IL-9 and its Receptor: From Signal Transduction
LAURENT KNOOPS and JEAN-CHRISTOPHE RENAULD*
Ludwig Institute for Cancer Research and Experimental Medicine Unit, Universite ´ de Louvain, UCL 74 59, Avenue Hippocrate 74,
B-1200 Brussels, Belgium
(Received 4 June 2004)
IL-9 is a multifunctional cytokine secreted by TH2 lymphocytes. Besides its role during immune
responses, its growth factor and antiapoptotic activities on multiple transformed cells suggest a
potential role in tumorigenesis. Indeed, IL-9 overexpression induces thymic lymphomas in mice, and
IL-9 production is associated with Hodgkin disease and HTLV-I transformed T cells in humans. IL-9
activities are mediated by a specific receptor chain that forms a heterodimeric receptor with the
common gamma chain also involved in IL-2,4,7,15 and 21 signaling. The IL-9 receptor and common
gamma chains associate with JAK1 and JAK3, respectively and trigger the STAT-1, -3 and -5, IRS and
RAS-MAPK pathways. Moreover, in vitro, dysregulated IL-9 response can lead to autonomous cell
growth and malignant transformation of lymphoid cells associated with constitutive activation of the
Keywords: Cytokine; Interleukin-9; Cancer; Signal transduction
IL-9 is a multifunctional cytokine secreted mainly by
activated TH2 lymphocytes. In vivo, IL-9 is implicated in
asthma and in the protection against nematode infections.
Biological targets include mast cells, T cell clones,
B lymphocytes, eosinophils, hematopoietic progenitors,
macrophages, epithelial cells and neurons (Renauld and
Van Snick, 2003). In addition to the activities in immune
and inflammatory responses, a series of observations in
mouse and human models point to this cytokine as a factor
promoting oncogenesis. In this review, we will discuss the
role of IL-9 in experimental or spontaneous tumoral
transformation, highlighting the signal transduction
cascades involved in this process.
ONCOGENIC ACTIVITIES OF IL-9
T Cell Lymphomas
Numerous observations suggest that dysregulated IL-9
expression and/or response could be implicated in T cell
tumorigenesis. In mouse, IL-9 was purified from helper
T-cell supernatants as a growth factor for T cell lines
(Uyttenhove et al., 1988). However, in contrast to other
T cell growth factors such as IL-2, IL-4 or IL-7, IL-9
turned out to be devoid of any activity on freshly isolated
T cells. In vitro, murine T cells acquired IL-9
responsiveness after prolonged culture, a process that
coincides with the blastic transformation seen in long term
T-cell culture (Renauld et al., 1995a). This specific effect
on transformed T cells was confirmed by the observation
that IL-9 was a potent growth factor for mouse thymic
lymphomas invitro (Vink et al., 1993) and protected those
cells from dexamethasone-induced apoptosis (Renauld
et al., 1995b). This protective effect was similar to that of
IL-4 and was even greater than that of IL-2, IL-7 or IL-10.
By contrast, IL-9 was completely inactive on normal
thymocytes (Suda et al., 1990a) except for fetal day 14
thymocytes, that proliferate in response to the combi-
nation of IL-9 and IL-2 (Suda et al., 1990b).
The possible role of IL-9 in T cell transformation
is further underlined by the fact that IL-9-dependent
T-helper cell clones transfected with the IL-9 cDNA gave
rise to autonomous T cell lines that were highly
tumorigenic in vivo (Uyttenhove et al., 1991). In another
model, an IL-2-dependent rat T cell lymphoma line
became IL-2-independent after infection by mink cell
focus-forming murine retrovirus, because of an IL-9
autocrine loop. The IL-9 production was caused by virus
infection, whereas IL-9 receptor expression resulted from
the insertion of the provirus in the 30non-coding sequence
ISSN 0897-7194 print/ISSN 1029-2292 online q 2004 Taylor & Francis Ltd
*Corresponding author. Tel.: þ32-2-764-74-64. Fax: þ32-2-762-94-05. E-mail: firstname.lastname@example.org
Growth Factors, December 2004 Vol. 22 (4), pp. 207–215
of the IL-9R gene, leading to transcriptional activation of
the endogenous IL-9R gene (Flubacher et al., 1994).
