is believed to translocate the soluble cytosolic 5-LO to the membrane by association with 5-LO activation protein (FLAP) (12, 13). FLAP, an 18-kDa membrane-associated protein with a leukocyte expression similar to that of 5-LO, is expressed on T lymphocytes but not on erythrocytes or endothelial cells. FLAP has been postulated to present or transfer AA to 5-LO for enzymatic degradation (14, 15). Although not fully understood, the inhibition of FLAP by the compound MK-866 disrupts LTA4 production, despite the presence of 5-LO (16). The molecular details behind the 5-LO/FLAP interaction, including their sites of action and their role in binding AA, are unknown.

LTA4 undergoes further transformation by one of two pathways depending on cellular makeup and enzyme presence: 1) hydrolysis to LTB4 by the zinc metalloenzyme LTA4 hydrolase or 2) glutathione conjugation to LTC4 by LTC4 synthase. LTA4 hydrolase is a 69-kDa widely distributed protein found in almost all mammalian tissue (17). Its product, LTB4, is a powerful chemotactic agent that, in contrast to its cysLT counterparts, has no direct role in bronchoconstriction or pulmonary vasoconstriction (18). LTB4 has two known extracellular receptors, BLT1 and BLT2. BLT1R has been characterized as a 43-kDa G-protein-coupled receptor (GPCR) expressed only in inflammatory cells (neutrophils predominantly) and with a high affinity for only LTB4. (19, 20). The second LTB4R, BLT2, has only recently been described and, although a GPCR similar to its BLT1 homolog, the BLT2R is ubiquitously expressed in all mammalian tissues (20, 21, 22). Both receptors are found on the same chromosome, but intriguingly, the open reading frame of the BLT2R is within the promoter region of the BLT1R (19). Activation of both BLTRs serves as a powerful stimulus for in vitro leukocyte chemotaxis, especially of neutrophils (23, 24). In vivo experiments have shown LTB4 to increase neutrophil rolling and adhesion and egress into the extravascular space through increased expression of adhesion proteins (integrins and selectins) (25). Additional actions of LTB4 include stimulation of IL-5 in T lymphocytes, chemotactic effects on IL-5-activated eosinophils, neutrophil secretion of superoxide anion radicals, and antiapoptotic effects on neutrophils (26, 27, 28, 29). LTB4, along with LTC4 and LTD4, has been shown to promote eosinophil survival by inhibiting apoptosis (30).

LTC4 is formed by conjugation of LTA4 with the tripeptide glutathione through the catalysis of LTC4 synthase. Stimulated by divalent cations and phosphatidylcholine, LTC4 synthase is an 18-kDa protein with a wide tissue distribution (31, 32). After LTC4 synthesis, the multidrug transporter ATP-binding cassette (Abc)c1 (formerly known as MRP-1) actively transports LTC4 out of the cell, where LTD4 and LTE4 are formed through the elimination of glutamine and glycine, respectively, by γ-glutamyl transpeptidase and dipeptidase (33, 34, 35). Failure to express Abcc1 has been shown to increase intracellular accumulation of LTC4 (36). LTC4 has been shown in animal models to be relatively short-lived with rapid conversion to LTD4 and LTE4 (6, 37). The transport of LTC4 by Abcc1 has also been shown to regulate dendritic and T cell migration to peripheral lymph nodes (5, 38). Antagonism of Abcc1 or 5-LO activity inhibits dendritic and T cell migration, which is restored after the addition of exogenous cysLTs (5, 38).

The cysLTs have two described GPCR-type cell surface receptors, cysLT1 and cysLT2. The potency of each ligand was determined through intracellular calcium mobilization with a rank order of LTD4 > LTC4 > LTE4 for cysLT1 and LTC4 = LTD4 > LTE4 for cysLT2 (39, 40). The cysLT1R is highly expressed in lung, spleen, and peripheral blood leukocytes (especially eosinophils) (41, 42). The cysLT2R is likewise expressed on these cells and is also highly expressed in the heart, adrenal glands, and brain (42). The significance of these differences is unclear. Activation of cysLT1Rs has been shown to elicit bronchospasm from the contraction of the bronchial smooth muscle cells that are prevalent in the asthmatic population (14). The cysLTs have also been shown to act through the receptors of both cysLTs to induce pulmonary vasoconstriction (43). This action is mediated through activation of cysLT2Rs on the vascular smooth muscle and of cysLT1Rs on the vascular endothelial cells. Activation of the cysLT1Rs has also been shown to increase the microvascular permeability in the airways through either a mechanism of endothelial cell contraction or an increase in the vascular endothelial hydrostatic pressure (44, 45). CysLT1R antagonism has been shown to block this response in animal models, but not in humans (46). In addition, cysLT1R activation also serves as a chemotactic stimulus for eosinophils and to increase mucus production (47, 48). Clinically, modification of the LT pathway through the use of 5-LO inhibitors (zileuton) or cysLT1R antagonists (montelukast or zafirlukast) (currently, no specific cysLT2R antagonist exists, although Bay u933 blocks both cysLTRs) have played an important role in the management of asthmatic patients (49, 50, 51). Although much is know about the LT pathway, there remain many areas requiring further definition. Future investigations into the compartmentalization of the LT intermediates, the binding mechanism of AA with the FLAP/5-LO interaction, and whether other eicosanoids play a role as lipid mediators may lead to novel discoveries with significant clinical implications.

