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Originally published online as doi:10.1189/jlb.0107051 on April 24, 2007

Published online before print April 24, 2007
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(Journal of Leukocyte Biology. 2007;82:16-32.)
© 2007 by Society for Leukocyte Biology

G-protein-coupled receptor expression, function, and signaling in macrophages

Jane Lattin*, David A. Zidar{dagger}, Kate Schroder*, Stuart Kellie*,{ddagger}, David A. Hume*,§ and Matthew J. Sweet*,{ddagger},1

* Cooperative Research Centre for Chronic Inflammatory Diseases and
§ Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, and
{ddagger} School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia; and
{dagger} Division of Cardiology, Duke University Medical Center, Durham, North Carolina, USA

1 Correspondence: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia. E-mail: m.sweet{at}imb.uq.edu.au


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ABSTRACT
 
G-protein-coupled receptors (GPCRs) are widely targeted in drug discovery. As macrophages are key cellular mediators of acute and chronic inflammation, we review here the role of GPCRs in regulating macrophage function, with a focus on contribution to disease pathology and potential therapeutic applications. Within this analysis, we highlight novel GPCRs with a macrophage-restricted expression profile, which provide avenues for further exploration. We also review an emerging literature, which documents novel roles for GPCR signaling components in GPCR-independent signaling in macrophages. In particular, we examine the crosstalk between GPCR and TLR signaling pathways and highlight GPCR signaling molecules which are likely to have uncharacterized functions in this cell lineage.

Key Words: ß-arrestin • heterotrimeric • immune • Toll-like receptor • kinase • inflammation


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INTRODUCTION
 
G-protein-coupled receptor (GPCR) classification
The seven-transmembrane domain GPCRs constitute the largest known superfamily of cell-surface receptors. They control a variety of cellular and physiological processes, such as perception of light, pain, taste and smell, neurotransmission, digestion, and cardiovascular regulation. GPCRs are also important regulators of innate and acquired immunity. The human genome encodes ~1000 distinct GPCRs, which are classified into three main families and numerous subfamilies on the basis of sequence similarity.

The rhodopsin-like family (or Family A) is by far the largest of these families and consists of rhodopsin, adenosine, melanocortin, neuropeptide, olfactory, chemokine, and melatonin receptors, amongst others. The secretin-like family (or Family B) consists of ~25 members, including the receptors for the gastrointestinal peptide hormone family (secretin, glucagon, vasoactive intestinal peptide, and growth hormone-releasing hormone), calcitonin, and parathyroid hormone, as well as corticotrophin-releasing hormone receptors. The metabotropic receptor family (or Family C) is the smallest family and consists of the GABAB receptor, the calcium-sensing receptor, and some taste receptors [1 2 3 ]. Recently, Metpally and Sowdhamini [4 ] used phylogenetic clustering across species as an alternative approach to classify GPCRs. This study identified eight major groups of GPCRs in humans: peptide receptors, chemokine receptors, nucleotide and lipid receptors, biogenic amine receptors, secretin receptors, glutamate receptors, cell adhesion receptors, and frizzled receptors. These were divided further into a total of 32 clusters. Despite this apparent diversity, all GPCRs mediate their effects, at least in part, through coupling to heterotrimeric G-proteins upon agonist-induced activation of the receptor.

Overview of GPCR signaling
Figure 1 outlines the central role of heterotrimeric G-proteins in GPCR signaling. In the absence of agonist, the ß{gamma}-subunit associates with the GDP-bound {alpha}-subunit. Agonist occupation of GPCRs stimulates the release of the {alpha}-subunit from the ß{gamma}-subunit, and the free subunits then positively or negatively regulate effector enzymes, such as ion channels, adenylyl cyclases, and PLs. The regulation of these second messengers modulates levels of intracellular mediators, such as cAMP, intracellular calcium, phosphoinositides, and DAG, which in turn activate or inhibit effectors such as PKA, PKC, and PI-3K, ultimately leading to a biological response (Fig. 1 , Steps 1 and 2) [5 6 7 ]. An array of different {alpha}-, ß-, and {gamma}-subunits has diverse effects on effector systems and thus enables the activation of distinct signaling pathways and biological responses. This process is not reviewed in detail here, and instead, the reader is referred to extensive reviews about the roles of different heterotrimeric G-protein complexes in GPCR signaling [3 , 8 ].


Figure 1
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  		Figure 1. GPCR signaling. 1. Agonist occupation of GPCRs stimulates a change in conformation of the receptor, which couples the receptor to the G-protein and promotes the exchange of GDP for GTP on the {alpha}-subunit. 2. The GTP-bound {alpha}-subunit dissociates from the ß{gamma}-subunit; the free subunits then regulate effector enzymes positively or negatively, ultimately leading to a biological response. 3. G-protein signaling is terminated via receptor desensitization and internalization. Desensitization is initiated by phosphorylation of activated receptors within the third intracellular loop or carboxy-terminal tail by GPCR kinases (GRKs) and/or second messenger-dependent protein kinases. 4. This phosphorylation promotes translocation of the cytosolic arrestin proteins to the membrane, where they bind to the receptor and promote internalization. In the case of Class A receptors, ß-arrestins (ARRBs) dissociate from the receptor prior to internalization, and they remain associated with Class B receptors throughout receptor internalization. 5. Internalized receptors may promote a second round of signaling through the ability of ARRBs to act as scaffolds in the assembly of signaling complexes. 6. The receptor is then recycled to the membrane to undergo further rounds of signaling or is targeted for degradation. Examples of GPCRs or components of the GPCR signaling machinery which are highly expressed or regulated in macrophages are highlighted in red boxes (refs. [27 , 29 , 39 40 41 , 85 , 88 , 170 171 172 , 185 , 221 , 222 ]; J. Lattin and M. J. Sweet, unpublished data; http://symatlas.gnf.org/SymAtlas/). ET-A/B, Endothelin-A/B; EMR1, epidermal growth factor (EGF) module-containing mucin-like hormone receptor; FPR, formyl peptide receptor; PLC-ß, phospholipase C-ß; ASK, apoptosis signal-regulating kinase 1; MKK4, MAPK kinase 4; MEK, MKK; DAG, diacylglycerol; PKC, protein kinase C; RhoGEFs, Rho guanine nucleotide exchange factors..

