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Leukotrienes, Sphingolipids, and Leukocyte Trafficking Adam C. Yopp,* Gwendolyn J. Randolph,* and Jonathan S. Bromberg1*†

nflammation is a response that protects tissues affected by AA is oxygenated by 5-lipoxygenase (5-LO) to form hydro- foreign pathogens or physical trauma. Inflammation is ini- peroxide 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetranoic I tiated through the carefully orchestrated movement of in- acid, which is subsequently dehydrated, yielding LTA4 (7). flammatory cells (neutrophils, monocytes/macrophages, and 5-LO is a 72- to 80-kDa monomeric soluble contain- lymphocytes) following the initial cellular insult. The traffick- ing one nonheme iron believed necessary for catalysis (8, 9). ing of these cells to the inflammatory nidus is regulated by nu- Active mainly in myeloid cells, including monocytes, B lym- ϩ merous cell surface receptors and ligands, along with the release phocytes, granulocytes, and mast cells, 5-LO requires Ca2 and of chemokines, cytokines, vasoactive amines, and bioactive is stimulated by ATP, phosphatidylcholine, and lipid hydroper- ϩ lipid mediators. Lipid mediators, primarily comprised of sphin- oxides (reviewed in Refs. 10 and 11). The Ca2 stimulation is golipids and derivatives, were once thought to be believed to translocate the soluble cytosolic 5-LO to the mem- just inert members of the bilipid cell membrane, but are now brane by association with 5-LO activation protein (FLAP) (12, known to play a decisive role not only in proinflammatory cell 13). FLAP, an 18-kDa membrane-associated protein with a leu- movement but also paradoxically in its resolution as well. kocyte expression similar to that of 5-LO, is expressed on T Eicosanoid lipids are derived from the activity of phospho- lymphocytes but not on erythrocytes or endothelial cells. FLAP lipase A2 on the 20-carbon membrane phospholipid arachi- has been postulated to present or transfer AA to 5-LO for en- donic acid (AA).2 Multiple divergent metabolic pathways use zymatic degradation (14, 15). Although not fully understood, AA as their substrate. One pathway metabolizes AA via the li- the inhibition of FLAP by the compound MK-866 disrupts poxygenase pathway to (LTs) and lipoxins. A sec- LTA4 production, despite the presence of 5-LO (16). The mo- ond major pathway forms the PGs and thromboxanes from AA lecular details behind the 5-LO/FLAP interaction, including via the pathway. The and lipoxins will their sites of action and their role in binding AA, are unknown. not be discussed in this review, because they have been the subjects LTA4 undergoes further transformation by one of two path- of numerous recent reviews (1–4). The sphingolipids, derived ways depending on cellular makeup and presence: 1) from sphingomyelin, include ceramide and its derivatives, sphin- hydrolysis to LTB4 by the zinc metalloenzyme LTA4 hydrolase

by guest on October 1, 2021. Copyright 2003 Pageant Media Ltd. gosine, and sphingosine 1-phosphate (S1P), and the novel immu- or 2) conjugation to LTC4 by LTC4 synthase. nomodulatory sphingosine analog 2-amino-2[2-(4-octylphenyl) LTA4 hydrolase is a 69-kDa widely distributed protein found in ethyl]-1–3-propanediol hydrochloride (FTY720), which has almost all mammalian tissue (17). Its product, LTB4,isapow- recently been reported to serve as an agonist for leukocyte migra- erful chemotactic agent that, in contrast to its cysLT counter- tion with potential clinical applications (5). This review focuses on parts, has no direct role in bronchoconstriction or pulmonary the biosynthetic pathways, cellular distribution, receptors, and vasoconstriction (18). LTB4 has two known extracellular recep- mechanisms of action of, as well as the interactions among, the LT tors, BLT1 and BLT2. BLT1R has been characterized as a 43- and sphingolipid bioactive mediators, particularly in reference to kDa G-protein-coupled (GPCR) expressed only in in- their role in leukocyte trafficking. flammatory cells (neutrophils predominantly) and with a high http://classic.jimmunol.org affinity for only LTB4. (19, 20). The second LTB4R, BLT2, has Leukotrienes only recently been described and, although a GPCR similar to LTs are a family of eicosanoid lipid mediators derived from the its BLT1 homolog, the BLT2R is ubiquitously expressed in all of AA. First described in 1937 as the slow-reacting mammalian tissues (20–22). Both receptors are found on the substances of , these compounds are now known as same , but intriguingly, the open reading frame of

