Mechanisms and Function of Granulocyte Signal Transduction
1. Signal Transduction Mechanisms Regulating Granulocyte Priming
Introduction
Human polymorphic granulocytes can be divided into three distinct types: neutrophils, eosinophils and basophils. While all three play a role in mediating allergic inflammatory reactivity, neutrophils and eosinophils are phagocytic cells which play a critical role in host defense against microbial infection. At the site of infection the granulocyte participates in the inflammatory reaction by (a) phagocytosis and intracellular killing of bacteria, and (b) production of inflammatory mediators such as chemotactic factors and vasoactive lipid metabolites as well as release of preformed cytotoxic enzymes and proteins (33, 36, 42). An unfortunate consequence of activation is the ability to cause tissue damage during acute inflammation and thus the activity of granulocytes must be tightly controlled.
Granulocyte function can be rapidly amplified by environmental factors through a mechanism termed 'priming' which is independent of protein synthesis. For example, traces of bacterial lipopolysaccharide (LPS), which itself does not cause activation of the respiratory burst, induces an enhanced superoxide formation upon subsequent stimlation with chemotactic factors such as N-formyl-methionyl-leucyl-phenylalanine (fMLP; 24). Activation thus refers to processes that lead to a measurable alteration in cells, for example degranulation. Priming, however, refers to a process whereby the response of cells to a subsequent (activating) stimulus is amplified if these cells were previously exposed to a (priming) stimulus (Figure 1). Quiescent neutrophils are not activated by formyl peptides in the context of respiratory burst activation (18). However, addition of platelet activating factor (PAF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF-a) to human granulocytes primes the generation of superoxide-release upon a subsequent activation with chemoattractant (7, 25, 54). This is dramatically demonstrated in Figure 2 where the oxidative response of neutrophils to fMLP is negligable without first priming with PAF. This doesn't preclude priming agonists from activation of other neutrophil responses, for example addition of PAF causes granulocyte degranulation (8). Thus it is the activation 'state' rather than the mere prescence of granulocytes in tissues that is important, and dissection of the mechanisms of priming enables elucidation of the pathogenesis of granulocyte-mediated tissue injury.
Mechanisms of Priming
Priming appears to be a multifaceted process such that different effector functions are primed through activation of distinct signalling pathways. Much work has been done to pinpoint downstream signalling events that are critical for individual priming stimuli in an attempt to find a common 'priming signal' (12). Priming effects have distinct activation profiles depending on the agonist employed. For example, priming by LPS and GM-CSF requires several minutes and is not maximal for 30-60 minutes, whereas priming by PAF occurs very rapidly and is maximal within a few minutes (56). Studies have demonstrated that human peripheral blood neutrophils incubated with priming agents such as LPS maintain an enhanced oxidative burst response to fMLP for at least 24 hours (26). Furthermore, in vivo neutrophils remain primed for at least 24 hours following LPS infusion and such studies have been interpreted to indicate that priming is essentially an irreversible phenomenon (4). Recent studies, however, have demonstrated that PAF-priming of neutrophils spontaneously decreases within 2 hours and the 'de-primed' cells retain their full capacity to be 're-primed' by an alternative priming agent or PAF itself (27). The differences observed with previous studies suggest that agonists may be either reversible e.g. PAF, or irreversible e.g. LPS, priming agents and may allow greater flexibility of granulocyte behaviour at an inflammatory site.
A role for Ca2+ has been implicated in a certain aspects of the priming response. For example, PAF induces a transient increase in free-Ca2+ concentration ([Ca2+]i) and primes the respiratory burst to subsequent activation with fMLP. Indeed, a transient increase in [Ca2+]i is itself sufficient to prime human granulocytes (28). This response is mimicked by addition of ionomycin, a calcium ionophore. However, priming induced by PAF is only partially inhibited under [Ca2+]i-buffering conditions, demonstrating that multiple priming pathways exist. Pre-treatment of eosinophils with GM-CSF, IL-3 or IL-5 enhances the respiratory burst induced by opsonized particles. Unlike the G-protein coupled receptor agonists PAF and fMLP, these cytokines do not induce a rise in [Ca2+]i and furthermore Ca2+-depeleted eosinophils are still primed after incubation with cytokines. This priming activity is accompanied by induction of tyrosine kinase activity (van der Bruggen et al., 1993). Indeed, one common feature of all priming agents is the induction of protein tyrosine phopshorylation (19, 20, 21, 22, 30, 35). Furthermore, priming may be inhibited by protein tyrosine kinase inhibitors (22, 30, 35) or induced with phosphotyrosine phosphatase inhibitors (30).