Upon agonist activation of receptors, a rapid attenuation of receptor responsiveness occurs through feedback mechanisms, which prevent acute and chronic overstimulation of the receptor (Fig. 1) . This process of desensitization is controlled by three families of regulatory molecules: second messenger-dependent protein kinases, GRKs, and arrestins [9 10 11 ]. Apart from receptor desensitization and internalization, these families also regulate GPCR trafficking, receptor recycling, and downstream signaling.

Desensitization is initiated by phosphorylation of activated GPCRs within the third intracellular loop or the carboxyl-terminal tail by GRKs and/or second messenger-dependent protein kinases [12 13 14 ]. This phosphorylation promotes translocation of the cytosolic adaptor arrestin proteins to the membrane, where they bind to the receptor and promote internalization through interaction with ß2-adaptin and clathrin components of the endocytic machinery [15 16 17 ]. As receptor-containing endosomes mature, the decreasing pH results in dissociation of the ligand from its receptor and receptor dephosphorylation. The receptor is then recycled to the membrane to undergo further rounds of signaling (resensitization) or is targeted for degradation to further down-regulate signaling (Fig. 1) . GPCRs can be divided into two classes, Class A or B, according to their affinity for the ß-arrestin (ARRB). Class A receptors bind ARRB2 with much higher affinity than ARRB1, and Class B receptors bind both ARRBs with equal affinities. The classes are distinguished further on the basis of their association with ARRB during receptor internalization; ARRBs dissociate from Class A receptors prior to internalization, and ARRBs remain associated with Class B receptors throughout receptor internalization (Fig. 1) . Class A receptors recycle rapidly, returning to the cell surface within ~30 min of initial stimulation, and Class B receptors remain ARRB- and endosome-associated 1 h after activation [18 , 19 ]. The process of receptor desensitization and resensitization is reviewed extensively elsewhere [20 , 21 ].


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GPCR FUNCTION IN MACROPHAGES
 
Macrophages are important cellular mediators of acute and chronic inflammation. Host cytokines such as IFN-{gamma} and bacterial products, such as the TLR4 agonist LPS, elicit the production of proinflammatory mediators from macrophages. Regulation of macrophage function by TLR agonists has been a central focus of research in innate immunity over the last 10 years and has been reviewed extensively [22 , 23 ]. It is important to note that host- and pathogen-derived GPCR agonists also regulate the inflammatory response through modulating macrophage chemotaxis, survival, and activation (for the purposes of this review, we define macrophage activation as an inducible change in function, for example, an altered production of inflammatory mediators). The chemokine receptors, which comprise a large branch of the rhodopsin-like family, modulate the numbers of cells in inflammatory sites by leukocyte adhesion and migration. In many cases, they also control the activation state of the recruited cells. Consequently, this family has been reviewed extensively [24 25 26 ]. For this reason, we will focus on other GPCRs that are less well-studied in macrophage biology or were not included in recent reviews, and consider their function in inflammation. Figure 2 provides an overview of some of the major functions of GPCRs in macrophages.


Figure 2
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  		Figure 2. Overview of GPCR function in macrophages. GPCRs regulate diverse macrophage functions including cell-cell contact, survival, chemotaxis and activation (e.g., inflammatory mediator production).

Peptide receptors
The complement receptor C5aR
The complement component C5a acts as a potent neutrophil and monocyte chemoattractant via the GPCR C5aR/CD88 [27 ]. It also up-regulates the expression of other complement receptors such as CR1 and CR3 on leukocytes, thus enhancing phagocytic capacity and the respiratory burst [28 ]. Further, C5a triggered the production of superoxide anion and PGE2 from resident and elicited mouse peritoneal macrophages [29 ], as well as TNF and IL-1 from human and mouse macrophage populations [30 , 31 ]. It is not surprising that given such pleiotropic, proinflammatory effects, the C5aR is an essential mediator of inflammation and disease progression in the collagen-induced arthritis (CIA) model [32 ]. In CIA in mice, C5aR ablation prevented the recruitment of neutrophils, T cells, and macrophages to joints, decreased the levels of inflammatory mediators (such as IL-1ß and TNF) and chemoattractants (including MIP-1{alpha}, MIP-2{alpha}, and epithelial-derived neutrophil-activating factor-78), and reduced joint inflammation, bone erosion, and paw swelling [32 ]. Similarly, systematic administration of anti-C5a mAb prevented disease onset and ameliorated established disease in the same mouse disease model [33 ]. C5a has also been implicated as a major mediator of human inflammatory diseases, including sepsis, acute lung injury, and asthma/allergy [34 ]. For example, sepsis triggers complement activation, leading to elevated levels of complement products, including C5a, in humans and in animal models [35 , 36 ]. In support of a central role for C5a in sepsis pathology, blockade of C5a action in experimental sepsis has proven beneficial. Administration of a rabbit anti-human C5a antibody increased the survival rate in a primate model of sepsis [37 ]. Similarly, anti-C5a treatment in a rat model of sepsis ameliorated the progression of multiple organ failure, which is associated with high mortality rate [38 ].

The FPR family
The FPR1, as well as the related family members FPR-like (FPRL)1 and -2, are expressed in a regulated manner in macrophages at mRNA and protein level [39 40 41 42 ]. FPR1 triggers cellular locomotion upon recognition of N-formylated methionine from bacterial proteins. The classic FPR1 agonist, fMLP, has a much higher affinity for FPR1 than FPRL1, and ectopic expression studies suggest that FPRL2 does not recognize this ligand [43 44 45 ]. However, an endogenous peptide ligand for FPRL2 was identified recently [46 ], and it is now clear that FPR1 and FPRL1 can also detect nonformylated bacterial proteins [47 ], as well as endogenous ligands such as annexin 1 [48 ], serum amyloid A [49 ], and amyloid ß-peptide of 42 residues [50 ]. Given the elevated production of such endogenous ligands in chronic inflammatory and neurodegenerative diseases, targeting of the FPR family may reduce leukocyte recruitment and inflammation in such settings [43 ]. FPRs also regulate the process of macrophage activation; fMLP induced the expression of inducible NO synthetase (iNOS) and production of NO in mouse peritoneal macrophages [51 ] and the secretion of IL-1{alpha}, IL-1ß, and IL-6 in human PBMC [52 ]. The importance of FPR in antimicrobial responses is highlighted by the increased susceptibility of FPR-deficient mice to Listeria monocytogenes [53 ].

