The University of Texas Medical Branch, Division of Allergy and Immunology, Department of Internal Medicine, Galveston, Texas 77555-0762
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ABSTRACT |
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Cytokines are important regulators of
hematopoiesis. They exert their actions by binding to specific
receptors on the cell surface. Interleukin-5 (IL-5) is a critical
cytokine that regulates the growth, activation, and survival of
eosinophils. Because eosinophils play a seminal role in the
pathogenesis of asthma and allergic diseases, an understanding of the
signal transduction mechanism of IL-5 is of paramount importance. The
IL-5 receptor is a heterodimer of - and
-subunits. The
-subunit is specific, whereas the
-subunit is common to IL-3,
IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF)
receptors and is crucial for signal transduction. It has been shown
that there are two major signaling pathways of IL-5 in eosinophils.
IL-5 activates Lyn, Syk, and JAK2 and propagates signals through the
Ras-MAPK and JAK-STAT pathways. Studies suggest that Lyn, Syk, and JAK2
tyrosine kinases and SHP-2 tyrosine phosphatase are important for
eosinophil survival. In contrast to their survival-promoting activity,
Lyn and JAK2 appear to have no role in eosinophil degranulation or
expression of surface adhesion molecules. Raf-1 kinase, on the other
hand, is critical for eosinophil degranulation and adhesion molecule
expression. Btk is involved in IL-5 stimulation of B cell function.
However, it does not appear to be important for eosinophil function.
Thus a clear segregation of signaling molecules based on their
functional importance is emerging. This review describes the signal
transduction mechanism of the IL-3/GM-CSF/IL-5 receptor system and
compares and contrasts IL-5 signaling between eosinophils and B cells.
interleukin-5; eosinophil; kinase; granulocyte-macrophage colony-stimulating factor
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INTRODUCTION |
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INTERLEUKIN-5 (IL-5) was initially found as a T
cell-replacing factor (TRF) that induced differentiation of B cells
into immunoglobulin-secreting cells (29, 111). It was subsequently
shown that TRF had B cell growth-promoting activity (termed BCGF II) on
BCL1 cells (116) and dextran
sulfate-stimulated B cells (41). Takatsu et al. (120) further
demonstrated that induction of cytotoxic T lymphocytes from thymocytes
required T cell-derived soluble mediators referred to as killer helper
factors (KHF) and found that KHF was identical to TRF (121). Because
TRF had pleiotropic activities on multiple cells, it was renamed IL-5
in 1987. Murine IL-5 is known to enhance several functions of murine B
cells, including immunoglobulin production, growth, and differentiation
(122). The response of human B cells to human IL-5 has been a subject
of controversy. Several recent publications tend to indicate that human
B cells are capable of responding to human IL-5 under certain
conditions. Human IL-5 augments immunoglobulin production of
Staphylococcus aureus Cowan I (SAC) or
pokeweed mitogen-stimulated human B blasts in the presence of specific
cytokines such as IL-2 or IL-4 (9, 73). Huston et al. (46) have
recently demonstrated that human IL-5 directly induces responsiveness
of B cells stimulated with Moraxella
catarrhalis (MCat) but not with SAC. They have also shown that freshly isolated human B cells express mRNA for IL-5R, IL-5R
, and soluble IL-5R
and that stimulation by either MCat or
SAC increases IL-5R
and IL-5R
mRNA and decreases soluble IL-5R
mRNA. Besides the effect on B cells, human IL-5 has also been shown to
act on T cells. Human IL-5 increases the expression of IL-2R
on
human T cells (84) and augments cytotoxic T cell generation (78).