One family of tyrosine phosphorylated proteins that appear to be activated by almost all granulocyte priming agents are the mitogen-activated protein kinases or MAP kinases which include ERK, JNK and p38 kinases (38). The various members of this family are activated by distinct subsets of cellular agonists that can be subdivided, although rather simplistically, into proliferation/differentiation or stress responses. The extracellular signal regulated kinases (ERKs) p44ERK1 and p42ERK2 were first identified as being activated by various growth factors but have subsequently been shown to be activated by most receptor systems. Indeed, in human granulocytes the priming agonists IL-5/GM-CSF and PAF, and activating stimuli such as fMLP have been demonstrated to induce activation of p44ERK1/p42ERK2 (21, 23, 46, 47, 51, 57). ERK activation by G-protein coupled receptor systems is very rapid and short-lived, while tyrosine kinase-based receptors are slower and of longer duration (46). This correlates well with priming characteristics of, for example, PAF and GM-CSF in granulocytes. Indeed a role for ERKs in priming of the respirtory burst has been previosly proposed although through indirect studies (13, 21, 23, 46, 51). Activation of respiratory burst first requires assembly of the multicomponent NADPH oxidase complex. Associated with this is the phosphorylation of the cytosolic component p47phox (15, 16). It has been suggested that phosphorylation of p47phox by MAP kinases may play a role in translocation and activation of the oxidase complex (13, 15). One possibility may be that this phosphorylation occurs as a priming response to, for example GM-CSF, assembling the oxidase complex in a pre-formed state ready for subsequent activation. Recent studies have demonstrated that p38 MAP kinase is activated by both pro-inflammatory cytokines as well as physical and chemical stresses. In neutrophils p38 is rapidly tyrosine phosphorylated and activated in response to PAF, TNF-a, GM-CSF and LPS (31, 32, 52) and is postulated to play a role in the activation of cytosolic phospholipase A2 (52) . GM-CSF/IL-3/IL-5 and LPS have been also demonstrate to activate JNK, ERK and p38 (6, 40, 44, 46), and TNF-a only JNK and p38 (39, 51). IL-4, however, which primes a subset of granulocyte effector functions, is unique amongst hemopoietic cytokines in being unable to induce activation of any MAP kinase family members in granulocytes (17; Coffer and Koenderman, unpublished data). Interestingly, the activation of p38 by PAF is greatly enhanced by prior incubation with LPS, suggesting a priming response in the activation of this signalling pathway (31). These data are summarised in Table I, demonstrating that different priming agents are capable of activating unique signalling pathways and suggests that priming itself is not dependent on a single signalling event.
Table I Activation of kinases by granulocyte priming agents
|
Priming Agent |
ERK |
JNK |
p38 |
PI-3K |
| GM-CSF/IL-5 |
Activation |
Activation* |
Activation |
Activation |
| PAF |
Activation |
n/d |
Activation |
Activation |
| TNF-a |
None |
Activation* |
Activation |
Activation |
| IL-4 |
None |
n/d |
None |
Activation |
n/d, not determined *cell-lines, not determined in granulocytes
A second signal transduction pathway that appears to play a critical role in both priming and activation of granulocyte effector functions involves the lipid kinase phosphatdylinositol 3-kinase (PI-3K). This enzyme phosphorylates the D-3 position of the inositol ring of phosphatidylinositol (PI), PI 4-phosphate and PI 4,5-biphosphate (5, 34). Several isoforms have been identified and in human neutrophils the activation of two distinct subtypes has been reported : p110a, activated classically by tyrosine kinase-linked receptors, and p110g, a novel isoform that appears to be activated predominantly by G-protein coupled receptors (43). The activation of both p110a and p110g can be inhibited by pre-incubation of cells with a the fungal metabolite wortmannin (2, 43, 45, 50). Several studies have demonstrated that addition of wortmannin to neutrophils results in the inhibition of fMLP-stimulated respiratory burst and degranulation without influencing agonist-induced [Ca2+]i changes (2, 9, 45). These studies led to the idea that priming involves at least two-distinct pathways: a calcium-dependent and a calcium-independent one. A second and somewhat more specific inhibitor of PI3K activation is the synthetic compound 2-(4-morpholinyl) -8-phenylchromone (LY294002). Figure 3 demonstrates the effect of addition of LY294002 prior to priming of fMLP-induced respiratory burst in human neutrophils. Three distinct receptor systems have been utilised for priming, GM-CSF, TNF-a and PAF, all three demonstrating strong priming responses. Pre-incubation of neutrophils with L294002 clearly inhibits oxidase activity, as measured by oxygen-consumption, of all three priming agents. Interestingly, while overall oxidase-activity is reduced dramatically, the initial phase of activation appears not to be effected. Instead, sustained activation is inhibited suggesting that PI-3K activity is necessary for a secondary signal maintaining the integrity of the response. The inhibition of LY294002 on PAF-priming is less than for GM-CSF and TNF-a (Figure 3). It has been reported that inhibition of p110g requires a higher concentration of inhibitor than for p110a (43). This distinction may explain why the PAF-primed response is more tolerant to LY294002 than GM-CSF or TNF-a, and could thus reflect a difference in the abilities of these three priming stimuli to activate different PI-3K isoforms (PAF, p110g; GM-CSF/TNF-a, p110a). Wortmannin has also been demonstrated to inhibit p47phox phosphorylation in vivo (11). Furthermore, it has been shown that introduction of a constitutively active form of PI-3K into a monoblastic phagocytic cell line (GM-1) resulted in enhanced phosphorylation of p47phox (10). Thus the possibility arises that PI-3K exerts its effects on respiratory burst by activation of downstream protein kinases that could directly phosphorylate components of the oxidase complex.
Recent studies have demonstrated that cytokines such as GM-CSF/IL-5 cause increased granulocyte chemokinesis (random-movement), distinct from chemotaxis induced by true chemotactic agents such as fMLP (41; Coffer and Koenderman, unpublished data). Wortmannin inhibits this chemokinetic response, but granulocyte chemotaxis is unaffected. Furthermore, PI-3K has been demonstrated to modulate cytoskeletal rearrangements in neutrophils (2, 14). A parallel to this observation is that in fibroblasts, wortmannin inhibits platelet-derived growth factor (PDGF) stimulated cytoskeletal rearrangements and lamellopodia-formation (membrane ruffles), probably by regulating the activation of the small GTP-binding protein p21rac (37, 55). Rac is also a critical component of the oxidase complex (1, 3), and thus the effects of PI-3K inhibition on both chemokinesis and respiratory burst may both be due to a common inhibition of p21rac activation. Indeed, oscillations in actin polymerisation induced by wortmannin in neutrophils are exactly paralleled by changes in respiratory burst activity (58).