Downloaded from the cysteinyl LTs (cysLTs) LTC4, LTD4, and LTE4 (6). Syn- the BLT2R is within the promoter region of the BLT1R (19). thesis of LTs can be divided into two pathways: one to create Activation of both BLTRs serves as a powerful stimulus for in cysLTs and another to create LTB4 (Fig. 1). Both pathways vitro leukocyte chemotaxis, especially of neutrophils (23, 24). share the common intermediate, the short-lived epoxide LTA4. In vivo experiments have shown LTB4 to increase neutrophil

*Carl C. Icahn Center for Therapy and Molecular Medicine and †Recanti/Miller 2 Abbreviations used in this paper: AA, ; LT, ; cysLT, cysteinyl Transplantation Institute, Mount Sinai School of Medicine, New York, NY 10029 LT; S1P, sphingosine 1-phosphate; 5-LO, 5-lipoxygenase; FLAP, 5-LO activation protein; GPCR, G-protein-coupled receptor; SpK, sphingosine kinase; SPP, S1P phosphohydro- Received for publication March 17, 2003. Accepted for publication April 9, 2003. lase; Edg, endothelial differentiation gene receptor; CCL, CC chemokine ; Abc, The costs of publication of this article were defrayed in part by the payment of page charges. ATP-binding cassette; FTY720, 2-amino-2[2-(4-octylphenyl)ethyl]-1–3-propanediol hy- This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. drochloride; P-FTY720, phosphorylated FTY720. Section 1734 solely to indicate this fact. 1 Address correspondence and reprint requests to Dr. Jonathan S. Bromberg, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1104, New York, NY 10029-6574. E-mail address: [email protected]

Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 6 LTs, SPHINGOLIPIDS, AND LEUKOCYTE TRAFFICKING

expressed in lung, spleen, and peripheral blood leukocytes (es- pecially eosinophils) (41, 42). The cysLT2R is likewise ex- pressed on these cells and is also highly expressed in the heart, adrenal glands, and brain (42). The significance of these differ- ences 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 popula- tion (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 re- sponse in animal models, but not in humans (46). In addition, cysLT1R activation also serves as a chemotactic stimulus for eo- sinophils and to increase mucus production (47, 48). Clinically, modification of the LT pathway through the use of 5-LO in- hibitors () or cysLT1R antagonists ( or ) (currently, no specific cysLT2R antagonist exists, al- though Bay u933 blocks both cysLTRs) have played an impor- tant role in the management of asthmatic patients (49–51). Al- though 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, FIGURE 1. LT biosynthetic pathway. Receptors for LTs are in parentheses. and whether other play a role as lipid mediators may lead to novel discoveries with significant clinical implications. rolling and adhesion and egress into the extravascular space through increased expression of adhesion (integrins Sphingolipids and selectins) (25). Additional actions of LTB include stimu- Sphingolipids, such as ceramide, sphingosine, and S1P, were by guest on October 1, 2021. Copyright 2003 Pageant Media Ltd. 4 lation of IL-5 in T lymphocytes, chemotactic effects on IL-5- originally thought to have only the rudimentary task of main- activated eosinophils, neutrophil secretion of superoxide anion taining the integrity of the bilipid cell membrane (Fig. 2). How- radicals, and antiapoptotic effects on neutrophils (26–29).