In humans, the biological effects of IL-5 are best characterized for eosinophils. IL-5 is not only essential for the terminal differentiation of eosinophils but is also important for the activation of mature eosinophils. These cells are the most important effector cells of allergic reactions. Allergic diseases were originally regarded as a manifestation of immediate hypersensitivity reactions, mostly mediated by mast cells. There is now clear evidence that the late-phase allergic reaction is an integral part of allergic disorders. The late-phase allergic reaction is characterized by the influx of huge numbers of eosinophils and, to a lesser extent, lymphocytes, monocytes, basophils, and neutrophils. In accordance with the foregoing statement, bronchial mucosa of asthmatic patients who die of severe bronchoconstriction show a marked eosinophilic infiltration (34). Eosinophils show signs of activation, e.g., increased release of eosinophil granular proteins and production of leukotriene C4 (LTC4) and superoxide. Eosinophil granular proteins, such as major basic protein (MBP), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPO) combined with H2O2 and halide, cause damage to respiratory epithelium in guinea pigs (74). LTC4 has a potential role in the induction of smooth muscle contraction, mucus production, and edema formation in the pathogenesis of asthma (96). IL-5 may be the most important cytokine that primes eosinophil function. T cells from allergic patients are mostly of Th2 functional subtype and produce large quantities of IL-4 and IL-5 (56). Once eosinophils infiltrate airways, they produce IL-5, establishing a positive feedback mechanism (12, 26). The major functions of IL-5 on eosinophils are shown in Table 1. IL-5 also acts on basophils to enhance the release of mediators such as histamine and LTC4 (10, 43, 66).
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IL-5 belongs to the hematopoietic growth factor family of cytokines. It
has significant functional homology with IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF). The reason
for this homology is that the -receptor subunit is common to all
three cytokines (Fig. 1) (72). The ligand
specificity is preserved by distinct
-receptor subunits. This is
similar to the common
-receptor subunit for IL-2, IL-4, IL-7, IL-9,
and IL-15. The
-subunits are specific for each cytokine and bind their specific ligand with low affinity. The
c-subunit forms a
high-affinity receptor with all three
-subunits, despite its lack of
capacity to bind the cytokines by itself. The
c-subunit is not only
required for the formation of the high-affinity receptor complex but is
also crucial for signal transduction. Most signal transduction studies
of the
c receptor have been performed with IL-3- or GM-CSF-dependent
cell lines. There are relatively few publications using primary cells
such as eosinophils or B cells. Studies with primary cell types are,
however, extremely important because many important granulocytic
functions such as degranulation, chemotaxis, or cytotoxicity cannot be
performed using cell lines.
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In this review, we discuss recent findings concerning IL-3/GM-CSF/IL-5 signaling in cell lines. We then analyze the findings of IL-5 signal transduction in eosinophils and B cells.
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A CLASSIFCATION OF INTRACELLULAR SIGNALING EVENTS |
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Receptor-driven signaling processes typically originate from the juxtamembranous region of the receptor. Some signaling molecules are physically associated with the receptor under basal conditions. Furthermore, many of them are N-acylated. N-acylation results in anchoring the signaling molecule into the lipid membrane (e.g., tyrosine kinases of the src family). The activation of these membrane-anchored tyrosine kinases and lipid kinases occur in the juxtamembranous hydrophobic milieu. Thus this initial step can be called the juxtamembranous signaling step (Fig. 2). In addition to membrane-anchored signaling molecules, there are cytosolic signaling molecules that frequently translocate from the receptor site to other cellular compartments (e.g., nucleus, cytoskeleton, mitochondria). These mobile signaling molecules mostly operate in a hydrophilic milieu. For the juxtamembranous signaling molecules to transduce signals to cytosolic signaling molecules, various interfacing molecules become necessary. The interfacing molecules either serve as docking sites for cytosolic signaling molecules or form multimolecular complexes with them and then translocate to other cellular compartments. Thus the second step can be called the signal interfacing step (Fig. 2). The third step of signaling involves the activation of mobile cytosolic signaling molecules. The latter molecules translocate into their target sites by unknown mechanisms. Subsequently, the signal is transduced and translated into biological functions. Thus this step can be called the mobile signaling step (Fig. 2). One possible outcome of the mobile signaling step is the activation of transcription factors and their migration to the nucleus, leading to initiation of gene transcription. This step can be called the transcription-activating step (Fig. 2).