Sphingolipids, such as ceramide, sphingosine, and S1P, were originally thought to have only the rudimentary task of maintaining the integrity of the bilipid cell membrane (Fig. 2). However, these products of sphingolipid metabolism have been shown to have critical roles in cell migration, proliferation, and survival. Sphingosine is formed by the metabolism of the sphingomyelin derivative ceramide through the action of the enzyme ceramidase (52). Although both sphingosine and ceramide have similar cellular actions, including the induction of apoptosis, the arrest of cell growth and proliferation, neither plays a direct role in cell migration (53, 54).

FIGURE 2.

Sphingolipid biosynthetic pathway.

FIGURE 2.

Sphingolipid biosynthetic pathway.

Close modal

S1P is the bioactive derivative of the phosphorylation of sphingosine by sphingosine kinase (SpK). Although seven cloned isoenzymes of SpK have been described, only two forms, SpK1 and SpK2, each with different tissue distribution and temporal actions, are predominantly found in humans and mice (55). SpK1 is a 42.4-kDa protein found in the cytosol of lung, spleen, and liver cells (55). SpK2, a proline-rich 65.6-kDa protein, is expressed in liver and heart cells (56). Both kinases are activated by the external stimuli PDGF, nerve growth factor, TNF-α, and IL-1β, driving the conversion of sphingosine to S1P (57, 58, 59, 60). Recent evidence shows that SpK is secreted by endothelial cells (61). This suggests that S1P can be made both intracellularly and extracellulary. Once formed, S1P is metabolized by S1P lyase to ethanolamine phosphate and hexadecanal, or dephosphorylated back to sphingosine by a lipid phosphohydrolase (62). The lipid phosphohydrolase family is composed of S1P phosphohydrolase (SPP) and the type 2 lipid phosphohydrolase. SPP includes three known mammalian (one murine/two human) homologs and two yeast counterparts and is specific to S1P, dihydrosphingosine 1-phosphate, and phytosphingosine 1-phosphate (63, 64, 65, 66). The first described human SPP isoenzyme is ubiquitously expressed unlike the second, which is limited to the endoplasmic reticulum of brain, heart, colon, kidney, small intestine, and lung cells (67). The type 2 lipid phosphohydrolase has a wide expression and substrate specificity, including S1P, lysophosphatide, and ceramide 1-phosphate (68, 69, 70, 71, 72).

The balance between the production and metabolism of S1P is the driving force behind the so-called sphingolipid rheostat of the cellular environment. This rheostat determines the cumulative effect on cell migration, proliferation, and apoptosis profiles of the concentration and receptor gradient between sphingosine and ceramide with S1P. High levels of sphingosine and/or ceramide compared with S1P will inhibit cell proliferation and migration and promote apoptosis (72). Reversing this balance will allow S1P to promote migration and proliferation. An example of this balance is seen in LT production within mast cells. If the balance is shifted to sphingosine, inhibition of LT production occurs; however, if S1P is predominant, increased LT synthesis results (73).

Similar to other lipid mediators, S1P has a dual role as both an extracellular ligand, via the S1PRs, and as an intracellular ligand, via an undefined second messenger system. Formerly known as the endothelial differentiation gene receptors (Edg), the S1PRs exist as five subtypes: S1P1 (Edg-1), S1P2 (Edg-5), S1P3 (Edg-3), S1P4 (Edg-6), and S1P5 (Edg-8). S1P1–3 have a wide tissue distribution, S1P4 is mainly found in lymphoid tissues and platelets, and S1P5 is confined to the nervous system. Although all five subtypes have different tissue distribution and mechanisms of action, they all have an effect on cell migration (whether positive or negative) (53). Activation of S1P1 by S1P causes cell migration through the activation of the guanine triphosphatase Rac, modifying the actin network to form lamellipodia and the filopodia on the leading edge of the migrating cell (74, 75, 76, 77). Homozygous deletion of the murine S1P1 gene leads to intrauterine vascular hemorrhage and death by embryonic day 13.5 due to failure of pericyte and smooth muscle cell migration, despite an intact vasculature (75). Activation of S1P2 inhibits induction of Rac and instead activates the guanine triphosphatase Rho and its subsequent stress fiber assembly, thereby inhibiting cell migration (78). Homozygous deletions of the S1P2 analog in the miles apart gene of the zebra fish causes abnormal heart development due to faulty myocardial cell migration. Stimulation of the S1P3R by S1P has a known antiapoptotic effect and is thought to aid in the promotion of cell migration (78). The roles of S1P4 and S1P5 are poorly defined, although S1P5 is found predominantly in oligodendrocytes and astrocytes and is presumed to play a role in the development of the nervous system (79). The seemingly contrary role of S1P as an agonist and an inhibitor of cell migration can be best explained as dependent on cellular concentrations of S1P and its respective receptors. Evidence shows that higher concentrations of S1P inhibit smooth muscle migration, whereas at lower concentrations, migration is induced, suggesting that different receptor subtypes are concentration sensitive (80).

