Involvement of P2Y receptors in the differentiation of haematopoietic ...

Involvement of P2Y receptors in the differentiation of haematopoietic cells Katrin Sak,*,† Jean-Marie Boeynaems,†,‡ and Hele Everaus* *Hematology-Oncology Clinic, University of Tartu, Estonia; †Institute of Interdisciplinary Research, School of Medicine, Universite´ Libre de Bruxelles, Brussels, Belgium; and ‡Department of Medical Chemistry, Erasme Hospital, Brussels, Belgium

Abstract: The effects of extracellular nucleotides are mediated by multiple P2X ionotropic receptors and G protein-coupled P2Y receptors. These receptors are ubiquitous, but few physiological roles have been firmly identified. In this review article, we present a survey of the functional expression of P2Y receptors in the different haematopoietic lineages by analyzing the selectivity of these cells for the various adenine and uracil nucleotides as well as the second messenger signaling pathways involved. The pharmacological profiles of metabotropic nucleotide receptors are different among myeloid, megakaryoid, erythroid, and lymphoid cells and change during differentiation. A role of P2Y receptors in the differentiation and maturation of blood cells has been proposed: In particular the P2Y11 receptor seems to be involved in the granulocytic differentiation of promyelocytes and in the maturation of monocyte-derived dendritic cells. It is suggested that the role of P2Y receptors in the maturation of blood cells may be more important than believed so far. J. Leukoc. Biol. 73: 442– 447; 2003. Key Words: purinoceptor 䡠 nucleotide 䡠 maturation of blood cell

INTRODUCTION Following their release in extracellular fluids by cell lysis, exocytosis, or membrane transport proteins, nucleotides can exert a wide range of biological effects mediated by multiple ionotropic P2X receptors and G protein-coupled P2Y receptors [1]. However, few physiological functions of those receptors have been firmly established, partly because of a lack of truly selective agonists and antagonists. Initially, the interest in nucleotide receptors was focused on the cardiovascular and nervous systems [2]. Adenosine 5⬘-diphosphate (ADP) was the first platelet-aggregating agent of low molecular weight to be identified, and it is now established that ADP receptors are involved in physiological platelet aggregation and generation of thrombosis [3]. It was also determined that nucleotide receptors activated by adenosine 5⬘-triphosphate (ATP) and uridine 5⬘-triphosphate (UTP) can participate in the regulation of chloride transport in the airway epithelial cells, thus providing a target for the treatment of cystic fibrosis [4]. The role of 442

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extracellular ATP in the differentiation of HL-60 [5– 8] and NB4 human promyelocytic leukaemia cells [7, 9, 10] into neutrophil-like cells was recently described. This suggests that nucleotide receptors could be involved in physiological granulopoiesis and also incites to study their involvement in the differentiation of other haematopoietic lineages. In this review article, we present a survey of the expression of P2Y receptors in haematopoietic cells based on molecular and pharmacological (nucleotide rank order of potency and signal transduction pathway) data.

DIVERSITY OF P2Y RECEPTORS AND SIGNAL TRANSDUCTION PATHWAYS ACTIVATED BY RECEPTOR STIMULATION To date, eight genuine, mammalian P2Y receptor subtypes have been identified on the basis of sequence homology and pharmacological profile. Among them, there are three ADPspecific receptors (P2Y1, P2Y12, and P2Y13), one subtype specific for ATP (P2Y11), receptors with mixed selectivity for which ATP and UTP are equipotent agonists (P2Y2 and rodent P2Y4), two uracil nucleotide-specific receptors [P2Y6 for uridine 5⬘-diphosphate (UDP) and human P2Y4 for UTP], and a receptor specifically activated by UDP-glucose and closely related molecules (P2Y14) [11–13]. In addition, several p2y receptors have been cloned from nonmammalian origin: The UDP-specific p2y3 is the avian ortholog of the mammalian P2Y6 receptor [14], whereas Xenopus p2y8 [15] and a p2y receptor cloned from a turkey blood cDNA library [16] are likely orthologs of a mammalian P2Y4 receptor [12]. Several orphan p2y receptors (p2y5, p2y9, and p2y10) have also been described, for which no functional response to nucleotides could be demonstrated, and p2y7 is actually a leukotriene B4 receptor [17]. Furthermore, some promising P2Y receptor candidates have been identified on the basis of sequence homology [18, 19], suggesting that eventually, the number of metabotropic nucleotide receptors will be larger than eight. One approach to establish the P2Y receptor subtype expressed in a given biological system is to determine the nu-