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IL-3/GM-CSF/IL-5 SIGNALING IN CELL LINES |
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The Juxtamembranous Signaling Step
Specific cytoplasmic regions of
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The binding of JAK2 kinase to receptors has been studied by Murakami et
al. (77). For this purpose they initially have studied the
gp130 subunit of the IL-6 receptor. They have postulated that the
so-called box 1 region is important for signaling via the gp130
receptor subunit. The proline-rich motif (PXP motif) in the box 1 region is conserved among many cytokine receptors, e.g., c receptor
of IL-3/GM-CSF/IL-5, IL-2 receptor
chain, granulocyte colony-stimulating factor receptor, and erythropoietin
receptor. The mutation of the two proline residues in the PXP motif of
gp 130 results in complete loss of IL-6 signaling activity. In
accordance with this observation, Watanabe et al. (133) have reported
that the box 1 region is essential for GM-CSF-dependent JAK2
activation. The deletion of box 1 from the receptors for growth hormone
and erythropoietin abolishes their JAK2-binding property (123).
Interestingly, however, Ogata et al. (86) have recently shown that a
GST fusion protein with the cytoplasmic region (amino acid
residues 456-544) of the
c, which contains the box 1 motif,
cannot bind JAK2. These results indicate that the box 1 region is
essential but not sufficient for JAK2 binding.
The IL-5 receptor -subunit is also known to be important for IL-5
signaling. A murine IL-3-dependent FDC-P1 cell line, into which mutant
mIL-5R
lacking its whole cytoplasmic domain was transfected, does
not respond to IL-5, indicating that the cytoplasmic region of the
-subunit is critical for IL-5 signaling (118). A study using the
COOH-terminal truncated cytoplasmic domain of IL-5R
has revealed
that JAK2 is constitutively associated with the IL-5R
and that the
region between amino acids 346 and 387 is responsible for this
association (86). Like the
c, at least two sites are indispensable
for JAK2 binding, the regions of amino acids 351-356 and
366-387 (Fig. 3). The former region contains the box 1-like PPXP
motif. The deletion or mutation of the proline-rich motif from IL-5R
causes loss of growth, stimulatory effects, induction of
c-fos,
c-jun, and
c-myc, and tyrosine phosphorylation of
cellular proteins including JAK2 (119).
Most cytokines exist in dimers under physiological conditions.
Consequently, receptors are likely to dimerize on ligand binding. The
same principle may also apply to IL-5, since it also exists as a dimer.
In this model, the dimerization brings the c receptor-associated JAK2 kinases to close proximity and promotes cross-phosphorylation. However, dimerization may not be an absolute requirement for signaling, since a modified monomeric form of IL-5 has been shown to activate cells (24). Alternatively, the IL-5R
-associated JAK2 may activate the
c-bound JAK2. This possibility is supported by the signaling capability of a chimeric receptor in which the cytoplasmic domain of
IL-5R
is substituted by that of
c (119). However, IL-5R
is
essential for IL-5 signaling because the
c receptor cannot bind the
ligand by itself.
The importance of JAK2 activation has been studied in cell lines. In
BA/F3 cells, a dominant negative JAK2 mutant, which lacks the kinase
domain, suppresses the activation of c, Shc
(src homologues and
collagen), SHP-2 (SH2-containing phosphatase-2), and
c-fos as well as
c-myc (133). The kinase domain of JAK2
also seems to be important for the induction of Bcl-2 (B cells
lymphoma/leukemia-2) and the maintenance of cell viability (106). JAK2
and other members of the Janus kinase family are known to transduce
signals via the signal transducers and activators of transcription
(STAT) transcription factors. Recently, JAK2 has been shown to activate the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway not only
through the receptor subunit but also directly. For example, Vav
associates with JAK2 after GM-CSF stimulation in MO7e cells (70).
Furthermore, tyrosine phosphorylation of Vav is significantly increased
when JAK2 is coexpressed with Vav in the insect cell line, Sf21. In
interferon-
(IFN-
)-stimulated cells, Raf-1 is activated by JAK2
in the presence of Ras, and a ternary complex of Ras, JAK2, and Raf-1
is observed (137). In this condition Raf-1 is phosphorylated on
tyrosine-340 and tyrosine-341 by v-Src, whereas JAK2 does not
phosphorylate these residues, suggesting that Raf-1 is regulated by
JAK2 and v-Src through a different mechanism.