Evidence also shows that the activation of S1PRs plays an important role sequestering T and B lymphocytes in secondary lymphoid organs by promoting egress from peripheral blood. For example, S1P enhances in vitro migration to the CCR7 ligands CC chemokine ligand (CCL)19 and CCL21 by T lymphocytes pretreated with the ligand (5). The role of S1P as an intracellular second messenger is not as well defined as its extracellular role. Although intracellular S1P is a known inhibitor of apoptosis and an inosine triphosphate-independent regulator of calcium homeostasis, the exact mechanisms and targets of these actions are not known (81). The mechanisms regulating sphingosine or S1P transport from the cytoplasm to the extracellular space are not known. Sphingosine, and perhaps S1P, can be transported out of the cytosol, similar to platelet activating factor, via the Abc family of proteins, in particular Abcb1 (formerly multidrug resistance) (5).

FTY720 is a synthetic derivative from ISP-1 (myriocin), a metabolite from the traditional Chinese herb Iscaria sinclarii (Fig. 2). A novel immunomodulator, FTY720 has been shown in numerous animal models to prolong allograft transplant survival and to reduce inflammation seen in a murine model for multiple sclerosis (82). Recent evidence shows that FTY720 is also effective in human renal transplantation, prolonging graft survival, although further clinical trials are currently underway (83). Originally postulated to act via apoptosis, FTY720 has been recently shown to prolong allograft survival by sequestering lymphocytes in secondary lymphoid organs, thereby preventing them from migrating to the inflammatory nidus of the transplanted organ (84, 85). Recent studies show that a single oral dose of FTY720 in mice depletes peripheral blood and splenic T lymphocytes, which become sequestered in peripheral lymph nodes and Peyer’s patches (5, 86, 87). Despite causing lymphocyte sequestration, FTY720 does not increase susceptibility to systemic viral infection and does not affect T lymphocyte priming or activation (85).

The mechanism of action behind FTY720 has only recently been elucidated. Because FTY720 is a structural homolog of sphingosine, it was proposed that it might share some of its properties and also function as a substrate for the sphingolipid enzyme cascade. In vivo studies have confirmed this hypothesis by showing FTY720 to be phosphorylated to a phosphate ester (P-FTY720), likely by SpK (87, 88). P-FTY720, analogous to S1P, also appears to be degraded by the sphingosine lyases and phosphohydrolases, although the exact isoenzyme and mechanism remain unclear. (87) That FTY720 was shown to elicit apoptosis at higher doses, but cell migration at lower doses, is analogous to the balance between the apoptotic influence of sphingosine and the promigratory one of S1P.

Because P-FTY720 is a homolog of S1P in both structure and in function, it was hypothesized that they may also share receptors. FTY720-driven lymphocyte trafficking is pertussis toxin sensitive, suggesting that P-FTY720 acts at a GPCR similar to S1PR (87). In vitro experiments have confirmed this by demonstrating that P-FTY720 binds with higher affinity than S1P itself to four of the five S1PRs (87, 88). The only receptor that displayed no response to P-FTY720 was S1P2, which in other studies antagonizes cell migration.

Interactions among lipid mediators

These investigations demonstrate that there is degeneracy in the bioactive lipid families, with multiple ligands for each receptor or multiple receptors for each ligand. In addition, there are nonhomogeneous and overlapping cellular and tissue distributions for these receptors. A number of interactions may take place among different members of the bioactive lipid mediator families, including autocrine, paracrine, and endocrine effects, and precise physiologic outcomes depend on the cellular constituents of an inflammatory infiltrate.