Whilst FPR antagonists may have applications as anti-inflammatory agents, agonists of the FPR family may have unexpected applications in the HIV field. The chemokine receptors, CXCR4 and CCR5, are coreceptors used by macrophage-tropic HIV strains to gain cellular entry [54 , 55 ]. Individuals who are homozygous for a 32-bp deletion in the CCR5 gene lack functional surface CCR5 yet have a normal phenotype and are relatively resistant to HIV-1 infection, thus highlighting the importance of this receptor in HIV pathogenesis [56 , 57 ]. Activation of FPR or FPRL1 by fMLP in human monocytes/macrophages rapidly induced serine phosphorylation and heterologous desensitization of CCR5 and CXCR4 [58 , 59 ]. Further, fMLP reduced the fusion and infection of particular strains of HIV-1 in macrophages by compromising the ability of CCR5 and CXCR4 to act as HIV-1 coreceptors [59 ]; therefore FPR agonists could be explored in the future as an approach to target HIV spread.

The protease-activated receptor (PAR) family
The PARs are a family of GPCRs that are activated upon proteolytic cleavage of their amino terminal exodomain. This unmasks a new amino terminal which acts as a tethered ligand to activate the receptor. Differentiation of human monocytes was associated with differential expression of functionally active PARs, particularly PAR-1 and PAR-2, which mediate distinct regulatory functions in inflammation [60 ]. In human monocytes, PAR-1 was the most abundantly expressed PAR, whilst PAR-3 was expressed weakly. In vitro differentiation of human monocytes to macrophages by treatment with GM-CSF or CSF-1 coincided with a marked increase in the expression of PAR-1, -2, and -3 at the mRNA and protein level [60 ]. Thrombin-induced activation of PAR-1 and -2 in human peripheral monocytes or macrophages induced the release of the proinflammatory mediators MCP-1 (CCL2) and IL-6 [60 ], while stimulation of PAR-2 by PAR-2 receptor-activating peptides in human peripheral blood monocytes increased the production of IL-1ß, IL-6, and IL-8 [61 ]. Several studies implicate PARs as regulators of inflammatory disease. PAR-1 is abundant in the synovial lining of rheumatoid arthritis (RA) and osteoarthritis patients and is highly expressed in regions rich in macrophages and smooth muscle cells such as atherosclerotic lesions [62 , 63 ]. PAR-1 null mice exhibited decreased secretion of the proinflammatory mediators IL-1, IL-6, and matrix metalloproteinase (MMP)-13, as well as reduced disease severity in a mouse arthritis model [64 ], while PAR-2 null mice showed diminished contact hypersensitivity responses and were completely resistant to adjuvant-induced arthritis [65 , 66 ].

Neuropeptide receptors
Rodent and human macrophages express the neurokinin-1 receptor (NK-1R or TACR1), which signals in response to neuropeptide substance P (SP) [67 , 68 ]. SP is distributed widely within the central and peripheral nervous systems, where it regulates neuronal cell survival and neurotransmission [69 ]. It also mediates proinflammatory effects on a number of inflammatory cells, including macrophages. SP induced the protein expression of IL-1, TNF, and IL-6 in human blood monocytes and human monocyte-derived macrophages [70 , 71 ] and increased production of reactive oxygen species and PGD2 secretion from guinea pig alveolar macrophages [72 ]. Expression of NK-1R and SP protein was induced in rat and human macrophages in response to LPS [67 , 68 , 73 ], suggesting the existence of an autocrine pathway.

As with SP, neuropeptide Y (NPY) also performs immunomodulatory functions. In the peripheral nervous system, NPY is concentrated in the sympathetic division, is released from sympathetic nerve endings and is thought to provide an avenue for neuroimmune crosstalk [74 ]. Secondary lymphoid tissues such as the spleen are richly innervated by sympathetic nerves which contain NPY [75 ] and there is physical evidence of synapses between the nerve endings and leukocytes [74 , 76 ]. Expression of functional NPY receptors on cells of the immune system, including macrophages, has been confirmed [77 , 78 ] and NPY modulated several effector functions of the macrophages [77 , 79 , 80 ]. For example, De la Fuente et al. [77 ] demonstrated that NPY stimulated adherence to substrate, chemotaxis, ingestion of latex beads and production of superoxide anion in murine peritoneal macrophages.

Endothelial (ET) receptors
ET-1, the predominant isoform of the ET peptide family that includes ET-1–4, regulates cell function through the GPCRs, ET receptor subtype A (ETAR) and ETBR. ET-1 is produced predominantly by endothelial cells in the cardiovascular system and is a powerful vasoconstrictor and stimulator of smooth muscle cell proliferation [81 , 82 ]. In addition, ET-1 modulates immune cell function during inflammatory responses [83 , 84 ]. In vitro stimulation of murine peritoneal macrophages with ET-1 induced cyclooxygenase 2 (COX-2) mRNA expression and PGE2 production [85 ]. ET-1 can also induce the secretion of proinflammatory cytokines by macrophages. For example, ET-1 treatment of the macrophage cell line J774.2 increased TNF secretion via the ETAR [86 ]. In human monocytes, ET-1 triggered TNF production, as well as other cytokines, including IL-8, GM-CSF, IL-1ß, and IL-6 [87 ]. ET-1 can also influence the production of superoxides by macrophages; ET-1 primed O2– production from rabbit alveolar macrophages [88 ]. Finally, ET-1, as well as ET-2, elicited MMP-2 and -9 production from human monocyte-derived macrophages when cocultured with breast cancer cells [89 ]. Given the elevated expression of ET-1 and the ET receptors in high grade, aggressive metastatic breast cancer [89 90 91 ], tumor-associated macrophages may promote tumor spread via this pathway.

Not only does ET-1 regulate macrophage function, but it is also secreted by this cell type; murine bone marrow-derived macrophages produced ET-1 upon challenge with gram-negative and gram-positive bacteria [92 ] and LPS [93 ]. Clinical observations in humans and animal models of inflammation suggest that macrophages are an important source of ET-1 during infection and inflammation [92 , 94 95 96 97 98 ]. Peripheral blood monocytes from septic patients expressed significantly higher levels of ET-1 mRNA in comparison with healthy subjects [94 ]. In addition, Kupffer cells (macrophages residing in the liver) released ET-1 in experimental models of endotoxemia [95 ]. These studies form part of a growing body of literature which suggest an involvement of macrophage-derived ET-1 in inflammation. Indeed, the ET system has been pursued as a target for the treatment of inflammatory cardiovascular disease and chronic obstructive pulmonary disease [89 90 91 , 99 100 101 102 103 104 ].