Signal-Interfacing Step
Adapter proteins. The next signaling step for many tyrosine kinases is the interfacing step with adapter proteins. The tyrosine phosphorylation ofIn response to IL-3, GM-CSF, and IL-5 stimulation, Shc not only binds
to c but also undergoes tyrosine phosphorylation (18, 25, 71). IL-3
and GM-CSF also induce tyrosine phosphorylation of a 140-kDa protein
that is constitutively bound to growth factor receptor-bound protein-2
(Grb2) through Shc activation (53, 61, 71). Liu et al. (65) identified
a 145-kDa protein that associates with Shc through its SH2 domain after
cytokine stimulation and competes with Grb2 for the same
tyrosine-phosphorylated site on Shc. This 145-kDa protein exhibits
inositol polyphosphate 5-phosphatase activity (19). Furthermore, it has
been shown that a 135-kDa protein having phosphatase activity is
constitutively associated with Grb2 and inducibly associated with Shc
in GM-CSF-stimulated UT-7 cells (85). These 140-kDa, 145-kDa, and
135-kDa proteins are now considered to be identical and are called
SH2-containing inositol-5'-phosphatase (SHIP). The interaction
with SHIP suggests that Shc is likely to propagate signals through the
Ras and inositol pathways.
The tyrosine phosphatase, SHP-2 (previously known as Syp, PTP1D, and
SHPTP2), is also known to associate with the c receptor via its SH2
domain and is activated after stimulation with IL-3 or GM-CSF (135).
Once phosphorylated on tyrosine residues, SHP-2 generates a binding
site for Grb2, which in turn leads to activation of the Ras signaling
pathway. SHP-2 tyrosine phosphorylation is mediated through multiple
sites of
c (Fig. 3). It has been shown that
c with a mutation of
tyrosine-577 to phenylalanine and a COOH-terminal truncated mutant at
position-589 are equally capable of inducing tyrosine phosphorylation
of SHP-2. This is in contrast to Shc, because its phosphorylation is
dependent on tyrosine-577 (Fig. 3). A guanine nucleotide-exchanging
protein, Vav, is known to regulate the Ras pathway. It is
constitutively associated with the SH3 domain of Grb2 and
phosphorylated on tyrosine residues by IL-3, GM-CSF, and IL-5 (40, 68,
70, 108). In addition, the involvement of JAK2 and Tec kinases for the
activation of Vav has been suggested (68, 70).
Activation of phosphatidylinositol
3-kinase. Phosphatidylinositol 3-kinase (PI3K) has been
implicated in various cell functions including mitogenic signals,
membrane ruffling, oxidative burst, and glucose transport. IL-3,
GM-CSF, and IL-5 activate PI3K (35, 107, 108). Because the c-subunit
does not have a consensus motif for PI3K binding, it is necessary for
c to use a distinct mechanism for its association with and
activation of PI3K. Several groups have identified molecules that
intermediate between
c and PI3K. One possible molecule is SHP-2,
which associates with
c and with the p85 subunit of PI3K after
treatment with IL-3 or GM-CSF (135). Jücker and Feldman (52) have
described an unknown p80 protein that is tightly associated with
Src/Yes and Lyn, as well as
c and the p85 subunit of PI3K in
GM-CSF-stimulated TF-1 cells (52). This report suggests that the
src family kinases may be involved in
tyrosine phosphorylation of PI3K. Recently, Tec tyrosine kinase has
been shown to link
c to PI3K through JAK2 kinase in IL-3 signaling
(117). PI3K transduces signals to a number of serine/threonine kinases,
such as novel/atypical protein kinase C (nPKC/aPKC) (83, 127), Akt,
c-jun
NH2-terminal kinase (JNK), and p70
S6 kinase (60). Although the functional role of PI3K in
IL-3/GM-CSF/IL-5 signaling is not well known, del Peso et al. (22) have
recently shown that IL-3 propagates signals via the PI3K-Akt-BAD
pathway, indicating that PI3K may participate in cell survival through
the phosphorylation of BAD.
