©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Signals and Receptors Involved in Recruitment of Inflammatory Cells (*)

Adit Ben-Baruch (1), Dennis F. Michiel (2), Joost J. Oppenheim (1)

From the (1) Laboratory of Molecular Immunoregulation, Biological Response Modifiers Program, NCI, National Institutes of Health, Frederick, Maryland 21702-1201 and the (2) Biological Carcinogenesis and Development Program, Program Resources, Inc./DynCorp., NCI, National Institutes of Health, Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

INTRODUCTION
Chemokines
Interleukin 8 and Other -Chemokines (C-X-C Chemokines)
-Chemokines (C-C Chemokines)
Receptors for Chemokines and Other Chemoattractants (CCRs)
Structure-Function Relationships in CCRs
Desensitization of CCRs
Signal Transduction by CCRs
Signaling Pathways in CCR-mediated Effects
The in Vivo Role of CCRs in Inflammation
Prospects and Unresolved Issues
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES


INTRODUCTION

The classical symptoms of inflammation (redness, swelling, heat, and pain) are the result of underlying biochemical events triggered by infection, foreign material, or tissue damage. The hallmark of inflammation is the infiltration of specific leukocyte subsets from the blood into the affected tissue. These leukocytes function as the primary line of host defense in the destruction of microorganisms and initiation of tissue repair. A variety of chemotactic proteins and their receptors orchestrate the directed migration of leukocytes to inflammatory sites. A number of neutrophil and monocyte chemoattractants such as fMLP,() C5a, LTB, and PAF have been studied for several decades (1) . Since 1986, a superfamily of closely related and conserved cytokines, which specialize in attracting a variety of leukocytes to sites of injury, has been identified, cloned, sequenced, and designated ``chemokines'' (short for chemoattractant cytokines). We will cryptically review the function and regulation of chemokines and focus on the signaling pathways mediated by chemokine receptors in comparison with receptors of other chemoattractants.


Chemokines

The chemokine superfamily consists of a number of small (8-10 kDa), inducible, proinflammatory proteins (2, 3) that show 20-50% homology at the amino acid level. This superfamily is divided into an -chemokine subfamily based on the presence of an intervening amino acid between the first and second of four conserved cysteine residues (C-X-C) and a -chemokine subfamily of proteins that has no intervening amino acid between the first two cysteine residues (C-C). The first cysteine forms a disulfide bond with the third cysteine, and the second with the fourth, resulting in a similar tertiary structure for many of the chemokines. So far at least 14 distinct -chemokines and 12 -chemokines have been described at the protein and/or cDNA level. Members of the human -chemokine subfamily include IL-8, GRO, IP-10, ENA-78, PF-4, MIP-2, GCP-2, and NAP-2; members of the human -chemokine subfamily include RANTES, MCAF/MCP-1, MCP-2, MCP-3/MARC, MIP-1, MIP-1, and I-309 (1, 3) . The - and -chemokine subfamilies differ in their cell target selectivity, with five of the -chemokines (IL-8, GRO, NAP-2, ENA-78, and GCP-2) acting primarily as potent chemoattractants and activators of neutrophils (3) . PF-4 and -TG attract both neutrophils and fibroblasts, whereas IP-10 attracts only monocytes, T cells, and NK cells (3) . An ELR motif (Glu-Leu-Arg) at positions 4, 5, and 6 preceding the first cysteine residue of -chemokines appears to be necessary, but not sufficient, for all neutrophil-stimulating chemokines (4) . In contrast to -chemokines, -chemokines primarily chemoattract monocytes and T lymphocytes and do not have a common NH-terminal motif similar to the ELR sequence (3) . In addition, - and -chemokines differ in their chromosomal location, with the -chemokine genes colocalized at chromosome 4q12-q21 and the -chemokine genes at chromosome 17q11-q21 (3) .

Recently, a T cell chemoattractant, named lymphotactin, was identified that has sequence homology with members of both the - and -chemokine subfamilies but has only two of the four conserved cysteine residues (5) . Lymphotactin may therefore be the representative of a third subfamily of chemokines.