Transient incubation of eosinophils with protein kinase C (PKC) inhibitors such as staurosporine, prior to activation of the respiratory burst with opsonized particles, results surprisingly in priming of this response (49). This is not observed for other priming-sensitive effector functions such as PAF-release demonstrating that different signal transduction routes are involved in the priming response. Most interestingly it suggests that, at least in eosinophils, an active signal exists whereby protein kinases function to maintain cells in an unprimed state. Such a signal is of course criticial in preventing the inappropriate activation of granulocytes in tissue.
Conclusions
The role of priming in the response of granulocytes to activating stimuli is critical. In an unprimed state these leukocytes are unable to effectively remove microbial infection by phagocytosis and respiratory burst. Priming provides a powerful regulatory mechanism whereby phagocytes can be controlled such that they respond to the local conditions of their environment. This level of control is important in restricting tissue damage during inflammatory responses. Furthermore, chemotactic and chemokinetic agonists such as PAF and GM-CSF not only target the migration of cells to the site of inflammation but also prime the cells for the approaching task of microbial clearance. Elucidation of signal transduciton pathways mediating specific priming of effector functions will allow not only a greater understanding of the processes leading to inflammatory reponses but will allow their manipulation in the control of acute inflammatory tissue damage associated with diseases such as allergic asthma and arthritis.
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2. Regulation of Proliferation, Differentiation and Survival by the IL-3 / IL-5 / GM-CSF Receptor Family
Cytokines of the IL-3 / IL-5 / GM-CSF family are important regulators of hematopoiesis through the modulation of proliferation, differentiation and survival of various hematopoietic cell lineages and their precursors (1). While IL-3 and GM-CSF act on various lineages such as granulocytes, macrophages, erythrocytes, megakaryocytes and early hematopoietic progenitors, the action of IL-5 in humans is restricted to the eosinophilic and basophilic lineage. Over the last decade, numerous studies have contributed to the understanding of how these cytokines can regulate a large number of distinct biological processes in multiple cell types. In particular, the cloning and mutational analysis of the receptors for IL-3 / IL-5 / GM-CSF have produced valuable information on the action of these cytokines. In this review, a concise overview will be given of recent advances in the understanding of IL-3 / IL-5 / GM-CSF receptor signalling.
A common b receptor chain results in redundancy in IL-3/IL-5/GM-CSF signalling
Although IL-3/IL-5/GM-CSF have distinct effects on different target cells, they elicit similar responses in cells responsive to all three cytokines (1,2) and they even cross-compete for binding to the same cell (3). These observations suggested that they might share the same receptor (component). Indeed, the molecular cloning of the IL-3/IL-5/GM-CSF receptors revealed the existence of a shared receptor subunit named the common b chain (b c). The IL-3/IL-5/GM-CSF receptors are composed of a cytokine-specific a -chain (IL-3Ra , IL-5Ra and GM-CSFRa ) complexed to the b c receptor (2,4-6). In mice, there are two b chain genes, one of which (b c) functions similar to the human b c, while the other (b IL-3) only dimerises with the mIL-3Ra , providing the mouse with two different receptors for IL-3 (7). Both the a and b c chains are members of the superfamily of cytokine receptors, characterised by conserved structural features such as four conserved cysteine residues in their extracellular domain and a typical WSXWS motif in the juxtamembrane region (2). The a chains can bind their ligands with low-affinity, while the b c chain does not bind ligand itself, but, when complexed with an a chain, forms a high-affinity signalling competent receptor (2,4-6) . Although the b c chain plays a major role in signal transduction through these receptors (see below), the cytoplasmic domains of the IL-3, IL-5 and GM-CSF receptor a chains including conserved proline-rich domains have been implicated in the regulation of proliferation and differentiation by these cytokines (8-15). The importance of the b c chain for IL-3/IL-5/GM-CSF function was also demonstrated by gene targeting studies. Eosinophil numbers were reduced in the b c mutant mice, a phenomenon accompanied by the lack of an eosinophilic response to parasites, and IL-5 and GM-CSF failed to stimulate colony formation in clonal cultures of bone marrow cells (16,17). By contrast, IL-3 function was normal, showing that IL-3 can also signal via receptors containing the b IL3 sub-unit (16,17) while knock-out studies of b IL-3 demonstrate that IL-3 can also signal via the b c containing receptor (18). In addition, deletion of b c leads to mice showing lung pathology consisting of lymphocytic infiltration and areas resembling alveolar proteinosis (16,17).
Recent evidence suggests that a bona-fide receptor is composed of two b c molecules and one a chain (19). However, others have shown that at least two functional a chains are necessary for a signalling-competent receptor (20). In addition, it was recently demonstrated that the GM-CSF receptor (a +b c) exists in a pre-formed complex in unstimulated cells (21). These studies clearly show that both a and b c subunits are important for high-affinity ligand binding and receptor function.