Lipid receptors
The platelet-activating factor receptor (PAFR)
Several lipid GPCR agonists are regulators of monocyte/macrophage function. PAF, which is produced and secreted by platelets, neutrophils, eosinophils, monocytes, and macrophages [105 , 106 ], triggered chemotaxis of murine peritoneal macrophages in a dose-dependent manner [107 ]. Indeed, the PAF/PAFR system has been implicated as a mediator of monocyte recruitment during the onset of atherosclerosis [108 ]. In addition to regulating macrophage migration, the PAFR modulates macrophage activation. PAF antagonists inhibited LPS-regulated iNOS mRNA expression and NO production in murine macrophages and rat Kupffer cells, implying an involvement of autocrine PAF in LPS responses [109 110 111 ]. Furthermore, a PAF antagonist reduced the toxicity of systemic administration of endotoxin and/or live bacteria [112 113 114 ].

Although the PAF/PAFR system contributes to excessive host inflammatory responses, it is also critical for phagocytosis and effective pathogen clearance. PAFR-deficient mice had enhanced bacterial load in the lungs following pulmonary challenge with Klebsiella pneumoniae and succumbed more rapidly than wild-type mice [115 ]. This protective role may be pathogen-specific; the PAFR did not regulate bacterial loads or disease severity during infection with another lung pathogen, Mycobacterium tuberculosis [116 ]. Conversely, the PAFR is actually exploited by Streptococcus pneumoniae to enable cellular invasion [117 ]. Apart from infectious disease, the PAF/PAFR has been implicated in the pathology of several inflammatory diseases including thrombosis, allergic disorders, anaphylactic shock and acute lung injury, as well as metastatic disease [118 , 119 ].

The leukotriene B4 receptor (LTB4R)
LTB4, an arachidonic acid derivative, acts via the two GPCR LTB4Rs, LTB4R1 (BLT1) and LTB4R2 (BLT2) [120 , 121 ], to stimulate macrophage, neutrophil, eosinophil, and mast cell chemotaxis [122 , 123 ]. Mast cells are a major source of LTB4 [124 ], but it is also secreted by human alveolar macrophages [125 ] and murine peritoneal macrophages [126 ], suggesting the existence of an autocrine pathway in this lineage. The importance of LTB4-mediated cellular recruitment is highlighted by the failure of inflammatory cells to infiltrate into joints and initiate CIA in LTB4R–/– mice [127 ]. In addition, inhibitor studies have implicated LTB4R in monocyte recruitment and foam cell formation in a mouse model of atherosclerosis [128 ]. LTB4 also initiates antimicrobial responses during pathogenic challenge. As with the PAFR, LTB4 appeared to be a critical factor for the phagocytosis of K. pneumoniae by alveolar macrophages [129 , 130 ]. Indeed, PAF and LTB4 have many overlapping biological activities, which may be explained to some extent by the observation that in neutrophils at least, PAF action was mediated partly via autocrine LTB4 [131 ]. Exogenous LTB4 activated the NADPH oxidase system in alveolar macrophages [132 ], as well as NO and TNF production and parasite killing in Trypanosoma cruzi-infected murine macrophages [133 ], indicating that the LTB4R can activate multiple antimicrobial pathways.

The EP family
PGE2, a small lipid mediator that regulates diverse processes including platelet aggregation and immune function, is produced by fibroblasts, some malignant cells and macrophages [134 ]. In vivo administration of PGE2 results in an acute inflammatory response characterized by pain, edema, and leukocyte infiltration [135 ]. Indeed, PGE2 is a major mediator of pathology in inflammatory diseases such as RA and osteoarthritis [136 137 138 ], and COX-2, a key enzyme in the PGE2 biosynthetic pathway, has been targeted extensively in therapeutic applications in inflammatory diseases [139 ]. PGE2 can signal through four EPs, EP1– 4, all of which are GPCRs [140 , 141 ]. Targeted disruption of each of these EPs has demonstrated that PGE2 mediates distinct functions downstream of each receptor: neuronal functions via EP1; female reproduction, vascular hypertension, and tumorigenesis via EP2; fever, gastric mucosal protection, pain hypersensitivity, kidney function, and antiallergic response via EP3; and ductus arteriosus closure and inflammation-associated bone resorption via EP4 [142 143 144 145 146 147 148 149 ].

PGE2 is also implicated in the development and maintenance of Th2 responses. PGE2 generally suppresses inflammatory cytokine production from monocytes and macrophages [150 151 152 153 154 ]. In fact, the effects are selective; PGE2 inhibited the production of the Th1-promoting cytokine IL-12 but amplified IL-10 production from human and mouse macrophages respectively [154 , 155 ]. Similarly, Kuroda et al. [156 ] showed that pretreatment of murine splenocytes with PGE2 suppressed the protein expression of the Th1-associated chemokine IFN-inducible protein-10 and enhanced production of macrophage-derived chemokine/CCL22, a ligand for the Th2 cell-expressed chemokine receptor CCR4. Such effects, as well as direct action on T cells [157 158 159 160 ], result in a polarized Th2 response in many Th1/Th2-biased disease models.

The endothelial differentiation gene (EDG) family
Members of the EDG family are activated by the lipid mediators lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) which are primarily derived from activated immune cells, including platelets, monocytes/macrophages, neutrophils, eosinophils and mast cells during blood clotting and wound healing [161 162 163 ]. LPA stimulates wound healing by inducing endothelial cells to express adhesion molecules and produce cytokines which recruit macrophages to the site of the wound, thereby mediating the interaction of macrophages with endothelial cells [164 165 166 ]. However, human monocytes and macrophages also express several EDG receptors including EDG1, -2, -4, -5, and -8 [167 ], suggesting that LPA regulates macrophage function directly. Certainly, rat alveolar macrophages responded to LPA and S1P by producing O2– at levels comparable with those induced by LPS or fMLP [167 ]. LPA is also implicated in regulating macrophage survival. The PI-3K-Akt pathway is required for macrophage survival [168 ] and LPA activated the PI-3K pathway to provide a survival signal in murine peritoneal macrophages during serum deprivation [169 ].