Correspondence: Katrin Sak, IRIBHM, 808, Route de Lennik, 1070 Brussels, Belgium. E-mail: [email protected] Received November 14, 2002; accepted January 21, 2003; doi: 10.1189/ jlb.1102561.

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cleotide rank order of potency. However, there are several points that complicate such pharmacological subtype determination. First, several subtypes are often simultaneously expressed in one cell line or type. Second, nucleotides are subject to enzymatic degradation at the cell surface (especially in the case of assay methods with longer incubation times) [20]. Third, nucleotides with different purity degree have been used in different experiments. Fourth, the number of functionally active receptors can differ in various biological systems—a factor that can influence the type of activity: For instance, ATP can behave as an agonist or an antagonist of the P2Y1 receptor, depending on the extent of receptor reserve [21]. Therefore, the measurement of nucleotide rank order of potency is insufficient for determining which P2Y receptor subtype is expressed in cells. The use of inhibitors is also limited, as specific antagonists are only available for P2Y1 (MRS2179; ref. [22]) and P2Y12 (AR-C67085 and congeners; ref. [23]) receptors. Other inhibitors such as pyridoxalphosphate-6-azophenyl-2⬘,4⬘-disulfonic acid, suramin, or reactive blue 2 are totally nonselective and can even produce nonreceptor-mediated effects [24]. The molecular biological approach is not always helpful, as reverse transcriptase-polymerase chain reaction often allows amplification of several subtypes with no assurance that the protein is expressed at a significant level [25]. Although specific antibodies could be instrumental in determining the functional expression of different subtypes in various tissues as well as their exact localization, their use is limited by their availability: Currently, antibodies have been described only for human [26, 27], rat, and bovine P2Y1 [28], human P2Y2 [29], rat P2Y2 and P2Y4 [30], and rat P2Y12 [31] receptors. Finally, gene targeting in mice constitutes a definitive method to determine the physiological role of a particular receptor. Currently, knockout mice are available for P2Y1 [32, 33], P2Y2 [34, 35], P2Y4 [36], and P2Y12 [37] receptors. Among the mammalian P2Y receptors, the stimulation of five subtypes (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11) leads to the activation of phospholipase C (PLC) followed by the formation of inositol phosphates and mobilization of intracellular calcium [1]. P2Y12, P2Y13, and P2Y14 receptors are coupled to Gi, and stimulation of these subtypes leads to the inhibition of intracellular cyclic adenosine monophosphate (cAMP) accumulation [11, 13, 31]. The P2Y11 receptor is the only subtype coupled to the activation of adenylyl cyclase and PLC, leading to the accumulation of cAMP and inositol phosphates [38].

NUCLEOTIDE SELECTIVITY OF P2Y RECEPTORS IN HAEMATOPOIETIC CELLS Myeloid cells The P2Y2 receptor is expressed in the myeloid lineage from the late myeloblastic stage up to mature neutrophils [39 – 41], where it is involved in the control of chemotaxis [42], superoxide anion production [5, 43– 45], and secretion of granule contents [45–50]. It has been suggested recently that extracellular nucleotides require leukotriene generation as an essential intermediate for neutrophil degranulation [51, 52]. The P2Y2 receptor is also active in human eosinophils, where ATP and