Generation of IL-9 transgenic mice confirmed in vivo
the role of IL-9 in murine T cell transformation, as 7% of
transgenic mice overexpressing IL-9 developed thymic
lymphomas. This rate was increased and accelerated
after irradiation, exposition to the chemical carcinogen
N-methyl-N-Nitrosurea (Renauld et al., 1994) or over-
expression of the oncogenic fusion protein NPM-ALK in
hematopoietic progenitors (Lange et al., 2003). Interest-
ingly, these lymphomas did not appear after hyperplasia of
normal progenitors as observed upon IL-6 or IL-7
overexpression (Suematsu et al., 1992; Rich et al.,
1993). This suggests that, in contrast to many growth
factors, tumoral transformation events are a prerequisite
for IL-9 to promote cell proliferation.
In humans, activated T cell lines and clones, but not
freshly isolated T cells respond to IL-9 (Houssiau et al.,
1993). However, in this experimental model, IL-9 could
not support the growth of cytokine-dependent cell line as
with mouse T cell clones. Another discrepancy with the
mouse model is that we could not demonstrate that human
T cell tumors are more responsive to IL-9 than normal
T lymphocytes. For instance, T-cell acute lymphoblastic
leukemias, the most likely human counterpart of mouse
thymic lymphoma cells, do not express the IL-9R, nor
show any biological response to IL-9 (Knoops et al.
unpublished results). This may be due to some specific
or due to the fact that the human counterpart of murine
thymic lymphomas generated by irradiation, chemical
mutagenesis or spontaneously in AKR mice (which all
responded to IL-9) correspond to a distinct entity.
IL-9 receptor expression and IL-9 responsiveness also
appeared to be infrequent in HTLV-I-transformed T cells
(Matsushita et al., 1997). By contrast, HTLV-I infection is
a potent inducer of IL-9 and most of these tumor cells
constitutively express IL-9 (Kelleher et al., 1991; Chung
et al., 2003). Interestingly, one HTLV-I-transformed
human T-cell line showed a cis/trans-activation of the
IL-9 receptor gene (Kubota et al., 1996), raising the
hypothesis that such leukemias need genetic rearrange-
ment of the IL-9R gene to be able to use IL-9 as an
autocrine factor, but that the tumoral transformation itself
is not sufficient to confer IL-9 responsiveness as in the
B Cell Lymphomas
As far as B lymphocytes are concerned, the activity of
IL-9 seems to be restricted to the B-1 lymphocyte subset.
Peritoneal B-1 lymphocytes express the IL-9 receptor
(Vink et al., 1999), respond to IL-9 by STAT-3
phosphorylation (unpublished data from our laboratory)
and are expanded in IL-9 transgenic mice (Vink et al.,
1999). In this respect, it should be stressed that IL-9
overexpression induces hyperplasia of normal B lympho-
cytes, but no B cell leukemia or lymphoma, in sharp
contrast to the above-described consequence of IL-9
overexpression for T cells. B-1 lymphocytes are
characterized by a specific cell surface phenotype (high
IgM, low IgD, Mac-1þand CD-232), by a preferential
localization in the peritoneal cavity and were described to
produce autoantibodies and to develop clonal proliferation
(Herzenberg et al., 1986). Interestingly, human chronic
lymphocytic leukemia (CLL) is considered as the tumoral
human counterpart of mouse B-1 lymphocytes, based on
similar surface markers (Sthoeger et al., 1989). However,
we failed to detect any IL-9R expression on 20 human
CLL samples, and no STAT-3 phosphorylation could be
detected in2samplesafter IL-9 stimulation (Knoopset al.,
data not shown). Further studies in the mouse system
showed that IL-9 acts preferentially in a subset of B-1
lymphocytes that do not express CD5, also called B-1b
cells (Vink et al., 1999; Knoops et al., 2004). By contrast,
human CLL express CD5 and are therefore, more related
to the mouse CD5þB-1 lymphocytes, also called B-1a
cells. The human counterpart of mouse B-1b lymphocytes,
and B cell tumors potentially related to this subpopulation
remains to be characterized.