The EGF family
The EGF family of GPCRs, which are thought to be involved in regulating cell-cell interactions, consists of six members in humans: EMR1–4, CD97 and EGF-TM7-latrophilin-related protein (ETL). Mice lack functional EMR2 and -3 genes. With the exception of ETL, which is expressed in smooth muscle, all of the family is expressed on hematopoietic cells. Further, EMR1–4 expression is restricted to the myeloid lineage. The founding member of the EGF-TM7 family, EMR1, originally named F4/80, is a definitive marker of murine macrophages and is expressed on a variety of macrophage subsets including liver Kupffer cells, resident bone marrow macrophages, thymic cortical macrophages, splenic red pulp macrophages, lymph node medullary macrophages, Langerhan cells, microglial cells and some CD8-negative myeloid dendritic cells (DC) [170 171 172 ]. A role for EMR1 in the adaptive immune response was demonstrated recently; Lin et al. [173 ] showed that EMR1 was essential for the development of functional, CD8-positive, antigen-specific regulatory T cells (Treg), which are necessary for tolerance. However, a ligand for EMR1 has not been identified and its exact role in regulating macrophage function remains poorly defined. In humans, EMR2 and CD97 were identified as receptors for cell surface chondroitin sulfate [174 ], suggesting that the ligand for EMR1 may be a proteoglycan. Given its role in the development of Treg, the EMR1 ligand may be expressed on this cell lineage.

EMR4, also known as F4/80-like receptor (FIRE), is most similar to EMR1 and is also expressed predominantly on tissue macrophages in the mouse [175 ]. Its protein expression is up-regulated during macrophage activation [175 ] but like EMR1, its function is unknown. EMR2 expression in humans is also restricted to myeloid cells including monocytes, macrophages, DC and granulocytes. CD97 is the closest family member to EMR2 shared by mice. However, unlike the restricted expression of EMR2, CD97 is expressed on a broad range on leukocytes [176 , 177 ]. EMR2 and CD97 are highly expressed on myeloid cells in the synovial tissue of RA patients where the ligands for these receptors, chondroitin sulfates and CD55 (decay-accelerating factor), are also present [178 ]. EMR2 and CD97 contribute to the recruitment and retention of macrophages to synovial tissue in RA [178 ]. EMR3 is expressed at the highest levels in neutrophils, monocytes and macrophages. Human monocyte-derived macrophages and activated human neutrophils bound EMR3 [179 ], suggesting the ligand regulates cell-cell interactions in the myeloid lineage. However, as with other members of the EMR family, little functional information is currently available.

Novel macrophage-specific GPCRs
Recent expression-profiling studies have enabled the identification of several tissue-specific genes. One example is the Genomic Institute of Novartis Research Foundation Symatlas dataset that characterized gene expression in a panel of human cell types including primary monocytes and other leukocyte populations (ref. [180 ]; http://symatlas.gnf.org/SymAtlas/). This dataset has revealed the existence of several macrophage-enriched, orphan GPCRs of unknown function. These include the purinergic receptors (P2RY)5 and -13 and GPCR 65. Across a panel of human cell types, P2RY5 and GPR 65 were expressed highly in several immune cell types including DC, CD4+ and CD8+ T cells, CD56+ NK cells, CD14+ monocytes and CD33+ myeloid cells. P2RY13 mRNA expression was strikingly restricted to macrophages being expressed only in whole blood and primary human CD14+ monocytes and CD33+ myeloid cells (http://symatlas.gnf.org/SymAtlas/). We have confirmed the macrophage-specific and/or regulated expression patterns of some of these GPCRs in the mouse. Figure 3A shows that P2RY6 mRNA expression was elevated in a panel of primary mouse macrophages and macrophage cell lines as compared with lymphoid and fibroblast cell lines. In the case of P2RY5, we confirmed that mRNA expression is induced during monocyte-to-macrophage differentiation in humans (J. Lattin and M. J. Sweet, unpublished data) and that expression was down-regulated dramatically by LPS in primary mouse macrophages (Fig. 3B) . The down-regulation in "classically activated macrophages" is consistent with a recent report that identified P2RY5 as a GPCR expressed by alternatively activated (M2) human macrophages [181 ]. Although ligands and functions for such GPCRs are unknown, future studies are likely to identify roles in inflammation and immunity.


Figure 3
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  		Figure 3. Expression analysis of P2RY5 and -6 in mouse macrophages. Quantitative real-time PCR analysis was used to assess the mRNA levels of (A) P2RY6 in a panel of murine cell types, including primary bone marrow-derived macrophages (BMM), macrophage cell lines (RAW264.7, WR19M), lymphoblast cell lines (EL4 and MOPC) and fibroblast cell lines (NIH3T3 and L929), and (B) P2RY5 in bone marrow-derived macrophages cultured in the presence of CSF-1 over a LPS time-course (0–21 h). Levels of mRNA are displayed as relative to the housekeeping gene hypoxanthine guanine phosphoribosyl transferase (HPRT; mean of triplicates+SD; representative of three independent experiments; A) or normalized to the untreated control across three independent experiments (mean+SEM; B).

Additional complexity of GPCR expression and function in macrophage biology
Many of the GPCRs described above have overlapping biological activities on macrophages. Despite the apparent redundancy/overlap in their biological effects on macrophages, gene knockout studies have generally demonstrated nonredundant roles for GPCRs in inflammation and immunity (e.g., C5aR [32 ], PAFR [115 ], EMR1 [173 ], EP2 and -4 [182 , 183 ], as well as the chemokine receptors not reviewed here). This is often the case even in the same model, for example, the commonly used CIA model in mice. Generally, such studies have assessed how a single GPCR agonist affects biological responses. However, tissue macrophages and recruited monocytes in an inflammatory setting are likely to encounter multiple agonists and in vitro studies using combinations of GPCR agonists would be more likely to reflect the in vivo environment. In vitro studies that assess combinatorial effects of GPCR agonists may identify synergistic, antagonistic, or truly redundant effects of GPCR ligands, which would not otherwise be apparent. The antagonistic effect of FPR and FPRL1 ligands on CCR5 and CXCR4 responses represents one example of such interplay [59 ]. Alternatively, the individual GPCRs might function in distinct stages of the inflammation process, effectively acting in a pathway that can be blocked at multiple levels.