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 http://classic.jimmunol.org an 18-kDa protein with a wide tissue distribution (31, 32). Af-

ter LTC4 synthesis, the multidrug transporter ATP-binding cassette (Abc)c1 (formerly known as MRP-1) actively trans-

ports LTC4 out of the cell, where LTD4 and LTE4 are formed through the elimination of glutamine and glycine, respectively, ␥ Downloaded from by -glutamyl transpeptidase and dipeptidase (33–35). Failure to express Abcc1 has been shown to increase intracellular accu-

mulation of LTC4 (36). LTC4 has been shown in animal mod- els 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 pe- ripheral lymph nodes (5, 38). Antagonism of Abcc1 or 5-LO activity inhibits dendritic and T cell migration, which is re- stored after the addition of exogenous cysLTs (5, 38). The cysLTs have two described GPCR-type cell surface re-

ceptors, cysLT1 and cysLT2. The potency of each ligand was determined through intracellular calcium mobilization with a Ͼ Ͼ ϭ rank order of LTD4 LTC4 LTE4 for cysLT1 and LTC4 Ͼ LTD4 LTE4 for cysLT2 (39, 40). The cysLT1R is highly FIGURE 2. Sphingolipid biosynthetic pathway. The Journal of Immunology 7

ever, these products of sphingolipid metabolism have been lipodia and the filopodia on the leading edge of the migrating shown to have critical roles in cell migration, proliferation, and cell (74–77). Homozygous deletion of the murine S1P1 gene survival. Sphingosine is formed by the metabolism of the sphin- leads to intrauterine vascular hemorrhage and death by embry- gomyelin derivative ceramide through the action of the enzyme onic day 13.5 due to failure of pericyte and smooth muscle cell ceramidase (52). Although both sphingosine and ceramide have migration, despite an intact vasculature (75). Activation of similar cellular actions, including the induction of apoptosis, S1P2 inhibits induction of Rac and instead activates the gua- the arrest of cell growth and proliferation, neither plays a direct nine triphosphatase Rho and its subsequent stress fiber assem- role in cell migration (53, 54). bly, thereby inhibiting cell migration (78). Homozygous dele- S1P is the bioactive derivative of the phosphorylation of tions of the S1P2 analog in the miles apart gene of the zebra fish sphingosine by sphingosine kinase (SpK). Although seven causes abnormal heart development due to faulty myocardial cloned isoenzymes of SpK have been described, only two forms, cell migration. Stimulation of the S1P3R by S1P has a known SpK1 and SpK2, each with different tissue distribution and antiapoptotic effect and is thought to aid in the promotion of temporal actions, are predominantly found in humans and cell migration (78). The roles of S1P4 and S1P5 are poorly de- mice (55). SpK1 is a 42.4-kDa protein found in the cytosol of fined, although S1P5 is found predominantly in oligodendro- lung, spleen, and liver cells (55). SpK2, a proline-rich 65.6-kDa cytes and astrocytes and is presumed to play a role in the devel- protein, is expressed in liver and heart cells (56). Both kinases opment of the nervous system (79). The seemingly contrary are activated by the external stimuli PDGF, nerve growth fac- role of S1P as an agonist and an inhibitor of cell migration can tor, TNF-␣, and IL-1␤, driving the conversion of sphingosine be best explained as dependent on cellular concentrations of to S1P (57–60). Recent evidence shows that SpK is secreted by S1P and its respective receptors. Evidence shows that higher endothelial cells (61). This suggests that S1P can be made both concentrations of S1P inhibit smooth muscle migration, intracellularly and extracellulary. Once formed, S1P is metab- whereas at lower concentrations, migration is induced, suggest- olized by S1P to ethanolamine phosphate and hexadeca- ing that different receptor subtypes are concentration sensitive nal, or dephosphorylated back to sphingosine by a lipid phos- (80). phohydrolase (62). The lipid phosphohydrolase family is Evidence also shows that the activation of S1PRs plays an im- composed of S1P phosphohydrolase (SPP) and the type 2 lipid portant role sequestering T and B lymphocytes in secondary phosphohydrolase. SPP includes three known mammalian (one lymphoid organs by promoting egress from peripheral blood. murine/two human) homologs and two yeast counterparts and For example, S1P enhances in vitro migration to the CCR7 li- is specific to S1P, dihydrosphingosine 1-phosphate, and phyto- gands CC chemokine ligand (CCL)19 and CCL21 by T lym- sphingosine 1-phosphate (63–66). The first described human phocytes pretreated with the ligand (5). The role of S1P as an SPP isoenzyme is ubiquitously expressed unlike the second, intracellular second messenger is not as well defined as its ex- which is limited to the of brain, heart, tracellular role. Although intracellular S1P is a known inhibitor colon, kidney, small intestine, and lung cells (67). The type 2 of apoptosis and an inosine triphosphate-independent regulator