Interleukin 8 and Other -Chemokines (C-X-C Chemokines)

IL-8, the most extensively studied chemokine, was originally identified as a neutrophil chemotactic factor produced by LPS-activated peripheral blood monocytes (6, 7) . IL-8 is also directly chemotactic for T cells and basophils (3) . Furthermore, IL-8 can attract T cells by an indirect mechanism: it induces neutrophils to degranulate and release potent T cell chemoattractants() in the presence of secondary activators such as TNF- or cytochalasin B, which enhance IL-8-stimulated neutrophil degranulation (9) . The resulting T cell chemoattractants were recently identified as the defensins HNP-1 and HNP-2 and CAP37/azurocidin.

The open reading frame of IL-8 codes for a 99-amino acid protein, which is shortened by a 20-amino acid signal sequence and by further cell type-dependent proteolysis of the NH terminus generating the two major natural forms: a 77-amino-acid form generated by tissue cells such as endothelial cells and fibroblasts and a more active 72-amino-acid form generated by monocytes and leukocytes (2) . Similar to a number of inflammatory cytokines, the mRNA for IL-8 contains a 3` AU-rich sequence that causes the mRNA to be highly unstable and to be degraded with a half-life of less than 1 h (10) .

Numerous exogenous agents and endogenous proinflammatory stimulants, such as endotoxin, lectins, hypoxia, viruses, bacteria, IL-1, and TNF-, stimulate IL-8 production in a wide variety of cell types (3) by stabilization of IL-8 mRNA (11) as well as by activation of IL-8 gene transcription (3) . The genomic sequence for IL-8 contains putative binding sites for several transcription regulatory elements in the 5`-flanking region preceding the first exon, including sites for NF-B, NF-IL-6-C/EBP, AP-1, glucocorticoid receptor, hepatocyte nuclear factor-1, interferon regulatory factor-1, and an octamer-binding motif (12, 13) . Analysis of the IL-8 promoter showed that the sequences between positions -91 and -71 contain the NF-B-binding site and the NF-IL-6 (or C/EBP) site and are sufficient for the induction of IL-8 gene transcription by LPS, IL-1, TNF-, phorbol 12-myristate 13-acetate, or hepatitis B virus protein X. Studies on Jurkat and HeLa cells showed that the IL-8 gene is regulated by a cooperative binding to the DNA of the C/EBP binding-protein (NF-IL-6) and the NF-B-binding protein (RelA) (13, 14) . These nuclear factors form a tertiary complex with the IL-8 promoter, resulting in a synergistic effect on IL-8 expression (14) . Overexpression of IB, the NF-B inhibitor, abolished this RelA/NF-IL-6-dependent synergistic effect (14) . However, the transcription of the IL-8 gene appears to be differentially regulated in various cell types, with cooperation at AP-1, NF-IL-6, and NF-B sites, possibly due to the availability and activation of different nuclear factors. In gastric cancer cell lines and monocytic cell lines only the NF-IL-6 site is indispensable for IL-8 gene expression (i.e. either AP-1 + NF-IL-6 or NF-B + NF-IL-6 can stimulate). On the other hand, in human glioblastoma cells the NF-B is required for IL-8 gene expression (stimulation at either AP-1 + NF-B sites or NF-IL-6 + NF-B sites) (15, 16, 17) .

Glucocorticoids, such as dexamethasone, are potent immunomodulating anti-inflammatory agents that have a marked inhibitory effect on the gene transcription of several proinflammatory cytokines including IL-1, TNF-, and IL-8. A glucocorticoid-responsive element, present at positions -330 to -325 in the IL-8 promoter, may play a role in a number of cell types in the inhibition of IL-8 expression observed with dexamethasone (12) . However, dexamethasone also suppresses IL-1-induced IL-8 production through the NF-B site (18) . Interferon- also appears to regulate inflammatory cytokine transcription as it inhibits TNF--induced IL-8 gene expression at the transcriptional level via the NF-B site (19) .

Other -chemokine genes appear to be under similar regulatory controls. IL-1 and TNF- stimulate the expression of many of the -chemokines including GRO, GRO (MIP-2), and GRO (MIP-2) in monocytes, fibroblasts, endothelial cells, and mammary epithelial cells through NF-B sites in their promoters (20) . There is, however, a growth-related serum-response pathway, not involving NF-B, that preferentially stimulates GRO expression (21) . ENA-78, one of the neutrophil attractant chemokines, is produced and secreted by epithelial cells in response to IL-1 or TNF-, along with IL-8, GRO, and GRO (3, 22, 23) .