There are also interactions between the members of different lipid families that have recently been elucidated by investigations on leukocyte migration. FTY720 enhances T lymphocyte migration to the CCR7 chemokine ligands CCL19 and CCL21 and to the CCR2 ligand monocyte chemoattractant protein-1 (5, 89). These observations, coupled with experiments that show that dendritic cell migration from the periphery was dependent on both of these chemokines and on the activity of the lipid transporters Abcb1 and Abcc1, led to additional experiments aimed at clarifying the molecular mechanism behind the action of FTY720 (5, 38, 90). These experiments suggest a model in which FTY720 is taken into cells, phosphorylated by SpK intracellularly, and effluxed through the Abcb1R, and then activates S1PRs in an autocrine or paracrine function. S1PR activation then enhances 5-LO activity, production of cysLTs, efflux of cysLTs by Abcc1, and autocrine or paracrine activation of cysLTRs. CysLTR activation sensitizes CCR7 and promotes chemotaxis to CCL19 and CCL21 (5). Thus, FTY720 promotes T cell peripheral lymph node migration by activating the Abcb1 sphingolipid transporter and the Abcc1 LTC4 transporter and enhancing 5-LO activity and cysLT production (5). This model of a multidrug transporter and chemokine-dependent pathway for lymph node homing depends on both sphingolipids and LTs. Ongoing work in our laboratories suggests that additional chemokine ligands and receptors are likely involved. Further, the PG lipid PGE2 may also influence CCR7-directed dendritic cell migration by increasing receptor expression (91).

Concluding remarks

Since the discovery of bioactive lipid mediators over 50 years ago, much critical progress has been made in defining their mechanisms of actions and how they can be harnessed for clinical applications. However, much more information is needed to define the intracellular receptors for sphingolipids and their derivatives; the cellular loci and mechanisms of action of the lipid receptors; the interactions between 5-LO and FLAP with AA in the production of LTs; the existence of other sphingosine analogs, similar to FTY720, that promote cell migration; and other novel, bioactive lipid mediators. Other important issues that remain to be resolved include the roles of bioactive lipid mediators in adaptive vs innate immunity and whether they play a role as autocrine, paracrine, or endocrine ligands.

2

Abbreviations used in this paper: AA, arachidonic acid; LT, leukotriene; cysLT, cysteinyl LT; S1P, sphingosine 1-phosphate; 5-LO, 5-lipoxygenase; FLAP, 5-LO activation protein; GPCR, G-protein-coupled receptor; SpK, sphingosine kinase; SPP, S1P phosphohydrolase; Edg, endothelial differentiation gene receptor; CCL, CC chemokine ligand; Abc, ATP-binding cassette; FTY720, 2-amino-2[2-(4-octylphenyl)ethyl]-1–3-propanediol hydrochloride; P-FTY720, phosphorylated FTY720.