Hodgkin disease is a tumoral process associated with
abnormal activation of lymphocytes. Malignant mono-
nucleated Hodgkin and multinucleated Reed–Sternberg
cells derive from germinal center B cells (Thomas et al.,
2004). Unbalanced production of Th2 cytokines and
chemokines has been well documented in this disease
(Skinnider and Mak, 2002), and some of these factors
might play an autocrine or paracrine role. IL-13, for
example, seems to act as an autocrine growth factor for
Reed–Sternberg cells (Kapp et al., 1999). The production
of IL-9 was clearly demonstrated for about half of
Hodgkin disease samples. IL-9 expression was detected in
6 out of 13 cases by Northern blot and in situ hybridization
(Merz et al., 1991) and in 2 out of 5 Reed–Steinberg
single cells by RT-PCR (Trumper et al., 1993). Increased
IL-9 serum level was measured in 18 out of 44 patients
with Hodgkin disease (Fischer et al., 2003), but not in the
serum from healthy controls.
By contrast, the response of Hodgkin cells to IL-9 is a
matter of controversy. IL-9 synergized with IL-3 to
promote the growth of cultured Hodgkin and Reed–
Sternberg cells (Aldinucci et al., 2002). In another report,
two Hodgkin lymphoma cell lines, HDLM-2 and KM-H2,
were shown to express the IL-9 receptor and respond to
IL-9 stimulation. The growth of HDLM-2 could even be
inhibited by IL-9-blocking antibodies or IL-9 antisense
oligonucleotides, suggesting the existence of an autocrine
loop (Gruss et al., 1992). However, we failed to detect any
IL-9R expression, or activity of IL-9 or anti-IL-9
antibodies on several Hodgkin cell lines tested in our
laboratory (Knoops et al., Unpublished data).
IL-9 was also expressed in 2 out of 6 cases of large cell
anaplastic lymphoma at the RNA level (Merz et al., 1991).
L. KNOOPS AND J.-C. RENAULD208
Although direct evidence is still lacking to support a direct
role of IL-9 in this type of lymphoma, the typical
morphology, cytokine profile and low sensitivity to
cyclophosphamide of human anaplastic lymphomas were
also observed when a mouse IL-9-responsive T cell line
transfected with the IL-9 gene to create an autocrine
loop was injected and developed in vivo in mice
(Bittner et al., 2000).
With the exception of mast cells (Hultner and Moeller,
1990; Godfraind et al., 1998), IL-9 activity on the myeloid
lineage seems to be restricted to immature hematopoietic
precursors. IL-9 acts essentially on erythroid progenitors,
in synergy with EPO, GM-CSF, or IL-3 (Donahue et al.,
1990; Holbrook et al., 1991; Bourette et al., 1992; Lu
et al., 1992; Sonoda et al., 1992; Schaafsma et al., 1993).
Interestingly, as mentioned earlier forT cells, those effects
were more pronounced on fetal progenitors (Holbrook
et al., 1991) whereas other cytokines act equally well on
fetal and adult progenitors. Acute myeloid leukemias
(AML) originate from such myeloid progenitors. The fact
that human IL-9 was originally cloned as a growth factor
for the megakaryoblastic leukemia cell line MO7e
reinforces the potential activity of IL-9 on AML blasts,
although the proliferative effect of IL-9 was much weaker
than that of IL-3 orGM-CSF on MO7e (Yang etal.,1989).
The MO7e cell line was originally derived from the blood
of an infant with acute megakaryoblastic leukemia, and
displays early marker of differentiation such as CD33 and
CD34, and markers for bipotent erythromegakaryoblastic
hematopoietic precursors (Yang et al., 1989). The
potential activity of IL-9 on AML samples and AML
cell lines was further explored by Lemoli and colleagues.
In clonogenic assays in methylcellulose, IL-9 increased
the number of colonies for three myeloid cell lines and for
32 out of 32 freshly isolated AML cells. This effect was
1996; Lemoli et al., 1997). In a different experimental
setting, using short term STAT phosphorylation as
readout, we failed to detect any IL-9 response from
14 AML samples whereas all these samples responded to
IL-3 and GM-CSF (Knoops et al., unpublished data).