IP-10 is one of the few -chemokines that is not active on neutrophils but is a chemoattractant for monocytes and T cells and promotes T cell-dependent antitumor activity. IP-10 was originally identified as an IFN--inducible protein of 10 kDa from the human U937 monocytic leukemia cell line (24) . IFN- induces IP-10 expression through an ISRE element present in the region flanking the transcription start site (25) . IL-4 can inhibit IFN- induction by activation of a negative regulator that competes for the ISRE site (26). LPS also stimulates IP-10 expression via the ISRE through the intermediate expression of endogenous IFN-/- and through two NF-B sites (27) . Similar to the IL-8 gene, optimal expression of IP-10 by either IFN- or LPS requires cooperation between at least two of these sites.


-Chemokines (C-C Chemokines)

MCP-1/MCAF was originally purified from human PBMC supernatants (2, 3). MCP-1/MCAF is induced by a number of irritants and endogenous stimuli in multiple non-lymphocytic cell types including endothelial cells, epithelial cells, fibroblasts, smooth muscle cells, and hematopoietic cells such as macrophages and mast cells (2, 3) . The -chemokines RANTES, MIP-1, MIP-1, and I-309 are largely produced by stimulated T lymphocytes. More recently, RANTES has been isolated from platelets and endothelial cells. -Chemokines also undergo similar proteolytic processing as many of the -chemokines to mature forms (2, 3) . In addition to chemoattracting and activating monocytes and T lymphocytes, eosinophils are also important targets for RANTES, MIP-1, and MCP-3 (3) . Several of the C-C chemokines, including MCP-1, MCP-2, MCP-3, RANTES, and MIP-1, induce histamine release and chemotaxis of basophils (28) . Furthermore, MCP-1 and RANTES also attract resting mast cells.() MIP-1 suppresses the replication of hematopoietic stem cells (3) . Interestingly, RANTES has overlapping activity with many of the other -chemokines, and it competes with MIP-1 and MCP-1 for the same receptors on monocytes.

-Chemokines show the usual pattern of cytokine responses with increases in mRNA on cell activation, whereas constitutive expression is seen only in transformed cell lines. Nevertheless, RANTES was shown to be constitutively produced by unstimulated T cells, and its mRNA and protein expression may be increased following T cell activation. The regulation of RANTES expression is therefore unique and suggests a distinct physiological role for RANTES.

Even less is known about the regulation of C-C chemokine gene expression than for IL-8. Potential binding sites for NF-B, NF-IL-6, AP-1, and AP-2 have been identified in the 5`-flanking region of the mouse MCP-1 (JE) gene (30) . NF-IL-6 (C/EPB), NF-B, and c-Ets sites have been identified in the promoter for MIP-1 (31) , and it was shown that LPS and IFN- rapidly up-regulate MIP-1 mRNA in macrophages. Much remains to be discovered about the activation elements regulating C-C chemokine expression.


Receptors for Chemokines and Other Chemoattractants (CCRs)

The receptors for chemokines and other chemoattractants (CCRs: Chemokine and Chemoattractant Receptors) belong to the serpentine superfamily of G protein-coupled receptors (GPRs) (1, 32, 33, 34) . Many similarities exist between CCRs and other members of the GPR family, yet CCRs initiate unique and specific cellular activities. A number of receptor cDNAs (from various species) have been cloned and functionally expressed, including those for IL-8 (designated IL-8RA and IL-8RB), MIP-1/RANTES, MCP-1, fMLP, C5a, PAF, and an ubiquitous chemokine receptor on red blood cells, known as Duffy antigen (1, 32, 34, 35) . The Duffy antigen was not yet shown to transduce signals and is thought to promote clearance of chemokines from the circulation (1, 32) . The genomic localization and organization of some of the genes for these receptors as well as of inactive isoforms and a pseudogene have also been established (1, 3, 34) . The CCRs are expressed on a number of responding cell types, and their expression is also regulated by exogenous and endogenous stimuli. For example, the transcription of IL-8RB gene in human T lymphocytes decreases with in vitro incubation at 37 °C and is restored by incubating T cells in the presence of monocytes (36) . Studies of the regulation of neutrophil expression of CCRs show that a 30-min incubation of neutrophils with granulocyte-macrophage colony-stimulating factor down-regulates the expression of IL-8R and C5a receptor (C5aR) and up-regulates fMLP receptor (fMLPR) expression (37) . In addition, in vitro incubation of neutrophils with granulocyte colony-stimulating factor enhances, whereas LPS inhibits, the expression of IL-8R mRNA, IL-8 binding, and chemotactic responses by neutrophils.() In contrast, LPS up-regulates the expression of neutrophil fMLP receptors by increasing gene transcription.()