The JAK / STAT pathway
Although the IL-3/IL-5/GM-CSF receptors do not posses any intrinsic kinase activity, tyrosine phosphorylation of cellular substrates is rapidly observed in any cell stimulated with IL-3/IL-5/GM-CSF. A large number of cytoplasmic tyrosine kinases have been implicated in IL-3/IL-5/GM-CSF signalling, including lyn, btk, Tec, fyn, hck, FAK and syk (22-32). However, one of the major discoveries in cytokine signalling of the last five years was the elucidation of the JAK / STAT signalling pathway (33-35). Janus Kinases (JAKs) are a family of cytoplasmic tyrosine kinases, which are associated with cytokine receptors and play a major role in cytokine signalling. Upon ligand binding, the JAKs are activated by trans-phosphorylation of two receptor-bound JAK molecules, and subsequently phosphorylate a number of substrates including the cytokine receptor (33-35). The phosphorylated receptor then provides docking sites for a variety of SH-2 domain containing proteins, including a novel family of cytoplasmic transcription factors, termed STATs (signal transducers and activators of transcription). STATs are then phosphorylated on a single tyrosine residue by the JAKs, after which the STATs dimerize, migrate into the nucleus and regulate gene transcription (Fig. 1). Although the signalling pathway seems rather simple, the availability of four different JAKs (JAK1, JAK2, JAK3 and Tyk2) and at least eight different STATs (STAT1a , STAT1b , STAT2, STAT3, STAT3b , STAT4, STAT5A, STAT5B and STAT6) all with different DNA binding and trans-activation properties allows cellular specificity in this signalling pathway.
Larner et al. were the first to demonstrate that this pathway is involved in signalling by receptors for IL-3/IL-5/GM-CSF (36). Since then, many studies have demonstrated the involvement of different STATs and JAKs in IL-3/IL-5/GM-CSF signalling (see table I). There is a general consensus that activation of IL-3/IL-5/GM-CSF receptors results in the rapid activation of JAK2, although Tyk2 activation has also been observed (see table I). In unstimulated cells, JAK2 is already bound through its N-terminal domain to a membrane proximal region of b c containing Box I (Fig. 2) (10,12,37-39). Deletion of this region renders the b c chain unable to activate JAK2 (10). However, the cytoplasmic region of the IL-3/IL-5/GM-CSF a chain receptor also appears to be involved in activation of JAK2 (10,12,14,15,40). When JAK2 is activated, it phosphorylates a number of tyrosine residues in the b c chain, including Y577, Y612, Y695 and Y750 (41-44). These sites then form docking sites for STAT proteins (45,46). Although activation of STAT1, STAT3 and STAT6 by IL-3/IL-5/GM-CSF receptors can be observed depending on the cell type studied, STAT5 (A, B and truncated STAT5 proteins, see below) seems to be the most predominant STAT activated by these receptors (see table 1).
After b c phosphorylation, STAT5 binds to one or more tyrosine residues through its SH2 domain (45,46) and is phosphorylated by JAK2, after which it can dimerize, translocate to the nucleus and regulate gene expression. Mutational analysis of the a and b c chains of the IL-3/IL-5/GM-CSF receptors shows that JAK2 is essential for STAT activation (14,15,47-49). Interestingly, a c-terminal deletion mutant of b c (b c 541), which is still able to activate JAK2, fails to activate STAT5, showing that JAK2 activation is necessary but not sufficient for STAT activation (49). Moreover, mutation of four tyrosine residues, Y577, Y612, Y695 and Y750 of the b c receptor completely blocks IL-5 induced STAT5 mediated transcription, indicating that STAT5 docking to the b c chain is necessary for its activation (Fig. 2) (43). Single mutation of any of these tyrosine residues does not influence STAT activation by IL-3/IL-5/GM-CSF, suggesting a high degree of redundancy in the Y residues of b c (41,43). By contrast, Okuda et al. have recently shown that GM-CSF can activate STAT5 in BaF3 cells expressing a b c chain with all of the cytoplasmic tyrosine residues mutated to phenylalanine (50). In these cells, STAT activation might well be mediated via endogenous mouse b c, since the GM-CSF receptor has been shown to exist in a pre-formed dimeric complex (21). Alternatively, STATs may well interact directly with JAK2, as was previously shown for cells overexpressing exogenous STATs (47,51).
Several studies have suggested that STAT5 might play a role in proliferation induced by the IL-3/IL-5/GM-CSF receptors. Mutations in the a or b c chains that fail to support STAT induction are defective in IL-3/IL-5/GM-CSF-mediated proliferation (9,10,12,15,52). Similarly, overexpression of dominant negative JAK2 strongly inhibits GM-CSF mediated proliferation and c-fos induction in BaF3 cells, although in these cells also STAT-independent signalling pathways are blocked (39). Moreover, inhibition of STAT5 activation in BaF3 cells using dominant negative STAT5 significantly repressed IL-3 dependent growth (53), although this effect was not observed in 32D3 cells (54). This study also identified a number of STAT5 target genes, that might be involved in IL-3 function, including c-fos, pim-1, osm and cis (Fig. 1) (53-55). Finally, macrophages from STAT5A deficient mice grew more slowly in the presence of GM-CSF compared to wild type macrophages, while also the expression of CIS and A1 was markedly inhibited in the cells derived from the knockout mouse (56). Interestingly, induction of c-myc was not dependent on STAT5 (53), but rather seemed to depend on another JAK2 mediated pathway resulting in the activation of transcription factor E2F (39,57).