Mobile Signaling Step
Ras-MAPK Pathway. The outcome of activation of various adapter proteins and GTPases in the interfacing step is the stimulation of p21 G proteins. One of the most extensively studied p21 G proteins is Ras. Ras translocates Raf-1 kinase to the juxtamembranous compartment, where the latter is activated by tyrosine kinases, protein 14-3-3, and possibly by PKC. Raf-1 regulates extracellular signal-regulated kinase (ERK), a member of the MAPK family, through activation of MAP or ERK kinase (MEK). ERK is a positive regulator of c-fos induction. IL-3, GM-CSF, and IL-5 are known to stimulate this signaling cascade, i.e., to activate Ras (27, 109), Raf (14, 55), and ERK (87, 100, 134). These cytokines also activate downstream targets of MAPK, p90 S6 kinase [ribosomal S6 kinase (RSK)] (51), and MAPK-activated protein (MAPKAP) kinase 2 (1). The characteristic feature of this step is that the involved signaling molecules easily translocate to various cellular compartments on activation. For example, a significant pool of Raf-1 translocates to mitochondrial membranes, whereas ERK migrates to the cytoskeleton, nucleus, and possibly other compartments.The Ras-ERK pathway is involved in the prevention of cell death in
certain cell types. BA/F3 cells expressing the truncated mutant of c
at position 544, which is unable to activate Ras, undergo apoptosis
despite GM-CSF stimulation (57). The expression of activated Ras
restores the capacity of the cells to survive. In agreement with this
finding, expression of an activated mutant of Ras prevents BA/F3 cells
from apoptosis caused by deprivation of IL-3, whereas the dominant
negative mutant of Ras exhibits no inhibitory effect on IL-3-dependent
cell proliferation (124). The results from these studies indicate that
the signaling pathway for DNA synthesis appears to be different from
the anti-apoptotic pathway. Several proteins of the Bcl-2 family have
been identified that participate either as inducers or repressors of
programmed cell death (104). The expression of Bcl-2 or
Bcl-XL genes is likely to be
involved in the inhibition of apoptosis following IL-3 stimulation (58,
62, 95). One possible mechanism of inhibition of apoptosis by Bcl-2 is
its ability to associate with Raf-1, translocating this kinase from the
cytosol to the mitochondrial membrane (131). Once there, Raf-1
phosphorylates BAD, a pro-apoptotic Bcl-2 family protein that abrogates
the cytoprotective functions of Bcl-2 and
Bcl-XL by heterodimerizing with
them. Only the nonphosphorylated BAD is able to heterodimerize with
Bcl-2/Bcl-XL to promote cell death
(33). Two recently published papers have shown that BAD is
phosphorylated on serine following IL-3 stimulation, indicating its
activation and possible participation in the inhibition of apoptosis
(22, 139).
The MAPK family. The MAPK family
consists of a growing number of serine/threonine kinases that are
characteristically activated by threonine and tyrosine phosphorylation.
The members include ERK1, ERK2, ERK5, and ERK6, JNK/stress-activated
protein kinase (SAPK) and various isoforms of p38 (p38, p38,
p38
-2, p38
, and p38
). JNK, activated by stimuli such as tumor
necrosis factor, ultraviolet radiation, or protein synthesis
inhibitors, binds to the c-jun
transactivation domain and phosphorylates serine-63 and serine-73 (23).
The p38 has an important role in the regulation of actin microfilament
dynamics through the activation of MAPKAP kinase 2/3 and heat shock
protein 27 (37). Recent studies have shown that major members of the
MAPK family, i.e., ERK1/2, JNK/SAPK, and p38 are involved in
c
receptor signaling. We have already discussed the activation of ERK. In
murine hematopoietic BA/F3-derived cell lines, a significant increase
of JNK1 activity is observed after IL-3 or GM-CSF stimulation (125).