UTP produce similar effects as on neutrophils: production of reactive oxygen metabolites, up-regulation of the integrin CD11b, actin polymerization, and chemotaxis [53–55]. In the human promonocytic cell line U937, the activation of P2Y2 receptors by extracellular ATP and UTP induces phenotypic changes characteristic of monocyte-to-macrophage differentiation: inhibition of proliferation, increased expression of complement receptor types 1 and 3, and increased responsiveness to chemotactic peptides [56]. Besides PLC-dependent calcium mobilization, the activation of P2Y2 receptors in U937 cells induces sequential phosphorylation of the mitogen-activated protein kinase kinase-1/2 and extracellular-regulated kinase-1/2, via coupling to phosphatidylinositol 3-kinase and c-src [57]. These two pathways might both contribute to the phenotypic changes observed. Furthermore, it has been demonstrated recently that activation of the P2Y2 receptor in human monocyte cell line THP-1 leads to morphological changes characteristic of cells undergoing apoptosis (e.g., caspase-3 activation) but also stimulates the secretion of the proinflammatory cytokine tumor necrosis factor ␣ (TNF-␣) [58]. In the latter cell line, the expression of the P2Y6 receptor has also been described, the stimulation of which activates interleukin (IL)-8 gene expression and IL-8 production by UDP [59]. As in other cells of myeloid lineage, the P2Y2 receptor is also expressed in human macrophages, where its activation enhances the oxidative burst induced by opsonized zymosan [60, 61]. The P2Y11 receptor is expressed in myeloid precursors but not in mature neutrophils and seems to play a role in granulocytic differentiation [5, 6, 8 –10]. However, until now, this concept is only supported by data from human leukaemia cell lines (HL-60 and NB4). These promyelocytic cells can differentiate into neutrophil- or monocyte-like cells depending on the inducer used. It has been demonstrated that ATP and several synthetic analogues induce the formation of mature, neutrophil-like cells through the stimulation of cAMP accumulation and with a ligand rank order of potency characteristic of the P2Y11 receptor [8, 62]. Also, agents known to induce granulocytic differentiation (dimethyl sulfoxide, dibuturylcAMP, retinoic acid, granulocyte-colony stimulating factor) up-regulate P2Y11 mRNA in HL-60 cells [5, 63], and inducers of monocytic differentiation (1,25-dihydroxy vitamin D3 and phorbol 12-myristate 13-acetate) have no effect on the expression level of these messengers [5]. These data indicate that the P2Y11 receptor is involved in the granulocytic maturation. However, further experiments demonstrating an effect on the differentiation of CD34⫹ progenitor cells and a study of the expression of the receptor at various stages of differentiation between myeloblasts and mature granulocytes are needed. The P2Y11 receptor also seems to be involved in the maturation of human monocyte-derived dendritic cells (DC), the most potent antigen-presenting cells of the immune system. That maturation is synergistically enhanced when TNF-␣ is used in combination with ATP, as revealed by the increase in the expression of cell-surface markers CD80, CD83, and CD86 [64, 65]. Based on the rank order of potency of various ATP analogues and their ability to activate cAMP synthesis, it has been proposed that this effect of ATP is mediated through the stimulation of the P2Y11 receptor [66]. This conclusion is

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supported by earlier data about the presence of the P2Y11 receptor mRNA in DC [64, 67] and more recent data showing that the expression level of P2Y11 messengers is similar in the monocytes and immature and mature DC [66]. In addition to up-regulation of surface markers, ATP and derivatives exert pleiotropic effects on DC: They modulate the functional expression of chemokine receptors as well as the repertoire of secreted chemokines [68], synergize with lipopolysachharide (LPS) and soluble CD40 ligand to stimulate IL-10 production [69], increase the release of IL-12p40 in response to TNF and low LPS concentrations [65, 66, 69], and inhibit the production of bioactive IL-12p70 [69, 70]. As a result of that last effect, ATP will impair the initiation of a T helper cell type 1 (Th1) response by T lymphocytes and favor a Th2 response or tolerance. ATP and different other nucleotides (UTP, ADP) also have chemotactic activity and stimulate migration-associated intracellular signaling events such as actin reorganization and mobilization of intracellular calcium ions in immature but not mature DC. The receptors involved in this process might be important in attracting of DC toward inflammatory sites, and loss of the responsiveness in mature DC allows their migration to lymph nodes [71]. Taken together, the equipotency of ATP and UTP to induce the accumulation of inositol phosphates and mobilization of intracellular calcium through activation of the P2Y2 receptor could be considered as a general characteristic of myeloid cells. The effects of other nucleotides and activation of alternative signaling pathways, especially the P2Y11 receptor and its activation of adenylyl cyclase, seem to be important only at certain myelopoietic differentiation stages.