STAT activation by IL-3/IL-5/GM-CSF might also play a role in differentiation processes. STAT5 was implicated in the differentiation of myelomonocytic cells (58,59) and erythroid cells (60). Similarly, evidence from studies with other cytokines suggests that STAT3 is likely to play a role in macrophage differentiation (61-63), neutrophil differentiation (64), osteoblast differentiation (65) and even early embryonic development (66). A role for IL-3/IL-5/GM-CSF-induced STAT5 in myeloid differentiation remains to be demonstrated. However, recent studies have shown that IL-3/IL-5/GM-CSF induce activation of c-terminally truncated forms of STAT5 (p77, p80) in immature myeloid cell lines, while in mature myeloid cell lines full-length STAT5 is activated (table 1) (67-69). These truncated forms are generated by proteolytic cleavage (69). By contrast, during the differentiation of primary CD34+ progenitor cells to eosinophils or neutrophils, there is a switch from IL-5 / GM-CSF activated wild-type STAT5 in undifferentiated cells to p80 in the differentiated cells (70,71). Interestingly, p77 and p80 have distinct DNA-binding properties, while synthetic deletions equivalent to p77 and p80 behave as dominant negative regulators of STAT5-mediated transcription in vitro (53,68-70,72). It is therefore likely that different target genes are regulated by STAT5 / p80 in undifferentiated versus differentiated cells, and suggesting a role for STAT5 in myeloid differentiation. However, direct evidence that IL-3/IL-5/GM-CSF-induced STAT activity is causally involved in differentiation processes is currently lacking. Therefore, it would be very interesting to perform a detailed analysis of the differentiation of various hematopoietic lineages in STAT5A or 5B or even 5A/5B knockout mice.
Activation of multiple MAP kinase signalling pathways by IL-3/IL-5/GM-CSF
The ERK1 and ERK2 members of the MAPK family have been shown to be activated by IL-3/IL-5/GM-CSF in multiple primary cellular lineages and cell lines (22,73-77). Analogous to ERK activation by growth factor receptors, ERK activation by IL-3/IL-5/GM-CSF is expected to occur via activation of Ras and c-Raf. Indeed, IL-3/IL-5/GM-CSF rapidly induce activation of Ras (22,76-80) and c-Raf (22,81-83). Activation of this pathway will eventually result in enhanced transcription of c-fos and c-jun (52,78,84) and might contribute to IL-3/IL-5/GM-CSF-induced proliferation (Fig. 1) (85). A region between aa 544 and aa763 in the cytoplasmic portion of the b c receptor is involved in the activation of this pathway (52,84). The adaptor protein Shc is likely to be involved in coupling the receptor to the activation of this pathway. Shc is rapidly phosphorylated on tyrosine residues after IL-3/IL-5/GM-CSF stimulation (23,42,84,86). Interestingly, overexpression of Shc potentiates ERK activation and the proliferative response to GM-CSF (86). Shc directly binds to the phosphorylated Tyr 577 residue in the b c upon IL-3/IL-5/GM-CSF signalling (Fig. 2) (87). After phosphorylation, Shc interacts with the Grb2 adaptor protein which, in turn, interacts with mSOS, the nucleotide exchange factor for Ras (88). Tyrosine 577 of the b c chain is essential for phosphorylation of Shc and the Shc-associated p140 as well as the interaction of Shc with Grb2 and b c (41,50,52,86), while tyrosine 750 also seems to be involved in Shc phosphorylation (42). These studies suggest the following order of events in the activation of ERK2 by IL-3/IL-5/GM-CSF : Y577 - Shc - Grb2/mSOS - Ras - Raf - MEK - ERK (Fig. 1). However, alternative mechanisms are likely to also be involved, since mutation of Y577 did not block Raf - ERK activation and proliferation by GM-CSF in BaF3 cells (41). The phosphatase SH-PTP2 (PTP-1D, SHP2, syp) interacts with Y612 (44,89) or both Y577 and Y612 (52) of b c after IL-3/IL-5/GM-CSF stimulation (Fig. 2). SH-PTP2 interacts with Grb2-SOS in eosinophils, and is involved in IL-5 induced ERK activation in these cells (44).
ERK1 and 2 are not the only MAPKs that are activated by IL-3/IL-5/GM-CSF. Activation of p38 , a kinase involved in cellular responses to stress, was observed by GM-CSF in human neutrophils (Fig. 1) (90), although this was not observed by others (91). Similarly, IL-3 can activate p38 in FDC-P2 cells (92). p38 induction by GM-CSF might be involved in activation of cytosolic phospholipase A2 (90). Activation of the third group of MAPKs, the JNK/SAPK kinases, has also been reported by IL-3/IL-5/GM-CSF in TF1, BaF3, FDCP2 and MC/9 cells (Fig 1) (93-97). The mechanism through which this pathway is activated is not completely clear. Y577 of the b c chain and JAK2 are likely to be involved (93,94,97). The cytoplasmic domain of the a chain is also involved (93). However, the role of Ras is unclear, since both ras-independent (93) as well as ras-dependent (94) activation of this pathway was observed. SEK-1 might be involved upstream of JNK/SAPK activation, since SEK1 phosphorylation is induced by IL-3 in MC/9 cells (96), while dominant-negative SEK1 partially blocks JNK/SAPK activation by IL-5 (93). However, IL-3 fails to activate SEK-1 in FDC-P2 cells (95). Downstream targets for JNK/SAPK might be transcription factors involved in c-jun and c-fos regulation such as TCF, ATF2 and cJun, since dominant-negative SEK partially inhibits TRE- and DSE-dependent transcription induced by IL-5 (93). Blocking JNK/SAPK activation with a serine/threonine/tyrosine phosphatase suggests that this pathway contributes to IL-3 dependent growth, but not survival (98). However, elucidation of the precise function of this pathway in primary cells awaits the availability of specific pharmacological inhibitors of its components.