Although these negative results do not rule out an
IL-9-effect mediated by other signaling pathways on AML
blasts, and may be explained by the method used
to test this potential IL-9 activity, this suggests that
IL-9-responsiveness of AML cells could be dependent on
subtle mechanisms that remains to be elucidated.
IL-9 RECEPTOR SIGNAL TRANSDUCTION
IL-9 binds to an heterodimeric receptor comprising
a specific chain (IL-9R) and gc, which is shared
by the receptors for IL-2, IL-4, IL-7, IL15 and
IL-21 (Demoulin and Renauld, 1998; Asao et al., 2001).
The specific chain comprises 468 and 521 amino acids in
mouse and human respectively, and belongs to the type I
hematopoietin receptor superfamily (Renauld et al.,
1992). Those receptors lack tyrosine kinase activity, and
are constitutively bound to Janus kinase (JAK), namely
JAK1 for the IL-9R and JAK3 for the gc (Demoulin et al.,
1996). The region required for JAK binding is a proline-
rich region close to the transmembrane domain, called the
Box 1 motif (Tanner et al., 1995; Zhu et al., 1997).
The IL-9-specific chain is sufficient to bind IL-9 with
high affinity (Renauld et al., 1992), but is not able to
mediate alone any signal. Upon receptor ligation,
juxtaposition of the two chains, or a change in receptor
conformation results in auto and/or trans-phosphorylation
of JAK kinases, phosphorylation of the receptor, and
activation of the pathways involved in IL-9 signaling: the
STAT, the IRS-PI3 kinase and the MAP kinase pathways
Two regions in the cytoplasmic domain of IL-9R are
required for STATactivation. Like for other hematopoietic
receptors, the proline-rich Box 1 region is required for
JAK binding, activation and every subsequent signaling
event including STAT phosphorylation (Zhu et al., 1997).
In addition to this region, one single tyrosine out of five
present in the cytoplasmic part of the IL-9R is required for
STAT-1, -3 and -5 activation (Demoulin et al., 1996). This
residue, tyrosine 407, surrounded by a typical STAT-3
consensus sequence is phosphorylated upon ligand
binding and serves as a docking site for the SH2 domain
of the STAT transcription factors. Subsequently, phos-
phorylated STAT molecules dimerize and migrate to the
nucleus where they bind regulatory sequences for de novo
The tyr407phe mutation abolished STATactivation and
biological activities of IL-9 in two cell lines, namely
growth stimulation in factor-dependent Ba/F3 cells, and
protection against dexamethasone-induced apoptosis,
Ly-6A2 induction as well as growth inhibition in
BW5147 thymic lymphoma cells (Demoulin et al.,
1996; Demoulin et al., 2001). It also dramatically affected
the induction of c-myc by IL-9 in the TS1 cell line
(Zhu et al., 1997). Thus, tyrosine 407 seems to be a critical
residue of the IL-9R because of its ability to directly
recruit three distinct STAT transcription factors. The
existence of a single STAT-recruitment site and the
superposition at this site of consensus sequences for both
STAT-3 (YXPQ) and STAT-5 (AYL) are relatively
unusual in cytokine receptors.
Interestingly, mutations around this tyrosine residue
allowed to obtain receptors that activate selectively either
STAT-1 and -3 when Leu 408 was changed into Arg, or
only STAT-5 when Gln410 was changed into Leu.
Both mutants were able to protect BW5147 from
dexamethasone-induced apoptosis and to promote Ba/F3
cell growth, indicating some kind of redundancy for these
IL-9 AND ITS RECEPTOR 209
factors, but only mutants that activated STAT-1 and STAT-
3 were able to support the induction of granzyme A and
L-selectin (Demoulin et al., 1999), and cell growth arrest
in BW cells overexpressing the human IL-9 receptor
(Demoulin et al., 2001). Thus, for oncogenesis-related
activities such as proliferation and inhibition of apoptosis,
both STAT-3 and STAT-5 seem to redundantly mediate
the effect of IL-9. In addition, STAT-1 and -3, but not
STAT-5 seem to be involved in activities that are more
related to differentiation processes.