Megakaryoid cells In two human megakaryocytic leukaemia cell lines (Dami and Meg-01), the functional expression of an ADP-specific receptor and a UTP receptor has been described [72, 73]. However, the exact molecular nature of these receptors remains unknown: The response to ADP is similar to that widely described in platelets, but the involvement of P2Y1, P2Y12, or both of these receptors in the early megakaryoid cells has not been confirmed. The UTP receptor could be the P2Y2 receptor or the elusive P2U2 (GPR91) receptor: Isolation of P2U2 mRNA from Dami cells has been reported [74], but a full characterization of that receptor has not yet been published. The response to UTP disappears during the megakaryocytic differentiation, and the P2Y receptors functionally expressed in platelets are strictly selective for adenine nucleotides. Stimulation of such cells by ADP leads to the activation of PLC and inhibition of adenylyl cyclase through P2Y1 and P2Y12 receptors, respectively [26, 31, 75–79]. These receptors mediate such physiologically essential processes as platelet shape change and aggregation and are thus directly linked to the generation of thrombosis [75, 77, 80]. Indeed, the inactivation of either receptor gene protects mice against lethal thromboembolism [32, 33, 37]. ATP behaves as a competitive antagonist of the ADP receptors in platelets [77, 80]. The role of the ADP receptor(s) in the early stage of megakaryoid cells as well as the significance of the down444

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regulation of the UTP receptor during the megakaryopoietic differentiation are unknown.

Erythroid cells Similar to the thrombocytic cells, the P2Y receptors expressed in erythroid cells are adenine nucleotide-selective. In two human erythroleukaemia cell lines [human erythroid leukaemia (HEL) and K562], the functional expression of an ADPspecific receptor coupled to the activation of PLC and inhibited by ATP has been described [81– 83]. As in the early stage of megakaryoid cells, a response to UTP is also detected in the HEL cells [83]. These effects could be related to the pluripotent nature of HEL or K562 human erythroleukaemia cells, which carry membrane markers for several haematopoietic lineages. However, UTP and ATP (acting through the P2Y2 receptor) as well as ADP (the response which is blocked by ATP) are also active on normal, human erythroid progenitor cells isolated from peripheral blood and amplified in suspension culture, yielding mainly erythroid colony-forming cells (burst-forming units and colony-forming units ) [84]. The possible physiological function of the P2Y receptors mediating these responses remains undetermined. ATP and ADP are able to activate PLC in avian erythrocytes via the P2Y1 receptor [85], thus providing a good model system to study the pharmacology of this subtype [86 – 89]. It is interesting that this receptor is not expressed in mature mammalian erythrocytes [90].