Activation of the phosphatidylinositol 3-kinase (PI3K) pathway
The lipid kinase PI3K, which generates the signalling molecule phosphatidyl-inositol 3,4,5-triphosphate, is involved in the regulation of multiple cellular processes (99). IL-3/IL-5/GM-CSF rapidly activates PI3K in multiple cell types, an event dependent on tyrosine phosphorylation (Fig. 1) (23,76,77,84,100-102). Kinases that are downstream of PI3K are also activated by IL-3/IL-5/GM-CSF. Recently it has been shown that PKB is rapidly activated by IL-3/IL-5/GM-CSF in human granulocytes, a process that was dependent on PI3K (77,103). Similarly, IL-3 activates PKB/Akt activity in multiple cell lines, a process thought to be involved in cellular survival (104,105) (see below). Similarly, the more downstream p70 S6 kinase can also be activated by IL-3 and GM-CSF (84,106). Interestingly, blocking IL-3 induced p70S6K in BaF3 cells with rapamycin partially inhibited IL-3 dependent 3H-thymidine incorporation, suggesting a role for this pathway in cellular proliferation (106).
The initiation of this pathway at the receptor level in not yet completely clear. PI3K and p70 S6K activation in BaF3 cells is dependent on the same region of the b c chain that is involved in Ras activation and it also depends on the cytoplasmic domain of the a chain (84). PI3K can interact with the b c in vitro (37). This interaction might be mediated by a novel adaptor protein (p80), which interacts with b c and the p85 subunit of PI3K in IL-3/IL-5/GM-CSF stimulated cells (107). Interestingly, this complex also contains the src-family kinases yes and lyn which themselves are activated by IL-3/IL-5/GM-CSF (100,107,108). Recently, it was shown that lyn is likely to be the kinase responsible for the activation of PI3K in response to GM-CSF (102). Cloning of p80 and further characterisation of its binding partners will be necessary to elucidate the precise mechanism by which IL-3/IL-5/GM-CSF activate the PI3K pathway. Another mechanism by which PI3K can be activated involves tyrosine phosphorylation of the p120 Cbl protein, which was recently observed for IL-3 and GM-CSF (109-111). Interestingly, Cbl forms a stable complex with the adaptor proteins Grb2, Crk and SHC (109-112). More importantly, PI3K can also be observed in this complex (110,113). However, a causal relationship between Cbl phosphorylation and activation of the PI3K pathway by IL-3/IL-5/GM-CSF remains to be demonstrated.
Survival through IL-3/IL-5/GM-CSF receptor signalling
It is well appreciated that one of the major functions of IL-3/IL-5/GM-CSF is the inhibition of apoptosis in their target cells, both in mature blood cells as well in early progenitors (114). However, the signalling pathways utilised by IL-3/IL-5/GM-CSF to overcome death signals have only recently started to become evident. The first molecular approach to tackle this problem was taken by Kinoshita et al (115), who showed that deletion of the cytoplasmic tail of the b c chain down to amino acid 544 completely inhibited cellular survival by GM-CSF in BaF3 cells. This deletion includes the region of the b c chain involved in activation of the RAS-ERK pathway. Moreover, overexpression of an activated Ras Val12 in cells containing the b c 544 mutant could overcome the defect in GM-CSF or IL-3 induced survival, further stressing the importance of Ras signalling in survival (115,116), although this effect might also be mediated by PI3K (see below). Similarly, overexpression of oncogenic Raf , a downstream target of Ras, also suppressed apoptosis induced by IL-3 withdrawal in 32D3 and BaF3 cells (117,118). Similarly, inhibition of ERK activation with a dominant negative MAPKK suppresses IL-3 dependent survival in BaF3 cells (119). A role for ERK in eosinophil survival was also suggested by studies showing that activation of the tyrosine phosphatase SHPTP2/SHP2 by IL-5 is necessary for both ERK2 activation as well as IL-5 mediated survival (44). Similarly, activation of the src-like kinase Lyn, which is thought to act upstream of the Ras-ERK pathway (22), is necessary for survival in IL-5 or GM-CSF treated eosinophils and neutrophils (31,32).
The targets important for cellular survival induced by IL-3/IL-5/GM-CSF seem to be proteins of the anti-apoptotic bcl-2 gene family (Fig. 1). Bcl-2 and bcl-x expression is rapidly induced by IL-3 or activated Ras in multiple cell types (115,120-122). Similarly, GM-CSF induces the expression of A1, a novel hemopoietic-specific homologue of bcl-2 (123). Jak2 activation by these cytokines seems to be involved in the induction of Bcl2 (124). Interestingly, overexpression of bcl-2 or A1 block apoptosis induced by IL-3 withdrawal in cell lines (125-127). Importantly, IL-5 treatment of primary eosinophils results in a significant increase in bcl-2 expression, which is a prerequisite for IL-5 mediated survival as demonstrated by antisense olignucleotide experiments (128). In addition, IL-3 induced bcl-2 phosphorylation on serine 70 contributes to survival, since bcl-2 (serine 70-alanine) is unable to support IL-3 independent survival (126).