IRS, PI3 Kinase and PKB
IRS-1 and IRS-2 are involved in IL-9 signal transduction.
These proteins are large cytoplasmic docking molecules
that contain a protein tyrosine binding (PTB) domain,
a pleckstrin homology (PH) domain and many sites for
serine/threonine and tyrosine phosphorylation. After
tyrosine phosphorylation, IRS proteins interact with
SH2-containing signaling proteins, such as p85, Grb-2,
Shp-2, Nck and PLCgamma. IRS-1/-2 play a key role in
insulin, IGF-1, IL-4 and other signaling pathways.
The role of IRS-1/-2 in IL-9 activities is reminiscent of
its role in IL-4 activities. IL-9 was able to induce the
phosphorylation of ectopically expressed IRS-1 in a T-cell
line (Yin et al., 1995) and of endogenous IRS-2 in
other hematopoietic cell lines (Demoulin et al., 1996).
IL-9-activated IRS-2 associates with p85, the regulatory
subunit of the PI3 kinase pathway in TS1 and Ba/F3 cells
(Demoulin et al., 1996). As shown previously for IL-4 and
insulin (Wang et al., 1993; Sun et al., 1995), the ectopic
expression of IRS-2 in 32D cells expressing the hIL-9R,
lacking endogenous IRS allowed those cells to proliferate
in response to IL-9 (Demoulin et al., 2000a).
However, other observations unravelled significant
differences between IL-9- and IL-4-mediated IRS
activation, pointing to some degree of specificity in IRS-
mediated cytokine signaling. IRS-2 phosphorylation
depends on the Box1 and downstream region (amino
acids 338–422) of the IL-9 receptor, which does not
contain the consensus sequence NPXY for the PTB
domain implicated in the binding of IRS to the insulin and
the IL-4 receptor (Zhu et al., 1997). For IL-9, IRS-1
phosphorylation was dependent on its PH domain (Xiao
et al., 2002), by a mechanism that remains to be
elucidated. Upon IL-9 stimulation, phosphorylated IRS-1
interacts with only p85 and Grb-2, while IRS-1 activated
by IL-4 also recognizes Shp-2 (Xiao et al., 2002).
In contrast to its role for the IL-4 response, PKB does not
seem to be the main effector of IL-9-activated IRS1/2.
Indeed, PKB was not significantly phosphorylated in 32D
cells growing following IL-9 stimulation (Demoulin et al.,
2000a), dominant negative PKB did not reduce the
proliferation of those 32D cells in response to IL-9 (Xiao
et al., 2002), and PKB activation did not correlate
with IRS1 phosphorylation (Demoulin et al., 2000a).
downstream targets mediating intracellular IL-9 effects. Those molecules belong to the JAK-STAT, the IRS-PI3 kinase and the MAP kinase pathways.
IL-9-activated signaling pathways. Upon IL-9 binding, IL-9 receptor activates JAK1 and JAK3, which in turn leads to the activation
L. KNOOPS AND J.-C. RENAULD 210
Taken together, these observations indicate that IRS
adaptors play a role in IL-9-induced cell proliferation but
that their modes of activation and downstream effectors
might differ from those triggered by other cytokines such
as IL-4 (Fig. 2).
The Erk MAP kinase pathway also contributes to some
extent to IL-9 signaling. This involvement, in contrast to
the STAT pathway, appeared to be restricted to certain cell
types and, for example, could not be detected in the MO7e
cell line (Miyazawa et al., 1992). Erk2 was phosphory-
lated upon IL-9 stimulation in the murine T helper cell line
TS1, the mast cell line MC9, and in Ba/F3 and 32D cells
transfected with the human IL-9 receptor. This phos-
phorylation correlated with an increased in vitro Erk
activity, with phosphorylation of the typical Erk substrate
p90/RSK, and with growth stimulation. The link between
Erk activation and IL-9-mediated proliferation is sup-
ported by the effect of MEK specific inhibitors and
dominant-negative RAS (Demoulin et al., 2003). How-
ever, it must be stressed that MAPK activation by IL-9 is
not as robust as that induced by IL-3, for example, which
might explain that previous studies failed to detect any
activation of components of the MAPK cascade in
similar cell lines by IL-9 (Bauer et al., 1998). In this
regard, using the same experimental approach based on
anti-phospho-Erk antibodies or anti-Erk2 immunopreci-
pitation, we coulddetect IL-4-mediated MAPK activation,
which was not observed previously. These discrepancies
might reflect the sensitivity of this readout system.