Structure-Function Relationships in CCRs

Hydropathy analysis of CCRs shows that CCRs contain seven hydrophobic putative transmembrane domains, separated by three intracellular and three extracellular loops. They all have an intracellular carboxyl terminus and an extracellular amino terminus (1, 33, 34) . Many CCRs share both sequence and structural similarities. Several recently published reviews discuss the characteristic structure-function relationships of CCRs. These include: domains involved in ligand binding, models for the ligand-binding site(s), and the potential role of cysteine residues and N`-glycosylation sites (1, 33, 34) . Studies on IL-8RA and receptors for fMLP and C5a suggest that both the amino terminus of CCRs and their extracellular loops are involved, although to a different extent and in a different manner, in the ligand-receptor interaction (1, 34, 38) . Studies on IL-8RA and IL-8RB show that although both receptors bind IL-8 with similar affinities, the ligand-receptor interaction to each of the receptors is mediated through different regions of IL-8. The ELR motif and a sequence from amino acids 7 to 50 are important for IL-8 binding to IL-8RA, whereas the ELR motif and the carboxyl terminus of IL-8 (amino acids 52-72) are important for binding to IL-8RB (39) .

The intracellular domains of CCRs that are involved in G protein coupling consist of two regions in the case of the human fMLPR, localized at the second intracellular loop and at a domain of the carboxyl terminus that is proximal to the plasma membrane (40) . Studies from our laboratory have identified the membrane proximal domain of the carboxyl terminus of IL-8RB to be involved in IL-8 signal transduction (41). Another motif that may be important for signal transduction in CCRs is the DRY (Asp-Arg-Tyr) sequence located in the second intracellular loop. This motif was shown to be highly conserved in many CCRs and in other GPRs and was implicated in signaling (1, 32, 34) .


Desensitization of CCRs

The cellular responses to chemokines are strictly regulated, mainly by a desensitization process that is characteristic of GPRs (33, 34) . Desensitization can be referred to as either ``homologous'' or ``heterologous.'' Homologous desensitization occurs characteristically at high concentrations of ligand, is relatively transient, and results in diminished responsiveness specific for the original desensitizing agent. Heterologous desensitization is a reversible loss of responsiveness to multiple ligands. In many GPRs homologous desensitization is the outcome of the activity of G protein-coupled receptor kinases, resulting in uncoupling of the G protein from the receptor. Heterologous desensitization involves phosphorylation by protein kinase A and protein kinase C (PKC) and results in uncoupling of the ligand-specific receptor and other receptors from the G proteins (34, 42) . Desensitization that results from uncoupling of the receptor from the G proteins is usually mediated by phosphorylation of sites located on the third cytoplasmic loop and/or the carboxyl terminus of GPRs (34, 42) . A recent report shows that during homologous desensitization fMLPR and C5aR are phosphorylated and that a PKC-mediated mechanism is involved in heterologously desensitizing the C5aR (43) . Additional evidence for phosphorylation-mediated desensitization in CCRs comes from recent data showing that the carboxyl terminus of PAF receptor is required for signal attenuation, induced by PAF through phosphate accepters (44) .


Signal Transduction by CCRs

As implied by the name of the receptor family, the activation of the receptors by specific ligands results in coupling to G proteins, followed by a cascade of events that leads to specific cellular responses. The G proteins consist of a large gene family coding for at least sixteen , four , and multiple subunits (45) . Most of the reactions induced by CCRs are pertussis toxin (PT)-sensitive, but some activities were shown to be PT-resistant. Recent studies with transfected cells identified the G involved in signaling by CCRs. These studies showed that G and G mediated the PT-sensitive activities of IL-8, fMLP, and C5a (46, 47) . The PT-resistant effects of C5a were mediated by G (48, 49), whereas those of IL-8 were induced by the activation of both G and G(46) . PAF-induced PT-resistant activities were proposed to be mediated by G and/or G(48) .