1
Funk, C. D..
2001
. Prostaglandins and leukotrienes: advances in eicosonoid biology.
Science
294
:
1871
2
Lawrence, T., D. A. Willoughby, D. W. Gilroy. Anti-inflammatory lipid mediators and insights into the resolution of inflammation.
Nat. Immunol.
2
:
787
3
Serhan, C. N..
2002
. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution.
Prostaglandins Other Lipid Mediat.
68–69
:
433
4
McMahon, B., S. Mitchell, H. R. Brady, C. Godson.
2001
. Lipoxins: revelations on resolution.
Trends Pharmacol. Sci.
22
:
391
5
Honig, S. M., S. Fu, X. Mao, A. Yopp, M. D. Gunn, G. J. Randolph, J. S. Bromberg.
2003
. FTY720 stimulates multidrug transporter and cysteinyl leukotriene dependent T cell chemotaxis to lymph nodes.
J. Clin. Invest.
111
:
627
6
Lewis, R. A., K. F. Austen, R. J. Soberman.
1990
. Leukotrienes and other products of the 5-lipoxygenase pathway: biochemistry and relation to pathobiology in human diseases.
N. Engl. J. Med.
323
:
645
7
Holtzman, M. J..
1991
. Arachidonic acid metabolism: implications of biological chemistry for lung function and disease.
Am. Rev. Respir. Dis.
143
:
188
8
Rouzer, C. A., T. Shimizu, B. Samuelsson.
1985
. On the nature of the 5-lipoxygenase reaction in human leukocytes: characterization of a membrane-associated stimulatory factor.
Proc. Natl. Acad. Sci. USA
82
:
7505
9
Percival, M. D..
1991
. Human 5-lipoxygenase contains an essential iron.
J. Biol. Chem.
266
:
10058
10
Radmark, O..
2002
. Arachidonate 5-lipoxygenase.
Prostaglandins Other Lipid Mediat.
68–69
:
211
11
Peters-Golden, M., T. G. Brock.
2001
. Intracellular compartmentalization of leukotriene synthesis: unexpected secrets.
FEBS Lett.
487
:
323
12
Rouzer, C. A., B. Samuelsson.
1987
. Reversible, calcium-dependent membrane association of human leukocyte 5-lipoxygenase.
Proc. Natl. Acad. Sci. USA
84
:
7393
13
Rouzer, C. A., S. Kargman.
1988
. Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187.
J. Biol. Chem.
263
:
10980
14
Ford-Hutchinson, A. W..
1991
. FLAP: a novel drug target for inhibiting the synthesis of leukotrienes.
Trends Pharmacol. Sci.
12
:
68
15
Mancini, J. A., M. Abramovitz, M. E. Cox, E. Wong, S. Charleson, H. Perrier, Z. Wang, P. Prasit, P. J. Vickers.
1993
. 5-lipoxygenase-activating protein is an arachidonate binding protein.
FEBS Lett.
318
:
277
16
Rouzer, C. A., A. W. Ford-Hutchinson, H. E. Morton, J. W. Gillard.
1990
. MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes.
J. Biol. Chem.
265
:
1436
17
Haeggstrom, J. Z..
2000
. Structure, function, and regulation of leukotriene A4 hydrolase.
Am. J. Respir. Crit. Care Med.
161
:
S25
18
Black, P. N., R. W. Fuller, G. W. Taylor, P. J. Barnes, C. T. Dollery.
1989
. Effect of inhaled leukotriene B4 alone and in combination with prostaglandin D2 on bronchial responsiveness to histamine in normal subjects.
Thorax
44
:
491
19
Kato, K., T. Yokomizo, T. Izumi, T. Shimizu.
2000
. Cell-specific transcriptional regulation of human leukotriene B4 receptor gene.
J. Exp. Med.
192
:
413
20
Yokomizo, T., T. Izumi, K. Chang, Y. Takuwa, T. Shimizu.
1997
. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis.
Nature
387
:
620
21
Kamohara, M., J. Takasaki, M. Matsumoto, T. Saito, T. Ohishi, H. Ishii, K. Furuichi.
2000
. Molecular cloning and characterization of another leukotriene B4 receptor.
J. Biol. Chem.
275
:
27000
22
Tryselius, Y., N. E. Nilsson, K. Kotarsky, B. Olde, C. Owman.
2000
. Cloning and characterization of cDNA encoding a novel human leukotriene B4 receptor.
Biochem. Biophys. Res. Commun.
274
:
377
23
Tager, A. M., J. H. Dufour, K. Goodarzi, S. D. Bercury, U. H. von Andrian, A. D. Luster.
2000
. BLTR mediates leukotriene B4-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis.
J. Exp. Med.
192
:
439
24
Ford-Hutchinson, A. W., M. A. Bray, M. V. Doig, M. E. Shipley, M. J. Smith.
1980
. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes.
Nature
286
:
264
25
Dahlen, S. E., J. Bjork, P. Hedqvist, K. E. Arfors, S. Hammarstrom, J. A. Lindgren, B. Samuelsson.
1981
. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response.
Proc. Natl. Acad. Sci. USA
78
:
3887
26
Sehmi, R., A. J. Wardlaw, O. Cromwell, K. Kurihara, P. Waltmann, A. B. Kay.
1992
. Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects.
Blood
79
:
2952
27
Yamaoka, K. A., J. P. Kolb.
1993
. Leukotriene B4 induces interleukin 5 generation from human T lymphocytes.
Eur. J. Immunol.
23
:
2392
28
Hafstrom, I., J. Palmblad, C. L. Malmsten, O. Radmark, B. Samuelsson.
1981
. Leukotriene B4: a stereospecific stimulator for release of lysosomal enzymes from neutrophils.
FEBS Lett.
130
:
146
29
Hebert, M. J., T. Takano, H. Holthofer, H. R. Brady.
1996
. Sequential morphologic events during apoptosis of human neutrophils: modulation by lipoxygenase-derived eicosanoids.
J. Immunol.
157
:
3105
30
Lee, E., T. Robertson, J. Smith, S. Kilfeather.
2000
. Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals.
Am. J. Respir. Crit. Care Med.
161
:
1881
31
Penrose, J. F., L. Gagnon, M. Goppelt-Struebe, P. Myers, B. K. Lam, R. M. Jack, K. F. Austen, R. J. Soberman.
1992
. Purification of human leukotriene C4 synthase.
Proc. Natl. Acad. Sci. USA
89
:
11603
32
Nicholson, D. W., A. Ali, J. P. Vaillancourt, J. R. Calaycay, R. A. Mumford, R. J. Zamboni, A. W. Ford-Hutchinson.
1993
. Purification to homogeneity and the N-terminal sequence of human leukotriene C4 synthase: a homodimeric glutathione S-transferase composed of 18-kDa subunits.
Proc. Natl. Acad. Sci. USA
90
:
2015
33
Cowburn, A. S., K. Sladek, J. Soja, L. Adamek, E. Nizankowska, A. Szczeklik, B. K. Lam, J. F. Penrose, F. K. Austen, S. T. Holgate, A. P. Sampson.
1998
. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma.
J. Clin. Invest.
101
:
834
34
Henderson, W. R., Jr..
1994
. The role of leukotrienes in inflammation.
Ann. Intern. Med.
121
:
684
35
Leier, I., G. Jedlitschky, U. Buchholz, S. P. Cole, R. G. Deeley, D. Keppler.
1994
. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates.
J. Biol. Chem.
269
:
27807
36
Wijnholds, J., R. Evers, M. R. van Leusden, C. A. Mol, G. J. Zaman, U. Mayer, J. H. Beijnen, M. van der Valk, P. Krimpenfort, P. Borst.
1997
. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein.
Nat. Med.
3
:
1275
37
Kumlin, M..
1997
. Measurements of leukotrienes in the urine: strategies and applications.
Allergy
52
:
124
38
Randolph, G. J., S. Beaulieu, M. Pope, I. Sugawara, L. Hoffman, R. M. Steinman, W. A. Muller.
1998
. A physiologic function for p-glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels.
Proc. Natl. Acad. Sci. USA
95
:
6924
39
Lynch, K. R., G. P. O’Neill, Q. Liu, D. S. Im, N. Sawyer, K. M. Metters, N. Coulombe, M. Abramovitz, D. J. Figueroa, Z. Zeng, et al
1999
. Characterization of the human cysteinyl leukotriene CysLT1 receptor.
Nature
399
:
789
40
Heise, C. E., B. F. O’Dowd, D. J. Figueroa, N. Sawyer, T. Nguyen, D. S. Im, R. Stocco, J. N. Bellefeuille, M. Abramovitz, R. Cheng, et al
2000
. Characterization of the human cysteinyl leukotriene 2 receptor.
J. Biol. Chem.
275
:
30531
41
Takasaki, J., M. Kamohara, M. Matsumoto, T. Saito, T. Sugimoto, T. Ohishi, H. Ishii, T. Ota, T. Nishikawa, Y. Kawai, et al
2000
. The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT2 receptor.
Biochem. Biophys. Res. Commun.
274
:
316
42
Hui, Y., G. Yang, H. Galczenski, D. J. Figueroa, C. P. Austin, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, C. D. Funk.
2001
. The murine cysteinyl leukotriene 2 (CysLT2) receptor: cDNA and genomic cloning, alternative splicing, and in vitro characterization.
J. Biol. Chem.
276
:
47489
43
Sarau, H. M., R. S. Ames, J. Chambers, C. Ellis, N. Elshourbagy, J. J. Foley, D. B. Schmidt, R. M. Muccitelli, O. Jenkins, P. R. Murdock, et al
1999
. Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor.
Mol. Pharmacol.
56
:
657
44
Garcia, J. G., T. C. Noonan, W. Jubiz, A. B. Malik.
1987
. Leukotrienes and the pulmonary microcirculation.
Am. Rev. Respir. Dis.
136
:
161
45
Joris, I., G. Majno, E. J. Corey, R. A. Lewis.
1987
. The mechanism of vascular leakage induced by leukotriene E4: endothelial contraction.
Am. J. Pathol.
126
:
19
46
Bernstein, J. A., P. A. Greenberger, R. Patterson, M. Glass, R. Krell, P. T. Thyrum.
1991
. The effect of the oral leukotriene antagonist, ICI 204,219, on leukotriene D4 and histamine-induced cutaneous vascular reactions in man.
J. Allergy Clin. Immunol.
87
:
93
47