An additional level of complexity is apparent at the level of gene regulation. Recent genome-wide analysis of transcription start sites using cap analysis of gene expression has demonstrated that alternative promoter use is applied extensively [184 ]. Indeed, several GPCRs including P2RY5, ETBR and EDG1, appear to use multiple promoters/transcription start sites, a phenomenon that is likely to impact on tissue-specific expression and function. Alternative splicing also occurs in some GPCR-encoded genes. For example, multiple alternatively spliced forms of EMR1 lack the transmembrane-spanning helices and presumably encode soluble, secreted dominant-negative forms of the receptor. Alternatively spliced forms of the related GPCRs, CD97 and EMR2, have variable numbers of EGF domains in the extracellular region. In the case of EMR2, only the full-length isoform was able to mediate cell-cell interactions through chondroitin sulfate [174 ]. Thus, regulation of alternative splicing is likely to impact on the function of several macrophage-expressed GPCRs.


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EXPRESSION AND FUNCTION OF GPCR SIGNALING COMPONENTS IN MACROPHAGES
 
Macrophage-enriched expression of GPCR signaling components
Given the diversity of GPCRs in macrophages, it is perhaps not surprising that GPCR signaling components are expressed at elevated levels in these cells. Aside from their function in signaling in response to the many GPCRs expressed by this lineage, an emerging literature is also documenting novel roles for these signaling components in GPCR-independent responses in macrophages. Here, we identify those GPCR signaling molecules that are highly expressed in macrophages and focus on their role in alternative pathways of cell activation, with particular emphasis on TLR signaling.

G-proteins
G-protein-mediated signal transduction is a functionally versatile system as a result of its modular architecture and the existence of numerous subtypes of G-proteins. The {alpha}-subunits are divided into four families (G{alpha}s, G{alpha}i/G{alpha}o, G{alpha}q/G{alpha}11 and G{alpha}12/G{alpha}13) and each family contains multiple subtypes. Unlike the {alpha}-subunits, the ß{gamma}-subunits are assembled from a relatively small repertoire: five ß-subunits and 12 {gamma}-subunits. Several G-proteins show restricted expression at the mRNA level; for example, G{alpha}O1, G{alpha}z, G{alpha}14, G{gamma}7, and G{gamma}13 are brain-specific while G{alpha}T1/2 and Gß3 are restricted to the visual system (http://symatlas.gnf.org/SymAtlas/).

Primary human and mouse macrophages express elevated levels of the pertussis toxin (PTx)-sensitive G{alpha}i2 and G{alpha}i3 subtypes (ref. [185 ]; http://symatlas.gnf.org/SymAtlas/). Several lines of evidence suggest that in macrophages, PTx-sensitive G-proteins regulate not only GPCR signaling, but also TLR signaling. Jakway and DeFranco [186 ] first showed that pretreatment of the macrophage cell line P388D1 with PTx reduced the production of IL-1 in response to LPS. PTx also impaired LPS responses in human monocytic U937 cells. Further, LPS stimulation caused G{alpha}i2 phosphorylation in these cells, implicating this G-protein as a player in LPS signaling [187 ]. In mouse peritoneal macrophages, PTx inhibited LPS-dependent NO production but amplified TNF protein production [188 ], although others reported no effect of this inhibitor on TNF secretion [189 ]. At the level of signaling, PTx reduced LPS-mediated activation of p38, ERK1/2 and AP-1, without affecting NF-{kappa}B activation [190 191 192 ]. Genetic approaches also support a role for PTx-sensitive G-proteins in TLR-mediated responses. For example, LPS-induced TNF, IL-10 and thrombaxane B2 protein production was reduced in peritoneal macrophages derived from mice lacking G{alpha}i2 or G{alpha}i1/3 [193 ]. Whether such effects are dependent on GPCRs is unknown, but at least one study has implicated the GPCR, CXCR4, as part of a CD14-independent LPS receptor complex [194 ]. While PTx-sensitive G-proteins can regulate GPCR and TLR signaling in macrophages, PTx-insensitive G-proteins appear to occupy a more conventional signaling role by coupling several chemotactic GPCRs [e.g., CXCR2, C5aR, C3aR, FPR and the IL-8 receptor (IL-8R)] to activation of NF-{kappa}B [195 196 197 198 ]. In many of these cases, G{alpha}15/16 was implicated as a specific player and a function for this PTx-insensitive G-protein in GPCR signaling in macrophages is supported by its elevated expression in primary human CD14+ monocytes and CD33+ myeloid cells (http://symatlas.gnf.org/SymAtlas/).

The ß-subunits Gß1 and Gß2L1 [also known as receptor for activated C kinase 1 (RACK-1)] are also expressed highly in primary mouse macrophages, primary human CD14+ monocytes and other leukocyte populations (http://symatlas.gnf.org/SymAtlas/), and evidence exists for roles in non-GPCR signaling. In human embryo kidney (HEK)293 cells, Gß1 interacted directly with histone deacetylase (HDAC)5 [199 ], a member of the HDAC family which regulates gene expression by modifying histone proteins and transcription factors post-translationally. HDACs have been reported to regulate LPS-induced proinflammatory gene expression in macrophages [93 ]; thus, Gß1 may impact on TLR signaling by regulating HDAC5 function. Gß2L1 also has roles beyond regulation of GPCR signaling; it mediated the recruitment of STAT1 and STAT3 to the IFN-{alpha}/ß and the tyrosine kinase insulin-like growth factor receptor 1 (IGFR-1) receptors, respectively [200 201 202 ].

Regulators of G-protein signaling (RGS)
The RGS control the rate of GTP hydrolysis on the G{alpha} subunit of heterotrimeric G-proteins. Along with GRKs and arrestins, they regulate the duration of signaling downstream of GPCRs. The RGS family is diverse, ranging in size from 17 kDa to 160 kDa and displaying widely variable and regulated expression patterns [203 ]. The family contains 30 members, all of which share a common RGS domain that is responsible for their GTPase-activating activity. Most RGS proteins have GTPase-activating activity specific for the G{alpha}i and G{alpha}q subfamilies of the {alpha}-subunits. Some RGS not only regulate G-protein signaling through controlling G{alpha} GTP hydrolysis but can also function essentially as effector antagonists through competitive inhibition of effector-G{alpha}-protein interactions [203 , 204 ].