The best characterized signal transduction pathway of G protein-coupled receptors starts with ligand binding, followed by activation of a heterotrimeric G protein. An exchange occurs in the subunit of the G protein from a GDP- to a GTP-bound state, resulting in a dissociation of the subunit from the subunits. The free subunit can activate both phospholipase C (PLC) 1 and PLC2, whereas the free complex activates preferentially PLC2. The activation of PLCs results in hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP) to generate two second messengers: inositol 1,4,5-trisphosphate (IP) and diacylglycerol (DG). IP mobilizes Ca from intracellular stores leading to a transient rise in [Ca], whereas DG stimulates PKC (1, 33, 34, 45) . Thereafter, a variety of effectors are phosphorylated and activated, giving rise to diverse cellular responses. Moreover, activation of PKC and elevation in cytosolic Ca can thereafter induce PLC and phospholipase D (PLD) to yield DG and phosphatidic acid, respectively, resulting in a positive feedback loop (50) . However, two additional second messengers, inositol 1,3,4,5-tetraphosphate and phosphatidylinositol 3,4,5-trisphosphate, also were recently reported to have an important role in signaling by GPRs and CCRs (51, 52) .

In general, PLC activation as well as stimulation of various second messengers and inositol phosphates participate in the response to chemokines and other chemoattractants, mainly IL-8, fMLP, C5a, PAF, and LTB(1, 46, 48, 51, 52, 53, 54, 55, 56) . The only receptor whose signaling mechanism seems to deviate from the general scheme is MCP-1R; MCP-1 stimulation of human monocytes does not result in PIP turnover and production of IP(57) . A ligand-stimulated increase in [Ca]was obtained in native cells with most of the chemokines and with other chemoattractants (1, 49, 52, 55, 56, 57, 58, 59, 60, 61) . Unlike many of the other ligands, the MCP-1- and MCP-3-induced rise in [Ca]depends on external Ca(57, 58) . MCP-2 is an exception since it does not induce an increase in [Ca]when assayed at chemotactic concentrations (58) .

PLD activation was also shown to be induced by IL-8, fMLP, C5a, PAF, and LTB(62) . PLD activation resembles PLC activation in terms of PT sensitivity. Yet, studies on fMLP-induced activation of both PLC and PLD suggest that the two pathways are mediated by distinct G proteins (63) . Activation of PKC and a number of additional serine/threonine kinases was demonstrated in response to IL-8, fMLP, MCP-1, MCP-2, and MCP-3 (58, 64, 65) . Tyrosine phosphorylation was also shown to be induced by almost all of the chemokines and chemoattractants (58, 66, 67) . The substrates of the tyrosine phosphorylation may belong to another pathway known as the MAP kinase cascade. The MAP kinase cascade involves a series of enzymes with phosphorylating activities (68) . The involvement of this signaling pathway in the action of IL-8, fMLP, C5a, PAF, and LTB has recently been implicated (64, 69, 70) . Buhl et al.(71) have proposed a model for the C5aR-induced signal transduction network in human polymorphonuclear leukocytes, proceeding from PLC through PKC to stimulation of the MAP kinase pathway.


Signaling Pathways in CCR-mediated Effects

There are indications that the different cellular activities, such as chemotaxis, degranulation, and respiratory burst, are mediated by distinct pathways of signaling. Although there is evidence that chemotaxis results from PLC activation and release of [Ca](1, 61) , other reports indicate that PKC activation or an increase in intracellular Ca is not always essential for a migratory response or for actin polymerization (58, 59, 72). Studies in polymorphonuclear leukocytes also indicate that PKC is probably not the major mediator of degranulation and of oxidative burst (73, 74) .

Recent information with regard to second messengers involved in superoxide production and the respiratory burst suggests that a respiratory burst with subsequent generation of superoxide anion by NADPH oxidase does involve formation of IP and DG but can be either Ca-dependent or Ca-independent (73, 75, 76) . Tyrosine phosphorylation as well as DG/PLD interaction were shown to be involved in superoxide anion production and in the assembly or activation of NADPH oxidase, respectively (66, 75, 77) . It is important to note that PLD activation by IL-8 and fMLP occurs in the concentration range needed for activation of respiratory burst, rather than the 10-100-fold lower concentrations that trigger chemotaxis (62) .

Consequently, the activity of chemokines and other chemoattractants is the outcome of a complex cascade that depends on the cell type, the ligand, the structure and configuration of the receptor, the G proteins involved, and the different enzymes that are available to be activated in a given cell type.