The studies described above suggest that IL-3 induced Ras - Raf - ERK - Bcl2 activation plays an important role in cellular survival (Fig. 1). However, recent reports have shown that this might be an oversimplification. Gotoh et al (129) have shown that also ras-ERK independent pathways can mediate survival by IL-3 in BaF3 cells. They identified two tyrosine residues on shc, Y239 and Y240, which mediate induction of the anti-apoptotic c-myc gene, but not Ras-ERK activation. Moreover, cells expressing shc Y239/240F, which activates Ras-ERK but not c-myc, were sensitive to apoptosis. On the other hand, cells expressing shc Y317F, which are unable to activate Ras-ERK, but still enhance c-myc expression, showed resistance to apoptosis. Similarly, mutation of Y750 in the b c chain results in a decrease in Shc phosphorylation accompanied by a decrease in GM-CSF induced survival (42). However, Shc phosphorylation is not absolutely required for GM-CSF mediated survival, since a b c mutant unable to induce Shc phosphorylation is still able to support survival of BaF3 cells (50). Others have also hinted to the role of ERK-independent pathways in survival. An activated form of the R-Ras protein, (Q87L), was shown to suppress cell death in IL-3 starved BaF3 cells in a manner dependent on the presence of serum IGF-I (130). Interestingly, this effect could not only be blocked with the MEK-MAPK inhibitor PD98059, but also with the PI3K inhibitors LY294002 and wortmannin, suggesting that the PI3K pathway also contributes to survival. Indeed, R-Ras was previously reported to activate PI3K (131). Similarly, the apoptosis-suppressing effect of another Ras mutant (G12V/V45E) in BaF3 cells could be overcome with PI3K inhibitors or by inhibiting p70S6K with rapamycin (118). Blocking the PI3K / p70S6K pathways in other cell types also hints to the involvement of these kinases in survival (132). Recent advances in the elucidation of this signalling pathway have indicated that the PKB/Akt kinase which lies downstream of PI3K is involved in cell survival in multiple cellular systems (133). Indeed, overexpression of active PKB/Akt results in IL-3 independent survival of 32D3 and BaF3 cells and promotes the expression of the anti-apoptotic c-myc and bcl-2 genes (Fig. 1) (104,134). Moreover, apoptosis after IL-3 withdrawal is accelerated by a kinase-dead mutant of PKB/Akt with dominant-negative properties (104). A major target for PKB/Akt in survival was shown to be the pro-apoptotic bcl-2 family member BAD. PKB phosphorylates BAD at the same residues that are phosphorylated in response to IL-3, thereby blocking its pro-apoptotic activity (Fig.1) (105,135).
Although the studies described above clearly show that both the ras-ERK and the PI3K-PKB pathways can be involved in cellular survival depending on the cell type studied, a number of questions remain unanswered. It would be important to test whether Y239/240 of Shc, which can induce c-myc and signal to survival, are involved in the activation of the PI3K-PKB pathway. The observation that PI3K can interact with Shc in chronic myelogeneous leukemia cells suggests that this might well be the case (136). Since most of the work was performed in cell lines, it is extremely important to test the relative contribution of the different signalling pathways to cellular survival using specific pharmacological inhibitors in primary target cells such as eosinophils and neutrophils. However, the upregulation of anti-apoptotic proteins (bcl-2 and c-myc) and the down-regulation of pro-apoptotic proteins (BAD) is clearly involved in survival, disregarding their upstream regulators.
Cellular effector functions
As described above, most of the work on IL-3/IL-5/GM-CSF signalling has focused on the regulation of proliferation, differentiation and cellular survival by these cytokines. It is widely acknowledged that IL-3/IL-5/GM-CSF receptors also modify various effector functions in myeloid cells, such as cellular migration and respiratory burst in granulocytes. Pre-incubation of neutrophils or eosinophils with IL-3/IL-5/GM-CSF strongly enhances effector functions regulated by other stimuli, such as FMLP, a phenomenon known as ‘priming’ (137). However, studies on the molecular mechanisms by which these effector functions regulated by IL-3/IL-5/GM-CSF receptors are relatively sparse. A role for ERK activation by IL-3/IL-5/GM-CSF in neutrophil effector functions was suggested (138,139). However, blocking ERK activation with PD098059 showed that it is not involved in GM-CSF- primed neutrophil respiratory burst or migration (76), analogous to the observation that IL-8 induced ERK activation does not play a role in neutrophil migration (140). By contrast, IL-3/IL-5/GM-CSF induced Erk activation might play a role in phospholipase A2-mediated release of the lipid mediator PAF (76) and granule secretion (141).
The role of the PI3K pathway in cellular effector functions has been more widely studied. FMLP-induced respiratory burst in neutrophils is dependent on PI3K, as was demonstrated using the PI3K inhibitors wortmannin and LY294002 (141-143). Recently it was shown that priming and activation of the PI3K pathway by GM-CSF is involved in the activation of the respiratory burst and chemokinesis by GM-CSF in neutrophils (76) and eosinophils (77).One of the targets of PI3K involved in the activation of the respiratory burst may be p47phox, which is thought to play a major role in the activation of the NADPH oxidase complex. Interestingly, wortmannin blocks FMLP induced p47phox phosphorylation (143). Moreover, overexpression of active PI3K in the monoblastic phagocyte cell line GM-1 caused constitutive phosphorylation of p47phox (144). However, clarification of the precise mechanism of respiratory burst activation in granulocytes awaits further study. The availability of specific inhibitors of the MAPK and PI3K pathways will undoubtedly be of great help in determining the roles of these pathways in various cellular effector functions regulated by IL-3/IL-5/GM-CSF.