Our own unpublished mouse microarray data, as well as human and mouse symatlas mRNA expression data (http://symatlas.gnf.org/SymAtlas/), indicate that RGS1, -2, -10, -18 and -19 are expressed in a macrophage-enriched manner or are strongly regulated by LPS. In addition, Hausmann et al. [205 ] showed that LPS and TNF increased RGS7 mRNA levels markedly in the macrophage-like cell line RAW264.7 [205 ]. RGS1, -2, -3, -4, and -13 regulate chemokine-mediated homing of B cells while RGS16 controls T cell migration [206 207 208 209 210 ]. A functional role for RGS1 in desensitizing several chemotactic receptors in human monocytes was also demonstrated [211 ]. However, it is somewhat surprising that almost nothing else is known of the function of this family in macrophage biology.

An obvious prediction is that other RGS family members also regulate macrophage migration, but there is also growing evidence to suggest RGS may perform GPCR-independent functions. First, several of the larger RGS proteins contain large N- and/or C-terminal regions which flank the RGS domain and have poorly defined functions [203 , 204 ]. In addition to its well-recognized role in activating the ERK and AKT pathways, the tyrosine kinase IGFR-1 signals via the heterotrimeric G-protein G{alpha}i2 [212 , 213 ]. RGS19 [also known as G{alpha}-interacting protein (GAIP) interacts specifically with the PDZ-containing protein, GAIP-interacting protein, C-terminus (GIPC) [214 ]. Interaction of the RGS19/GIPC heterodimer with the IGFR-1 consolidates IGF-1 signaling to MAPK activation [215 ]. RGS19 and GAIC can also form a complex with the nerve growth factor receptor, TrkA [216 ], although it remains unclear how this complex affects signaling through these receptors. Although functional studies about RGS19 have not been performed in macrophages, IGF-1 can stimulate proliferation of mouse macrophages and their progenitors [217 , 218 ]. Thus, RGS19 is likely to regulate IGF-1 signaling in macrophages, and given the macrophage-enriched expression of many RGS family members, other functions in this lineage are likely to exist.

GRKs
The GRK family consists of seven members and can be grouped, according to homology, into the rhodopsin/visual GRK group (GRK1 and -7), GRK2 and -3 group (also known as the ß-adrenergic receptor kinase 1 and 2, respectively) and GRK4 group (GRK4, -5, and -6) [219 , 220 ]. Although GRK2, -5 and -6 are reportedly expressed ubiquitously in mice and humans, they are expressed highly at mRNA levels in monocytes and macrophages [221 ] (http://symatlas.gnf.org/SymAtlas/), and GRK2 and -6 protein levels are induced during monocyte differentiation [222 ]. Array data suggest that GRK2 and -6 mRNA expression is down-regulated by LPS in bone marrow-derived macrophages (http://symatlas.gnf.org/SymAtlas/). In addition, several studies have documented regulated expression of GRKs during inflammatory responses. Protein expression of GRK2 and -5 was elevated in the lungs of IL-1ß-treated rats [223 ] while oxygen radicals and the inflammatory cytokines, IL-6 and IFN, reduced GRK2 protein in human T lymphocytes and human PBMC, respectively [224 , 225 ]. Furthermore, GRK2 and -5 protein expression was down-regulated by LPS in polymorphonuclear neutrophils, thereby augmenting chemokine responsiveness [226 ]. In RA patients, GRK2 and -6 protein levels in PBMC were decreased markedly [225 ]. Similar effects on GRK2 and -6 expression were apparent in mouse splenocytes during all phases of the mouse model of multiple sclerosis, experimental autoimmune encephalitis (EAE) [227 ]. Grk2 heterozygous knockout mice showed an earlier onset of EAE which was associated with an increase in early infiltration of T cells and macrophages [228 ]. Locomotion of T cells derived from Grk2-/+ mice was enhanced in response to chemokines such as MIP-1{alpha} and MIP-1ß [229 ]. Thus, reduced GRK expression in inflammatory diseases is likely to enhance leukocyte infiltration and disease progression.

As with the RGS family, GRKs have functions which are independent of GPCR desensitization [230 , 231 ]. First, GRKs are able to phosphorylate nonreceptor substrates such as tubulin [232 ], synucleins [233 ] and phosducin [234 ]. In addition, GRKs modulate signaling in a phosphorylation-independent manner by interacting with proteins involved in signaling and trafficking, including PI-3Ks, guanosinetriphosphatase-activating protein, G{alpha}q and Gß{gamma}, ERK and AKT [235 236 237 238 239 240 ]. Binding of GRK2 or -3 to the Gß{gamma} complex induces activation of these GRKs [238 , 241 ], while selective binding of GRK2 and -3 to activated G{alpha}q selectively inhibits G{alpha}q signaling [242 , 243 ]. GRKs can also regulate ERK activation. T cells derived from GRK2 heterozygous mice, which have reduced expression of GRK2, had significantly enhanced ERK1/2 signaling in response to CCR5 ligands in vitro [229 ]. Furthermore, GRK5 knockdown resulted in enhanced ERK phosphorylation and I{kappa}B kinase (IKK)-mediated p105 phosphorylation and degradation in response to LPS in the macrophage cell line RAW264.7. GRK5 also bound to and phosphorylated p105, implying that p105 phosphorylation by GRK5 negatively regulates LPS-stimulated ERK activation [244 ]. Finally, GRKs also regulate signaling in response to TGF-ß and EGF in a GPCR-independent manner [245 , 246 ]. These data suggest that GRKs, such as GRK2, -5 and -6, are likely to modulate macrophage function by acting as regulatory components within GPCR and non-GPCR signaling pathways. They may therefore coordinate crosstalk between the major players within such pathways.

ARRBs
Although ARRBs are reported to be expressed ubiquitously, expression data generated by our laboratory suggest that although ARRB1 and -2 mRNA and protein are detectable in a range of cell types, ARRB1 and in particular, ARRB2 are constitutively expressed at high levels in mouse and human macrophages (J. Lattin and M J. Sweet, unpublished data). As well as regulating GPCR desensitization and therefore downstream signaling, ARRBs also regulate macrophage signaling in a GPCR-independent manner. In macrophages, growth, survival, differentiation and activation signals are generally transduced through the PI-3K, ERK, JNK and p38 MAPK pathways, as well as the NF-{kappa}B pathway. ARRBs regulate signaling via each of these pathways through their ability to act as adaptor molecules in the assembly of signaling complexes and by regulating the intracellular compartmentalization of these complexes [247 248 249 ].