The in Vivo Role of CCRs in Inflammation

Many of the chemokines have been detected in multiple disease states that have an inflammatory component (3, 34) , and antibodies that neutralize IL-8 have been shown to reduce the self-destructive inflammation seen in reperfusion injury, acute glomerulonephritis, and arthritis (29) . Other evidence for the role of CCRs in inflammation arises from the generation of ``knockout'' mice lacking the murine IL-8 receptor homologue. In these mice neutrophils exhibited a markedly reduced capacity to migrate in response to thioglycolate in vivo and to human IL-8 and murine MIP-2 in vitro, indicating that this receptor is a major mediator of neutrophil migration. In addition, these mice developed bone marrow hyperplasia, lymphadenopathy, and splenomegaly based on excessive myelopoiesis and plasmacytopoiesis (8) . These findings suggest that this receptor normally participates in down-regulating the development of neutrophils and B cells.


Prospects and Unresolved Issues

There are a number of general principles and concepts concerning chemokines that highlight their pivotal roles, which for the sake of brevity can only be alluded to as ``appetizers'' in this minireview. 1) Chemokines have direct chemotactic effects as well as indirect activities. Generally, their indirect action does not result from induction of other cytokines but rather from the induction of other effector molecules (such as histamine, oxygen intermediates, or the release of defensins, CAP-37, and enzymes) (3) .2) Although chemokines have been proposed to contribute to the homing and migration of cells in development, this hypothesis needs more data in order to be evaluated. 3) Chemokines generally appear to promote cell functions and differentiation rather than cell growth (3) . 4) The observation that the deletion of the murine IL-8 receptor homologue results in a phenotype with excessive myelopoiesis suggests that chemokines may also be negative regulators of hematopoiesis (8) . 5) There are reports that chemokines may be important positive (e.g. IL-8) and negative (e.g. PF4) regulators of angiogenesis (3). 6) Chemokines modulate leukocyte adhesion and enhance the binding capacity of leukocytes (3) . 7) The angiogenic activities of chemokines and their ability to induce adhesion proteins suggest that they may have a role in tumor growth and metastatic spread. The expression of chemokines by tumor cells (3) also suggests that chemokines may have a role in anti-tumor defenses. 8) The extensive redundancy in the activities of chemokines remains a mystery to be clarified. Obviously, further elucidation of their ligand-receptor interactions and signal transduction processes is needed to generate antagonists and inhibitors with therapeutic promise.


FOOTNOTES

*
This minireview will be reprinted in the 1995 Minireview Compendium, which will be available in December, 1995.

The abbreviations used are: fMLP, formyl-Met-Leu-Phe; C5a, complement component C5a; C5aR, C5a receptor; CCR, chemokine and chemoattractant receptor; DG, diacylglycerol; fMLPR, formyl-Met-Leu-Phe receptor; GPR, G protein-coupled receptor; IL, interleukin; IL-8R, IL-8 receptor; IP, inositol 1,4,5-trisphosphate; LPS, lipopolysaccharide; LTB, leukotriene B; MAP, mitogen-activated protein; NF, nuclear factor; PAF, platelet-activating factor; PKC, protein kinase C; PLC, phospholipase C; PLD, phospholipase D; TNF-, tumor necrosis factor-; IFN, interferon; ISRE, interferon stimulus response element; PBMC, peripheral blood mononuclear cells; PIP, phosphatidylinositol 4,5-bisphosphate; PT, pertussis toxin.

D. F. Michiel, O. Chertov, L. Xu, J. Wang, A. Pereira, D. D. Taub, and J. J. Oppenheim, submitted for publication.

Taub, D., Dastych, J., Inamura, N., Upton, J., Kelvin, D., Metcalfe, D., and Oppenheim, J. (1995) J. Immunol., in press.

A. R. Lloyd, A. Biraygn, J. A. Johnston, D. D. Taub, D. Michiel, H. Sprenger, J. J. Oppenheim, and D. J. Kelvin, submitted for publication.

J. Johnston, A. Biragyn, A. R. Lloyd, H. Sprenger, J. J. Oppenheim, and D. Kelvin, unpublished observation.


ACKNOWLEDGEMENTS

-We thank Dr. E. Leonard, Dr. P. Murphy, Dr. D. Taub, and Dr. D. Longo for critically reviewing the manuscript. The secretarial assistance of R. Unger is gratefully acknowledged.


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