Lymphoid cells Compared with the other haematopoietic differentiation lineages, the activity of nucleotides in lymphoid cells is much less studied, and the knowledge about the functional expression of P2Y receptors during lymphopoiesis is rather obscure. On the other hand, the published data enable us to suppose that the expression of P2Y receptors in lymphoid cells is most sensitive to the developmental stage, source, and pathological state of cells. There is no evidence about the activity of P2Y receptors in the early stage of lymphoblastoid cells [40, 41, 91]. However, ATP is able to activate PLC in the T cells isolated from bone marrow of patients with T-acute lymphoblastic leukaemia CB1 [92]. At the same time, this nucleotide has no effect on PLC activity in Molt-4 human T cell lymphoblastic leukaemia cells [40, 41], human peripheral blood T lymphocytes [61, 93], as well as human tonsilar T lymphocytes [94]. Similarly, ADP is active in the HPB-ALL human T-leukaemia cell line [92] but inactive in several other human cultured T-leukaemia lines [92]. UDP is able to induce the mobilization of intracellular calcium via the P2Y6 receptor in T cell mitogen-activated peripheral blood lymphocytes [95], while UTP has no activity in lymphoid cells [91, 92, 94, 96]. Recent evidence indicates that some nucleotides increase cAMP in CD4⫹ T cells from peripheral blood and thereby exert an immunosuppressive effect: The receptor involved remains unidentified [97]. ATP (but not ADP) is able to activate PLC in human tonsilar B lymphocytes [94] but is unable to mobilize Ca2⫹ in cells isolated from patients with B cell chronic lymphocytic leukaemia and with acute lymphocytic leukaemia FAB L2 [40]. http://www.jleukbio.org

However, recently published data show that ATP and ADP (but not UTP) can increase cAMP concentration in B lymphocytes from patients with chronic lymphocytic leukaemia, presumably via activation of the P2Y11 receptor [98]. Similarly, ATP does not evoke calcium mobilization in human natural killer (NK) cells [61] but is able to increase intracellular cAMP, an effect that might be involved in the suppression of NK cell proliferation [99]. It is interesting that no activity of metabotropic nucleotide receptors has been found in lymphopoietic cells isolated from the mouse [96].

physiological role of these receptors in haematopoiesis may be more important than it is believed so far.

ACKNOWLEDGMENTS The research of K. S. was supported by the Marie Curie Fellowship of the European Community Programme Human Potential under contract number HPMF-CT-2001-01472. The author is solely responsible for the information published, and the European Community is not responsible for any views or results expressed.

CONCLUSION REFERENCES The data presented above demonstrate that P2Y receptors functionally expressed in the cells of different haematopoietic lineages have different pharmacological profiles that also change during differentiation. In particular, the nucleotide rank order of potency as well as the activated intracellular signal transduction pathway(s) seems to be related to the differentiation lineage of haematopoietic cells. In progenitor cells of myeloid, megakaryoid, and erythroid lineages, UTP is able to activate PLC followed by the accumulation of inositol phosphates and mobilization of intracellular calcium. The functional expression of UTP- and ATPactivated P2Y2 receptors is characteristic during the whole myelopoietic differentiation, starting from myeloblasts, having an important role in the regulation of several physiological processes and being involved in the immune responses of mature myeloid cells. The expression of other P2Y receptor subtypes in myelopoietic cells, especially the P2Y11, seems to be essential only at certain developmental stages. Different from myeloid cells, the functional expression of the UTP-activated receptor disappears during megakaryopoiesis and erythropoiesis: Its expression has been described in megakaryocytes and erythroid colony-forming cells but not in mature platelets and erythrocytes anymore. In mature platelets as well as immature megakaryoid cells (megakaryocytes), the response to ADP seems to be characteristic: Stimulation of platelets by ADP leads to activation of PLC and inhibition of adenylyl cyclase through activation of P2Y1 and P2Y12 receptors, respectively. The responsiveness to ADP is also characteristic for erythroid cells, where adenine nucleotides stimulate the P2Y1 receptor and activate PLC in early erythroid colonyforming units. However, unlike mature avian erythroid cells, mammalian erythrocytes do not functionally express the P2Y1 receptor. It is rather difficult to bring forth a common feature for lymphoid cells, as the functional expression of P2Y receptors in these cells seems to be most sensitive to the developmental stage, source, and pathological state. In conclusion, despite the ubiquity of metabotropic nucleotide receptors, the pharmacological profiles of these receptors expressed in the blood progenitor cells maturing along different haematopoietic lineages seem to be rather different. Such expression of P2Y receptors with different selectivity toward the extracellular nucleotides as well as the second messenger signaling pathways in different blood cells suggests that the

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