Dominant-negative Ras fails to induce JNK1 activation by IL-3, and the
constitutively active form of Ras causes no increase in JNK1 activity,
suggesting that Ras is essential but not sufficient for IL-3-induced
JNK1 activation. IL-5 also induces JNK activation, which seems to be responsible for
12-O-tetradecanoylphorbol 13-acetate
response element- and serum responsive element (SRE)-dependent
transcription (21). Nagata et al. (79, 80) have shown that IL-3 also
activates p38 MAPK as well as JNK. In this system, IL-3 does not
activate their upstream signaling molecules, SEK1 (SAPK/ERK kinase
1)/MKK4 (MAPK kinase 4), and MKK3/MKK6, respectively. Taken together, signaling pathway(s) other than the Ras-MAPK, e.g., the PI3K pathway (60) or the Ca2+ signaling pathway
(115), may be involved in the regulation of JNK and p38.
The JAK-STAT pathway and its cross talk with the
Ras-MAPK pathway. The JAK-STAT pathway is important for
signaling of many cytokine receptors, including
IL-3/GM-CSF/IL-5 receptors (47). The activated JAK kinases
phosphorylate members of the STAT family of nuclear factors on tyrosine
residues. Thus far, seven members of the STAT family have been
identified: STAT1 (STAT1, STAT1
), STAT2, STAT3, STAT4, STAT5A,
STAT5B, and STAT6. The tyrosine-phosphorylated STATs form homo- or
heterodimers, which cause their translocation to the nucleus and
binding to the
-activating sequences (GAS) motif of
the promoter region of various genes. IL-3, GM-CSF, and IL-5 mainly
utilize STAT5 homologues, currently known as STAT5A and STAT5B, in
myeloid cell lines (5, 75, 89). Although the importance of STAT5
activation in IL-3/IL-5/GM-CSF action is not fully clear,
GM-CSF-stimulated cell proliferation and gene transcription are
impaired in STAT5A knockout mice (31). Besides STAT5, these cytokines
also activate STAT1 (11, 81), STAT3 (11, 13, 81), and STAT6 (99).
The Ras-MAPK and the JAK-STAT pathways converge at various levels. The
c-fos promoter contains SRE and SIE
(c-sis-inducible element) sites, and the former is regulated by MAPK, whereas the latter
carries the GAS sequence, which is the DNA binding site for STAT (32,
69). Mui et al. (76) have shown that activated Ras alone can induce
c-fos expression but that the maximal
expression requires the action of both Ras and STAT5. Another
converging point is the gene transcription by STAT proteins. STAT1 and
STAT3 have been shown to be serine phosphorylated in response to
cytokine stimulation (136, 140). For STAT1, the site of phosphorylation is serine-727, which is a consensus phosphorylation site for a proline-directed serine kinase such as MAPK and is likely to be important for transcriptional activation. Interestingly, MAPK appears
to be associated with the -subunit of IFN-
/
receptor and
modifies STAT proteins to activate early response genes (20). A study
using a dominant negative MAPK has shown that STAT1 and STAT3 are
regulated not only by tyrosine kinases but also partially by MAPK in
GM-CSF signaling (101). However, it is controversial whether MAPK
actually regulates serine phosphorylation of all STAT proteins. For
example, STAT5 activation requires a distinct serine/threonine kinase
other than MAPK in IL-2 signaling (8).
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IL-5 SIGNALING IN PRIMARY CELLS |
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IL-5 Signaling in Eosinophils
The results of studies with human eosinophils agree in many respects with the findings using cell lines. IL-5 activates Lyn (93, 138), Syk (138), JAK2 (6, 94, 129) tyrosine kinases, and PI3K (16), which transduce signals to downstream molecules. It has been suggested that these tyrosine kinases have a critical role in the survival of eosinophils (Table 1). Lyn knockout mice are eosinopenic and have reduced eosinopoiesis in bone marrow, further confirming the role of Lyn kinase in eosinophil growth and differentiation (42). In addition to tyrosine kinases, SHP-2 tyrosine phosphatase has an important function in IL-5 signaling in eosinophils. SHP-2 is physically associated with theTransforming growth factor- (TGF-
) is a broadly active
anti-inflammatory and immunomodulatory cytokine. It antagonizes the majority of the effect of cytokines on eosinophils (2). The molecular
targets of TGF-
action on eosinophils appear to involve Lyn, MAPK,
JAK2, and STAT1 (91). TGF-
inhibits IL-5-induced tyrosine
phosphorylation of these proteins. The mechanism of this inhibition may
be due to the interception of initial signaling molecules such as Lyn
and JAK2. However, TGF-
does not modulate the function of tyrosine
phosphatases such as SHP-2.