by guest on October 1, 2021. Copyright 2003 Pageant Media Ltd. lipid phosphohydrolase has a wide expression and substrate of calcium homeostasis, the exact mechanisms and targets of specificity, including S1P, lysophosphatide, and ceramide these actions are not known (81). The mechanisms regulating 1-phosphate (68–72). sphingosine or S1P transport from the cytoplasm to the extra- The balance between the production and metabolism of S1P cellular space are not known. Sphingosine, and perhaps S1P, is the driving force behind the so-called sphingolipid rheostat of can be transported out of the cytosol, similar to platelet activat- the cellular environment. This rheostat determines the cumu- ing factor, via the Abc family of proteins, in particular Abcb1 lative effect on cell migration, proliferation, and apoptosis pro- (formerly multidrug resistance) (5). files of the concentration and receptor gradient between sphin- FTY720 is a synthetic derivative from ISP-1 (myriocin), a gosine and ceramide with S1P. High levels of sphingosine metabolite from the traditional Chinese herb Iscaria sinclarii http://classic.jimmunol.org and/or ceramide compared with S1P will inhibit cell prolifera- (Fig. 2). A novel immunomodulator, FTY720 has been shown tion and migration and promote apoptosis (72). Reversing this in numerous animal models to prolong allograft transplant sur- balance will allow S1P to promote migration and proliferation. vival and to reduce inflammation seen in a murine model for An example of this balance is seen in LT production within multiple sclerosis (82). Recent evidence shows that FTY720 is mast cells. If the balance is shifted to sphingosine, inhibition of also effective in human renal transplantation, prolonging graft LT production occurs; however, if S1P is predominant, in- survival, although further clinical trials are currently underway Downloaded from creased LT synthesis results (73). (83). Originally postulated to act via apoptosis, FTY720 has Similar to other lipid mediators, S1P has a dual role as both been recently shown to prolong allograft survival by sequester- an extracellular ligand, via the S1PRs, and as an intracellular ing lymphocytes in secondary lymphoid organs, thereby pre- ligand, via an undefined second messenger system. Formerly venting them from migrating to the inflammatory nidus of the known as the endothelial differentiation gene receptors (Edg), transplanted organ (84, 85). Recent studies show that a single the S1PRs exist as five subtypes: S1P1 (Edg-1), S1P2 (Edg-5), oral dose of FTY720 in mice depletes peripheral blood and S1P3 (Edg-3), S1P4 (Edg-6), and S1P5 (Edg-8). S1P1–3 have a splenic T lymphocytes, which become sequestered in peripheral wide tissue distribution, S1P4 is mainly found in lymphoid tis- lymph nodes and Peyer’s patches (5, 86, 87). Despite causing sues and platelets, and S1P5 is confined to the nervous system. lymphocyte sequestration, FTY720 does not increase suscepti- Although all five subtypes have different tissue distribution and bility to systemic viral infection and does not affect T lympho- mechanisms of action, they all have an effect on cell migration cyte priming or activation (85). (whether positive or negative) (53). Activation of S1P1 by S1P The mechanism of action behind FTY720 has only recently causes cell migration through the activation of the guanine been elucidated. Because FTY720 is a structural homolog of triphosphatase Rac, modifying the actin network to form lamel- sphingosine, it was proposed that it might share some of its 8 LTs, SPHINGOLIPIDS, AND LEUKOCYTE TRAFFICKING