In addition, many previous studies were based on
measures of GTP loading onto RAS, and can not exclude
that activation of the MAPK pathway by IL-9 and IL-4
depends on a RAS family member distinct from those that
have been tested in those reports.
The protein scaffold that links the IL-9R to the MAPK
pathway is not fully identified. IL-9 induced the
phosphorylation of SHC, an adaptor protein, which
binds Grb2. Grb2 can subsequently activate SOS by
targeting it to the plasma membrane. SOS is a major GTP-
exchange factor for RAS GTPases. SHC usually binds
receptors phosphotyrosine by its SH2 or PTB domain.
However, the domain of the IL-9 receptor linked to SHC
and ERK2 phosphorylation lacks any tyrosine (Demoulin
et al., 2003), suggesting another interaction between
IL-9R and SHC, maybe through another adaptor protein.
IRS might play such a role but the IRS-Grb2 association
triggered by IL-9 did not seem sufficient to induce MAPK
activation (Xiao et al., 2002). A RAS isoform is clearly
involved in the cascade, because dominant-negative M-
RAS inhibited ERK activation by IL-9 (Demoulin et al.,
2003). Downstream RAS, a role for Raf-1 has been
suggested for the mitogenic response of the MO7e cells to
IL-9 (Brennscheidt et al., 1994), and MEK1/2 was found
phosphorylated and associates to downstream targets to mediate some IL-4 effects. IL-9-mediated IRS activation requires by contrast, IRS PH domain,
and differs from IL-4-mediated activation by the lack of SHP2 interaction, the weak PKB phosphorylation and the possible existence of still unknown
downstream effectors. The similarity between IRS residues phosphorylated by IL-9 and IL-4 is still to be determined.
Differences between IL-4- and IL-9-mediated IRS activation. IRS recruited by its SH2 domain to the IL-4 receptor, is subsequently
IL-9 AND ITS RECEPTOR 211
to be phosphorylated in response to IL-9 in various cell
lines (Demoulin et al., 2003).
Other IL-9R Associated Proteins
The yeast two hybrid technology was used by the Yang
group to unravel novel IL-9R-associated signaling path-
ways, showing that Tat-interactive protein 60kDa (Tip60)
and 14-3-3zeta interact with the C-terminal region of the
human IL-9R (Sliva et al., 1999; Sliva et al., 2000).
Tat-interactive protein 60kDa is a member of a family of
protein, highly conserved from yeast to human, which
possesses intrinsic histone acetylase activity. Interest-
ingly, Tip 60 was further shown to associate with histone
deacetylase 7 (HDAC7) and with STAT, and exogenous
overexpression of Tip60 could inhibit IL-9-induced c-myc
expression (Xiao et al., 2003), suggesting that Tip60 could
modulate signaling by the Jak-STAT pathway. The 14-3-3
proteins are a family of highly conserved acidic proteins
that are involved in a variety of cellular processes
including mitogenic signaling, cell cycle control, apopto-
sis, cell adhesion and nuclear localization. The 14-3-3zeta
isoform was found to associate with the human IL-9R
through its C terminal tail R-S-W-T-F, and peptide
competition experiments suggested that phosphorylation
of either the Ser or the Thr residue of the receptor was
required for this interaction. However, as this part of the
receptor is not conserved in the mouse (Renauld et al.,
1992) and as deletion of the C-terminus of the IL-9R does
not seem to affect signaling (Demoulin et al., 1996), it is
not likely that this protein plays an important role in IL-9
Indirect Regulation of Signaling Pathways by IL-9
In addition to the above-mentioned pathways that are
directly activated downstream the IL-9 receptor, the
identification of genes regulated by this cytokine showed
that IL-9 indirectly regulates other pathways. For instance,
IL-9-induced STAT-3 activation promotes the expression
was transcriptionally induced but not directly activated by
IL-9 (Louahed et al., 1999). However, M-Ras could be
activated by other cytokines such as IL-3. Thus, by this
mechanism IL-9 stimulation could modulate the response
to other factors, and act as a kind of competence factor.