IL-3, GM-CSF, and IL-5 promote growth and survival of eosinophils and prime their function such as degranulation, chemotaxis, and cytotoxicity. Coffer et al. (16) have shown that PI3K, but not Ras-MAPK, has a role in zymosan-stimulated superoxide production in IL-5-primed eosinophils. We have demonstrated that Lyn and JAK2 are important for eosinophil survival but not for degranulation and upregulation of CD11b (92). In contrast, Raf-1 appears to be critically involved in all of the above functions. Antisense inhibition of Raf-1 blocks IL-5-induced eosinophil survival, ECP release, and expression of CD11b. This paper tends to suggest a central role for Raf-1 kinase in controlling eosinophil function (Table 1).
IL-5 Signaling in B cells
The IL-5-induced B cell proliferation is defective in a Fyn knockout mouse model, indicating the involvement of Fyn in IL-5 signaling in mice (4). IL-5 activates JAK2 and Btk tyrosine kinases as well as PI3K, Shc, Vav, and HS1 in an IL-5-dependent murine B cell line, Y16 (108). The importance of Btk has been shown in the model of X-linked immunodeficient (XID) mice. The B cells from XID mice that carry the xid gene with a point mutation in the pleckstrin homology domain of Btk exhibit impaired responsiveness to murine IL-5 (103, 126). The XID B cells express fewer ![]() |
CONCLUDING REMARKS |
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In summary, IL-3/GM-CSF/IL-5 activate multiple tyrosine kinases and
other signaling molecules, leading to the propagation of signals via
the JAK-STAT and the Ras-MAPK pathways. Both pathways are important for
cell proliferation in factor-dependent cell lines. Thus far, only
signaling similarities but not differences among the three
hematopoietins have been found. The signaling similarities may explain
the functional homology among the cytokines. However, they do not
explain why the three cytokines have distinct roles in growth and
differentiation of eosinophils, neutrophils, and monocytes.
Particularly, the critical role of IL-5 in eosinophil differentiation
cannot be explained with the current knowledge of the signaling
pathways. One possibility is that the ligand-specific receptor
generates distinct signaling pathways that result in specific
biological actions. From this standpoint, the elucidation of the
signaling mechanism of IL-5R
will be extremely useful.
Unlike cell lines, very few signal-function relationship studies have been performed with primary cells such as terminally differentiated eosinophils. However, signal transduction studies with primary cells are extremely important, because cell functions, such as chemotaxis and degranulation, cannot be investigated with cell lines. The few studies that have been performed with eosinophils have already produced interesting results. For example, despite their critical role in cell proliferation and eosinophil survival, Lyn and JAK2 do not appear to be important for eosinophil degranulation or regulation of adhesion molecules. In contrast, Raf-1 seems to play a central role in regulating most of the eosinophil functions, including survival, degranulation, and adhesion. The identification of critical signaling molecules that are responsible for important eosinophil functions will help develop specific inhibitors for therapeutic use in asthma and other allergic diseases.
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ACKNOWLEDGEMENTS |
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The work is supported by National Institute of Allergy and Infectious Diseases Grant AI-35713 and by the McLaughlin Fellowship Fund and the John Sealy Memorial Fund.
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FOOTNOTES |
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Address for reprint requests: R. Alam, The Univ. of Texas Medical Branch, Division of Allergy & Immunology, Dept. of Internal Medicine, 301 Univ. Blvd., Galveston, TX 77555-0762.
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