ß-ARR1 and -2 can both contribute to ERK1 and -2 activation. Activation of a number of GPCRs leads to phosphorylation of ERK which is independent of G-proteins yet dependent on ARRBs. For example, ARRB2 was required for CXCR4, PAR-2, ß2-adrenergic receptor, and angiotensin II Type 1A-mediated ERK activation via direct binding to components of the ERK pathway such as SRC and RAF-1 [250 251 252 253 254 255 256 ]. Further, direct binding of ARRB to ERK enhanced ERK phosphorylation and targeted it to the cytosol [251 , 254 ]. Activation of a number of receptor tyrosine kinases, including the CSF-1 receptor, which is required for macrophage survival and proliferation [257 ], leads to activation of ERK1/2 [258 ]. Therefore, it is possible that ARRBs regulate ERK signaling, not only in response to GPCR agonists but also in response to receptor tyrosine kinase ligands. This is certainly the case for the IGFR-1 [259 , 260 ]. Further, a recent publication demonstrated that knockdown of ARRB1 resulted in increased ERK1/2 phosphorylation in response to LPS in RAW264.7 [244 ].

ARRB2, but not ARRB1, activated JNK3 signaling through its ability to act as a scaffold [261 ]. Antagonism of angiotensin II Type 1A in COS-7 cells resulted in binding of ARRB2 to JNK3 and JNK3 retention in the cytosol in intracellular vesicles. The interaction among JNK3, ARRB2 and ASK1 resulted in the assembly of signaling complexes and enhanced phosphorylation of JNK3. A conserved JNK docking domain in the C-terminal of ARRB2 (RRSLHL, amino acids 196–201) is required for this response [261 , 262 ]. The JNKs are critical for CSF-1-mediated proliferation and survival of macrophages [263 ]. Whether ARRB2 regulates CSF-1-regulated JNK activation in macrophages is currently unclear, but preliminary studies in this laboratory have shown that the JNK docking domain of ARRB2 does indeed regulate macrophage survival (J. Lattin and M. J. Sweet, unpublished data).

ARRBs also regulate macrophage signaling through interaction with NF-{kappa}B, a family of proinflammatory transcription factors. ARRB1 and -2 interacted with the I{kappa}B{alpha} component of the NF-{kappa}B signaling complex in a range of cell types including HEK293, HeLa, Jurkat, COS-7 and THP-1 cells [264 , 265 ]. This interaction involved the N-terminal of ARRB2 and the C-terminal of I{kappa}B{alpha} [264 ]. Overexpression of ARRB1 or -2 in HeLa cells inhibited TNF-induced NF-{kappa}B activation [265 ]. Similarly, overexpression of ARRB2 in HEK293 cells inhibited TNF-induced NF-{kappa}B DNA binding, while RNA interference-mediated knockdown of ARRB2 had an opposing effect [264 ]. These inhibitory effects of ARRB2 on NF-{kappa}B activation apparently occur via the prevention of I{kappa}B{alpha} phosphorylation and degradation [264 , 265 ]. Consistent with these effects on signaling, knockdown of ARRB2 enhanced the mRNA and protein expression of the NF-{kappa}B target genes IL-6 and IL-8 in response to proinflammatory stimuli [264 ].

A recent publication by Wang et al. [266 ] further demonstrated a role for ARRBs in TLR-mediated macrophage activation. In response to TLR or IL-1 family ligands, TNF receptor-associated factor (TRAF)6 is auto-ubiquitinated, oligomerizes and subsequently initiates downstream signaling events, including activation of IKK and JNK [267 , 268 ]. ARRB1 and -2 interacted with TRAF6 upon TLR4 or IL-1R activation and prevented TRAF6 auto-ubiquitination, oligomerization and IKK activation [266 ]. Therefore, ARRBs act at multiple levels to inhibit TLR signaling. Such data are likely to be a prelude to the identification of other GPCR signaling molecules (e.g., G-proteins, RGS family members, GRKs) within the TLR signaling framework.

In summary, a number of GPCR regulatory molecules play important roles in macrophage function through regulation of signal transduction downstream of GPCRs, as well as non-GPCRs, such as TLRs. The ability of GPCR regulatory proteins to interact with components of multiple pathways would allow these proteins to mediate signaling crosstalk (Fig. 4 ), thus enabling the coordination of a precise and appropriate cellular response. Dysregulated expression or function of these regulatory proteins may thus contribute to pathology in acute and chronic inflammatory diseases.


Figure 4
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  		Figure 4. GPCR signaling components regulate TLR signaling. The ability of GPCR regulatory proteins to interact with components of multiple pathways allows them to mediate signaling crosstalk between GPCRs and non-GPCRs, such as the TLRs. Gray arrows depict potential crosstalk mechanisms including transactivation of GPCRs, such as CXCR4, in response to the TLR agonist and GPCR regulatory component mediation of signaling downstream of non-GPCRs, such as NF-{kappa}B, TRAF6, ERK1/2, JNK and p38 [186 187 188 , 198 , 212 , 213 , 215 , 221 , 222 , 226 , 235 , 244 , 247 , 261 , 265 , 269 ]. Crosstalk between GPCR and non-GPCR pathways enables the coordination of precise and appropriate cellular responses. Mal, MyD88 adapter-like; TPL2, tumor progression locus-2; TRIF, Toll/IL-1R translation initiation region domain-containing adaptor-inducing IFN-ß; IRAK, IL-1R-associated kinase; IRF3, IFN regulatory factor 3; MEKK1, MEK kinase 1; ATF2, activating transcription factor 2.


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CONCLUSIONS
 
GPCRs and their signaling molecules have diverse and central roles in regulating macrophage function. Several macrophage-expressed GPCRs have been targeted in therapeutic approaches in disease areas, which range from infectious disease to cancer. Here, we have documented other poorly characterized GPCRs, as well as GPCR signaling components that are highly expressed in macrophages or are regulated during macrophage activation. Future studies about such molecules will provide further insight into macrophage biology and are likely to lead to novel approaches for targeting macrophage-mediated disease.


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ACKNOWLEDGEMENTS
 
We apologize to the authors of many relevant studies, who because of space limitations and the broad research area that was covered, were not cited in this review. This work was supported by a grant from the National Health and Medical Research Council of Australia (ID 301210).

Received January 22, 2007; revised March 29, 2007; accepted April 1, 2007.


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