Another example of indirect regulation of a signaling
pathway was provided by the induction of Bcl3 expression
by IL-9 (Richard et al., 1999). Bcl3 is a protein related to
the IkB family and associated with p50/p50 NF-kB
homodimers. It was originally identified at the breakpoint
in the t(14;19) chromosome translocation in some cases of
regulated transcriptionally in cells with the corresponding
remains controversial but Bcl3 induction could inhibit
TNF-induced NF-kB mediated transcription in mouse T
expression could block apoptosis induced by IL-4
deprivation in mouse T cell lines indicating that this
processes (Rebollo et al., 2000).
NEGATIVE REGULATION OF IL-9 SIGNALING
Cytokine binding to their respective receptors stimulates
not only positive activation pathways, but also negative
regulatory pathways, which are involved in the termi-
nation of the signal transduction. Downregulation of cell
surface IL-9R after IL-9 stimulation is controlled in part
by degradation through the Ubiquitin-proteasome path-
way. Upon stimulation, the IL-9R was shown to undergo
polyubiquitination, and ubiquitinylated receptor were
targeted to proteasomal degradation through association
with vasolin-containing protein (VCP), a proteasome-
associated putative chaperone (Yen et al., 2000).
Suppressors of cytokine signaling (SOCS) proteins are
key physiological regulators of cytokine activity and act as
a negative feedback loop activated by these factors. IL-9
induces the expression of three members of this family:
cytokine-inducible SH2-containing protein (CIS), SOCS-
2 and SOCS-3, but only SOCS-3 overexpression appeared
to inhibit IL-9-induced signal transduction, suggesting
that SOCS proteins should not be critical for controlling
the IL-9 response (Lejeune et al., 2001).
Activation of phosphatases is another classical mechan-
ism of signal termination. Although this aspect of IL-9
signaling has not been extensively studied, phosphatases
seem to play a minor role in IL-9R deactivation as
compared to other cytokines. In PC60 cells, IL-9 induced
a prolonged STAT-5 activation that resulted in increased
expression of IL-2Ralpha. By contrast, EPO, which only
induced short-term STAT-5 activation, failed to upregulate
this gene. Treatment of PC60 cells with vanadate, a
protein tyrosine phosphatase inhibitor, prolonged STAT-5
activation induced by EPO, which was then able to induce
IL-2Ralpha expression, buthad no effect on IL-9 signaling
(Imbert et al., 1999). This suggests that differential
activation of phosphatases in response to a cytokine
dictates duration and amplitude of STAT activation, and
subsequently affects gene induction and biological
responses to this factor.
Duration of the IL-9 signal might also be dependent on
the levelof expression of the IL-9R, which might therefore
determine the biological outcome of IL-9 stimulation.
This point was illustrated by studies focusing on
antiproliferative effect of IL-9. BW5147 is a mouse
lymphoma cell line that expresses endogenous IL-9R but
whose spontaneous proliferation is not affected by murine
IL-9. When the human IL-9R was transfected into these
cells, human IL-9 was able to block the proliferation of
these cells. IL-9R signaling did not appear to be
qualitatively different through the endogenous mouse
receptor or through the transfected human IL-9R. Both
receptors activate STAT-1, -3 and -5, but the higher
L. KNOOPS AND J.-C. RENAULD212
number of transfected receptors was associated with a
prolonged STAT-3 activation and subsequent P19ink4d
induction, which could be responsible for a growth
inhibition. Thus, while STAT-5 activation was always
associated with proliferation, the role of STAT-3 in IL-9-
induced oncogenesis might be much more subtle as,
depending on the context, STAT-3 activation leads to
either promotion or inhibition of cell growth (Demoulin
et al., 2001).