Laitinen, L. A., A. Laitinen, T. Haahtela, V. Vilkka, B. W. Spur, T. H. Lee.
1993
. Leukotriene E4 and granulocytic infiltration into asthmatic airways.
Lancet
341
:
989
48
Wanner, A., M. Salathe, T. G. O’Riordan.
1996
. Mucociliary clearance in the airways.
Am. J. Respir. Crit. Care Med.
154
:
1868
49
Suissa, S., R. Dennis, P. Ernst, O. Sheehy, S. Wood-Dauphinee.
1997
. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma: a randomized, double-blind, placebo-controlled trial.
Ann. Intern. Med.
126
:
177
50
Grossman, J., I. Faiferman, J. W. Dubb, D. J. Tompson, W. Busse, E. Bronsky, A. Montanaro, L. Southern, D. Tinkelman.
1997
. Results of the first U.S. double-blind, placebo-controlled, multicenter clinical study in asthma with pranlukast, a novel leukotriene receptor antagonist.
J. Asthma
34
:
321
51
Reiss, T. F., P. Chervinsky, R. J. Dockhorn, S. Shingo, B. Seidenberg, T. B. Edwards.
1998
. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial: Montelukast Clinical Research Study Group.
Arch. Intern. Med.
158
:
1213
52
Kolesnick, R., Y. A. Hannun.
1999
. Ceramide and apoptosis.
Trends Biochem. Sci.
24
:
224
53
Spiegel, S., S. Milstien.
2000
. Sphingosine-1-phosphate: signaling inside and out.
FEBS Lett.
476
:
55
54
Spiegel, S., A. H. Merrill, Jr..
1996
. Sphingolipid metabolism and cell growth regulation.
FASEB J.
10
:
1388
55
Kohama, T., A. Olivera, L. Edsall, M. M. Nagiec, R. Dickson, S. Spiegel.
1998
. Molecular cloning and functional characterization of murine sphingosine kinase.
J. Biol. Chem.
273
:
23722
56
Liu, H., M. Sugiura, V. E. Nava, L. C. Edsall, K. Kono, S. Poulton, S. Milstien, T. Kohama, S. Spiegel.
2000
. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform.
J. Biol. Chem.
275
:
19513
57
Olivera, A., S. Spiegel.
1993
. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens.
Nature
365
:
557
58
Xia, P., L. Wang, J. R. Gamble, M. A. Vadas.
1999
. Activation of sphingosine kinase by tumor necrosis factor-α inhibits apoptosis in human endothelial cells.
J. Biol. Chem.
274
:
34499
59
Edsall, L. C., G. G. Pirianov, S. Spiegel.
1997
. Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation.
J. Neurosci.
17
:
6952
60
Nikolova-Karakashian, M., E. T. Morgan, C. Alexander, D. C. Liotta, A. H. Merrill, Jr..
1997
. Bimodal regulation of ceramidase by interleukin-1β: implications for the regulation of cytochrome p450 2C11.
J. Biol. Chem.
272
:
18718
61
Ancellin, N., C. Colmont, J. Su, Q. Lin, N. Mittereder, S. Chae, S. Stefansson, G. Liau, T. Hla.
2002
. Extracellular export of sphingosine kinase-1 enzyme.
J. Biol. Chem.
277
:
6667
62
Van Veldhoven, P. P., G. P. Mannaerts.
1993
. Sphingosine-phosphate lyase.
Adv. Lipid Res.
26
:
69
63
Mandala, S. M., R. Thornton, I. Galve-Roperh, S. Poulton, C. Peterson, A. Olivera, J. Bergstrom, M. B. Kurtz, S. Spiegel.
2000
. Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1-phosphate and induces cell death.
Proc. Natl. Acad. Sci. USA
97
:
7859
64
Le Stunff, H., C. Peterson, R. Thornton, S. Milstien, S. M. Mandala, S. Spiegel.
2002
. Characterization of murine sphingosine-1-phosphate phosphohydrolase.
J. Biol. Chem.
277
:
8920
65
Mao, C., M. Wadleigh, G. M. Jenkins, Y. A. Hannun, L. M. Obeid.
1997
. Identification and characterization of Saccharomyces cerevisiae dihydrosphingosine-1-phosphate phosphatase.
J. Biol. Chem.
272
:
28690
66
Mandala, S. M., R. Thornton, Z. Tu, M. B. Kurtz, J. Nickels, J. Broach, R. Menzeleev, S. Spiegel.
1998
. Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response.
Proc. Natl. Acad. Sci. USA
95
:
150
67
Ogawa, C., A. Kihara, M. Gokoh, Y. Igarashi.
2003
. Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hSPP2.
J. Biol. Chem.
278
:
1268
68
Waggoner, D. W., A. Gomez-Munoz, J. Dewald, D. N. Brindley.
1996
. Phosphatidate phosphohydrolase catalyzes the hydrolysis of ceramide 1-phosphate, lysophosphatidate, and sphingosine 1-phosphate.
J. Biol. Chem.
271
:
16506
69
Kai, M., I. Wada, S. Imai, F. Sakane, H. Kanoh.
1997
. Cloning and characterization of two human isozymes of Mg2+-independent phosphatidic acid phosphatase.
J. Biol. Chem.
272
:
24572
70
Dillon, D. A., X. Chen, G. M. Zeimetz, W. I. Wu, D. W. Waggoner, J. Dewald, D. N. Brindley, G. M. Carman.
1997