Turning off the signal : of phosphatases and STAT-induced STAT repressors
Continuous activation of the signalling pathways described above would lead to cytokine-independent growth of the target cells (145). Therefore, feedback mechanisms exist to ensure a transient response to the IL-3/IL-5/GM-CSF cytokines. The tyrosine phosphatase HCP (also called PTP1C, SHPTP1, SHP or SHP1) appears to be a major player in this process. Increased levels of HCP lead to a reduction of the level of b c phosphorylation as well as the suppression of IL-3 dependent cell growth, whereas reduced HCP levels show the opposite effect (146,147). Following ligand binding, HCP specifically associates with the b c chain, probably via Y612 (Fig. 1) (89,146,147). The role for HCP in the down-regulation of IL-3/IL-5/GM-CSF signalling might explain the dramatic hematopoietic abnormalities observed in HCP mutant (motheaten) mice, which die soon after birth due to overproliferation and accumulation of macrophages in the lung (148-150).
Other phosphatases have also been implicated in IL-3/IL-5/GM-CSF signalling. SHPTP2 also interacts with Y612 of the activated b c chain, while this residue is also a good substrate for SHP2 in vitro (89). However, the precise role of SHP2 in IL-3/IL-5/GM-CSF signalling remains to be determined, since it also seems to play a positive role in IL-3/IL-5/GM-CSF signalling, coupling the receptor to Grb2 and PI3K (44,151). Recently, a number of different inositol phosphatases, including SHIP and pp135, were implicated in the negative regulation of IL-3/IL-5/GM-CSF signalling (97,152,153). However, the exact contribution of this class of phosphatases to IL-3/IL-5/GM-CSF signalling remains to be determined.
A novel mechanism of terminating IL-3/IL-5/GM-CSF signalling was demonstrated by Yoshimura et al (154). They cloned a cytokine inducible gene named CIS (cytokine inducible SH2 containing protein). CIS is rapidly and transiently induced by various cytokines including IL-3 and GM-CSF . Interestingly, CIS binds stably to the tyrosine phosphorylated b c chain (154). CIS is thought to be a negative regulator of IL-3/IL-5/GM-CSF signalling, since overexpression of CIS represses IL-3 dependent growth (154), oncostatin M induction and STAT5 activation (155). CIS is upregulated via a STAT5 dependent mechanism (Fig.1), since BaF3 cells overexpressing dominant-negative STAT5 fail to induce CIS in response to IL-3 (53). Moreover, in bone marrow-derived macrophages from STAT5A deficient mice, CIS induction by GM-CSF was markedly inhibited (56). Indeed, the CIS promoter contains four STAT binding sites which are activated by STAT5 (155). Recently, it was shown that CIS is a member of a large family. Three CIS-related SOCS genes (suppresser of cytokine signalling) were cloned, that are also rapidly induced by a variety of cytokines including IL-3 and GM-CSF (156). Similarly, JAB (JAK binding protein), SSI-1 (STAT-induced STAT inhibitor) and CIS2-4 are CIS-related SH2 containing proteins that are rapidly induced by a variety of cytokines (157-159). Similarly, STAT3 function can be blocked by a novel protein PIAS3 (protein inhibitor of activated STAT), which associates with STAT3 only in cytokine-stimulated cells (160). SOCS, SSI-1, JAB and CIS3 also inhibit activation of the JAK - STAT pathway, apparently by directly interacting with the JAKs (157,158). The precise mechanism by which this occurs is at present unclear, but might involve SOCS/JAB/SSI associated phosphatases that directly dephosphorylate JAK, thereby inhibiting its activity.
Future Directions
Since the appreciation that tyrosine phosphorylation of a common set of substrates plays an important role in IL-3/IL-5/GM-CSF signalling (161), much progress has been made in understanding the mechanisms by which IL-3/IL-5/GM-CSF regulate a wide variety of cellular processes. The cloning of the IL-3/IL-5/GM-CSF receptor components and their mutagenesis have revealed some but not all of the mechanisms by which IL-3/IL-5/GM-CSF induce signalling cascades such as the Ras-ERK, p38/JNK, PI3K, and JAK-STAT pathways. Moreover, the availability of specific inhibitors of some of these pathways has opened the way to more extensive studies on the relative contribution of each of these pathways to cellular functions regulated by IL-3/IL-5/GM-CSF. New insights into IL-3/IL-5/GM-CSF signalling are also expected to arise from studies using the yeast two-hybrid system to clone (novel) proteins which interact with the IL-3/IL-5/GM-CSF receptors. In particular, it is important to determine whether the a chains interact with cytoplasmic proteins in a cytokine-specific manner, since the ligand-specific effects of IL-3/IL-5/GM-CSF (1,162) are likely to be mediated via the a chains. Similarly, the availability of techniques to generate lineage-specific knock out mice will also contribute to the understanding of IL-3/IL-5/GM-CSF signalling. Finally, relevant IL-3/IL-5/GM-CSF target genes are now beginning to be cloned using novel techniques such as differential display PCR (163). It is therefore likely that much progress will be made in the coming years in delineating the mechanistic aspects of IL-3/IL-5/GM-CSF-regulated signal transduction, proliferation, differentiation, survival and cellular effector functions.
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