FROM IL-9-DEPENDENT CELL GROWTH TO
AUTONOMOUS TUMORAL PROLIFERATION
The link between tumoral transformation and (dys)regula-
tion of IL-9R signaling pathways is illustrated by two
experimental models of in vitro transformation of murine
lymphocytes (Fig. 3). As mentioned above, the response
of murine helper T clones to IL-9 is gradually acquired by
long-term in vitro culture. Early T cell clones, like freshly
isolated T cells, are not responsive to IL-9. After a few
passages in vitro, T helper clones respond to IL-9 by blast
transformation, IL-6 secretion, enhanced survival, but no
significant proliferation. After some more weeks in
culture, short-term proliferation can be observed but
only in synergy with other cytokines such as IL-4 and
IL-3. After months of culture, IL-9 alone induces
significant proliferation. During this progressive tran-
sition, cells become blastic during the complete culture
period and require more frequent passages. At this stage,
permanent IL-9-dependent cell lines can be derived,
which grow rapidly, increase in cell size and lose most of
T cell markers such as Thy1, CD4, CD3 and T cell
receptor expression. At this stage, transfection with the
IL-9 cDNA allow these cells to proliferate autonomously
and to form tumors in vitro indicating that the acquisition
of IL-9 responsiveness correlated with tumoral transform-
ation (Uyttenhove et al., 1991; Renauld et al., 1995a).
Interestingly, cytokine-independent cells can also spor-
adically arise from these IL-9-dependent T cell
clones. Although these autonomous cells do not
produce any cytokine as an autocrine loop, they show a
constitutive STAT-3 and -5 activation indicating that they
succeeded in activating the same pathways as those
triggered by IL-9, but bypassing IL-9 and its receptor
(Demoulin et al., 2000b).
A similar story is observed for factor-dependent Ba/F3
cells transfected with a defective IL-9 receptor. Ba/F3 is a
cell line derived by culturing Balb/c bone marrow B cell
progenitors in the presence of IL-3 (Palacios and
Steinmetz, 1985). Although these cells grow without
limitation in the presence of IL-3, they usually never
generate cytokine-independent sub-populations. When
Ba/F3 cells were transfected with an IL-9 receptor mutant
that lacks the STAT-binding site (tyr407phe), IL-9 almost
completely failed to induce STAT activation and
proliferation. However, a small number of cells could
manage to survive and even proliferate, and IL-9-
dependent cell lines could be derived. STAT-5 was
shown tobe required forthis first selection step.In contrast
to parental cells, those IL-9-selected cells progress to
cytokine-independent tumorigenic clones at low but
significant frequencies (Demoulin et al., 2000b). Again,
these cytokine independent tumoral cells showed a
constitutive activation of STAT factors and particularly
Taken together, these observations suggest that IL-9
signals might be critical at some particular stages of
tumorigenesis, but that, especially when the IL-9R signal
is suboptimal, cytokine-dependent cells will proceed to a
further stage of transformation by endogenously activating
cytokine-response signaling pathways. Although such
in vitro models using mouse lymphocyte cell lines are
definitely very artificial experimental systems, the in vivo
analysis of IL-9 transgenic mice gave some further
credence to this model. In these mice, IL-9 expression had
no detectable effect on T lymphocyte proliferation before
they underwent a first stage of transformation that could
be triggered by low doses of irradiation or of chemical
mutagens. Then, IL-9 promotes the emergence of T cell
lymphomas, which remained dependent on IL-9 for their
in vitro growth, but eventually gave rise to cytokine-
independent tumors, as demonstrated by using tumors that
immunization, antigen specific T cells can be derived from mice. After
few weeks in culture, some IL-9 responding cells can be obtained, which
in turn can lead to the generation of cytokine-independent T cells that are
highly tumorigenic invivo. B. Ba/F3 cells are IL-3 dependent pro-B cells
derived from Balb/c mice. When transfected with the defective phe116
IL-9R, some cells can be selected for IL-9 response. Highly tumorigenic
cytokine-independent cells can then be derived, but not from Ba/F3 cells
growing in IL-3 or in IL-9 after transfection of the wild-type IL-9
In vitro models of multistep tumorigenesis. A: After
IL-9 AND ITS RECEPTOR 213
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