. Mammalian Mg2+-independent phosphatidate phosphatase (PAP2) displays diacylglycerol pyrophosphate phosphatase activity.
J. Biol. Chem.
272
:
10361
71
Roberts, R., V. A. Sciorra, A. J. Morris.
1998
. Human type 2 phosphatidic acid phosphohydrolases: substrate specificity of the type 2a, 2b, and 2c enzymes and cell surface activity of the 2a isoform.
J. Biol. Chem.
273
:
22059
72
Cuvillier, O., G. Pirianov, B. Kleuser, P. G. Vanek, O. A. Coso, S. Gutkind, S. Spiegel.
1996
. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate.
Nature
381
:
800
73
Prieschl, E. E., R. Csonga, V. Novotny, G. E. Kikuchi, T. Baumruker.
1999
. The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fcε receptor I triggering.
J. Exp. Med.
190
:
1
74
Liu, Y., R. Wada, T. Yamashita, Y. Mi, C. X. Deng, J. P. Hobson, H. M. Rosenfeldt, V. E. Nava, S. S. Chae, M. J. Lee, et al
2000
. Edg-1, the G protein–coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation.
J. Clin. Invest.
106
:
951
75
Garcia, J. G., F. Liu, A. D. Verin, A. Birukova, M. A. Dechert, W. T. Gerthoffer, J. R. Bamberg, D. English.
2001
. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement.
J. Clin. Invest.
108
:
689
76
Hobson, J. P., H. M. Rosenfeldt, L. S. Barak, A. Olivera, S. Poulton, M. G. Caron, S. Milstien, S. Spiegel.
2001
. Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility.
Science
291
:
1800
77
Okamato, H., N. Takuwa, T. Yokomizo, N. Sugimoto, S. Sakurada, H Shigematsu, Y. Takuwa.
2000
. Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3.
Mol. Cell. Biol
20
:
9247
78
Ishii, I., B. Friedman, X. Ye, S. Kawamura, C. McGiffert, J. J. Contos, M. A. Kingsbury, G. Zhang, J. H. Brown, J. Chun.
2001
. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3.
J. Biol. Chem.
276
:
33697
79
Graeler, M., G. Shankar, E. J. Goetzl.
2002
. Cutting edge: suppression of T cell chemotaxis by sphingosine 1-phosphate.
J. Immunol.
169
:
4084
80
Ghosh, T. K., J. Bian, D. L. Gill.
1994
. Sphingosine 1-phosphate generated in the endoplasmic reticulum membrane activates release of stored calcium.
J. Biol. Chem.
269
:
22628
81
Brinkmann, V., D. Pinschewer, K. Chiba, L. Feng.
2000
. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation.
Trends Pharmacol. Sci.
21
:
49
82
Budde, K., R. L. Schmouder, R. Brunkhorst, B. Nashan, P. W. Lucker, T. Mayer, S. Choudhury, A. Skerjanec, G. Kraus, H. H. Neumayer.
2002
. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients.
J. Am. Soc. Nephrol.
13
:
1073
83
Chiba, K., Y. Yanagawa, Y. Masubuchi, H. Kataoka, T. Kawaguchi, M. Ohtsuki, Y. Hoshino.
1998
. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing.
J. Immunol.
160
:
5037
84
Nagahara, Y., S. Enosawa, M. Ikekita, S. Suzuki, T. Shinomiya.
2000
. Evidence that FTY720 induces T cell apoptosis in vivo.
Immunopharmacology
48
:
75
85
Pinschewer, D. D., A. F. Ochsenbein, B. Odermatt, V. Brinkmann, H. Hengartner, R. M. Zinkernagel.
2000
. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory.
J. Immunol.
164
:
5761
86
Yanagawa, Y., K. Sugahara, H. Kataoka, T. Kawaguchi, Y. Masubuchi, K. Chiba.
1998
. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo.
J. Immunol.
160
:
5493
87
Mandala, S., R. Hajdu, J. Bergstrom, E. Quackenbush, J. Xie, J. Milligan, R. Thornton, G. J. Shei, D. Card, C. Keohane, et al
2002
. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
Science
296
:
346
88
Brinkmann, V., M. D. Davis, C. E. Heise, R. Albert, S. Cottens, R. Hof, C. Bruns, E. Prieschl, T. Baumruker, P. Hiestand, et al
2002
. The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
J. Biol. Chem.
277
:
21453
89
Chen, S., K. B. Bacon, G. Garcia, R. Liao, Z. K. Pan, S. K. Sullivan, H. Nakana, A. Matsuzawa, V. Brinkmann, L. Feng.
2001
. FTY720, a novel transplantation drug, modulates lymphocyte migratory responses to chemokines.
Transplant. Proc.
33
:
3057
90
Robbiani, D. F., R. A. Finch, D. Jager, W. A. Muller, A. C. Sartorelli, G. J. Randolph.
2000
. The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3β, ELC)-dependent mobilization of dendritic cells to lymph nodes.
Cell
103
:
757
91
Scandella, E., Y. Men, S. Gillessen, R. Forster, M. Groettrup.
2002
. Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells.
Blood
100
:
1354