properties and also function as a substrate for the sphingolipid Concluding remarks enzyme cascade. In vivo studies have confirmed this hypothesis Since the discovery of bioactive lipid mediators over 50 years by showing FTY720 to be phosphorylated to a phosphate ester ago, much critical progress has been made in defining their (P-FTY720), likely by SpK (87, 88). P-FTY720, analogous to mechanisms of actions and how they can be harnessed for clin- S1P, also appears to be degraded by the sphingosine and ical applications. However, much more information is needed phosphohydrolases, although the exact isoenzyme and mecha- to define the intracellular receptors for sphingolipids and their nism remain unclear. (87) That FTY720 was shown to elicit derivatives; the cellular loci and mechanisms of action of the apoptosis at higher doses, but cell migration at lower doses, is lipid receptors; the interactions between 5-LO and FLAP with analogous to the balance between the apoptotic influence of AA in the production of LTs; the existence of other sphingosine sphingosine and the promigratory one of S1P. analogs, similar to FTY720, that promote cell migration; and Because P-FTY720 is a homolog of S1P in both structure and other novel, bioactive lipid mediators. Other important issues in function, it was hypothesized that they may also share recep- that remain to be resolved include the roles of bioactive lipid tors. FTY720-driven lymphocyte trafficking is pertussis toxin mediators in adaptive vs innate immunity and whether they sensitive, suggesting that P-FTY720 acts at a GPCR similar to play a role as autocrine, paracrine, or endocrine ligands. S1PR (87). In vitro experiments have confirmed this by dem- onstrating that P-FTY720 binds with higher affinity than S1P References itself to four of the five S1PRs (87, 88). The only receptor that 1. Funk, C. D. 2001. Prostaglandins and leukotrienes: advances in eicosonoid biology. Science 294:1871. displayed no response to P-FTY720 was S1P2, which in other 2. Lawrence, T., D. A. Willoughby, and D. W. Gilroy. Anti-inflammatory lipid medi- studies antagonizes cell migration. ators 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. Interactions among lipid mediators 4. McMahon, B., S. Mitchell, H. R. Brady, and C. Godson. 2001. Lipoxins: revelations on resolution. Trends Pharmacol. Sci. 22:391. These investigations demonstrate that there is degeneracy in the 5. Honig, S. M., S. Fu, X. Mao, A. Yopp, M. D. Gunn, G. J. Randolph, and bioactive lipid families, with multiple ligands for each receptor J. S. Bromberg. 2003. FTY720 stimulates multidrug transporter and cysteinyl leuko- triene dependent T cell chemotaxis to lymph nodes. J. Clin. Invest. 111:627. or multiple receptors for each ligand. In addition, there are non- 6. Lewis, R. A., K. F. Austen, and R. J. Soberman. 1990. Leukotrienes and other prod- homogeneous and overlapping cellular and tissue distributions ucts of the 5-lipoxygenase pathway: biochemistry and relation to pathobiology in hu- man diseases. N. Engl. J. Med. 323:645. for these receptors. A number of interactions may take place 7. Holtzman, M. J. 1991. Arachidonic acid metabolism: implications of biological chem- among different members of the bioactive lipid mediator fam- istry for lung function and disease. Am. Rev. Respir. Dis. 143:188. ilies, including autocrine, paracrine, and endocrine effects, and 8. Rouzer, C. A., T. Shimizu, and B. Samuelsson. 1985. On the nature of the 5-lipoxy- genase reaction in human leukocytes: characterization of a membrane-associated stim- precise physiologic outcomes depend on the cellular constitu- ulatory factor. Proc. Natl. Acad. Sci. USA 82:7505. ents of an inflammatory infiltrate. 9. Percival, M. D. 1991. Human 5-lipoxygenase contains an essential iron. J. Biol. Chem. 266:10058.

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