IL-9 signaling pathway
Interleukin-9 (IL-9) is a multifunctional cytokine
secreted by T helper 2 (Th2) lymphocytes. IL-9 exerts
various effects on a variety of cell types associated with allergic inflammation.
IL-9 stimulates the growth and proliferation of T cells,
enhances the production of IgE from B cells, and promotes the proliferation and
differentiation of mast cells and hematopoietic progenitors , . Besides the role of IL-9 during immune responses,
its growth factor and antiapoptotic activities on multiple transformed cells suggest its
potential role in tumorigenesis .
IL-9 binds to the heterodimeric receptor
(IL-9 receptor) comprising a specific chain
(IL9R) and gamma chain (IL-2R gamma
chain). IL-2R gamma chain is shared by the
receptors for Interleukins IL-2, IL-4, IL-7, IL-15 and IL-21.
IL-9 receptor ligation results in auto and/or
trans-phosphorylation of Janus kinases 1 and 3 (JAK1 and
JAK3), phosphorylation of the receptor, and activation of
the pathways involved in IL-9 signaling. These pathways
include Signal transducer and activator of transcription 1, 3 and 5
(STAT1, STAT3 and
STAT5), Insulin receptor substrate 1 and 2
(IRS-1 and IRS-2)/
Phosphoinositide-3-kinase (PI3K reg class IA/
PI3K cat class IA) and Extracellular signal regulated
kinases 1 and 2 (ERK1/2) .
In response to IL-9, transcriptional activities of
STAT1 and STAT3 are more
related to differentiation processes, whereas STAT5, or both
STAT1 and STAT3, are more
related to the protection against apoptosis and cell proliferation .
STAT3, activated by
IL-9, up-regulate the transcription of Interleukin-22
(IL-22), an inducible cytokine belonging to the IL-10 family
that is involved in the generation of inflammatory and allergic responses .
IL-9 induces the expression of three cytokine signal
inhibitors, Cytokine inducible SH2-containing protein (CISH), Suppressors of cytokine
signaling 2 and 3 (SOCS2 and
SOCS3). However, only SOCS3
exerts a negative effect on IL-9 activities, such as
STAT3 activation and protection against apoptosis , .
IL-9 also induces B-cell CLL/lymphoma 3
(Bcl-3) transcription by STAT1
and STAT3 in T cells and mast cells.
Bcl-3 expression is followed by an increase in the DNA
binding of Nuclear factor-kappa B p50 homodimers (NF-kB
p50/p50) that can efficiently compete with NF-kB p65/p50 heterodimers
(NF-kB p50/p65) for the sites of NF-kB DNA binding . Tumor necrosis factor alpha
(TNF-alpha), a proinflammatory cytokine, induces
NF-kB p50/p65 transcriptional activity via Tumor necrosis
factor receptor superfamily member 1A (TNF-R1)/
TNFRSF1A-associated via death domain (TRADD)/ TNF
receptor-associated factor 2 (TRAF2)/ Mitogen-activated
protein kinase kinase kinase 14 (NIK(MAP3K14)/ NF-kB
inhibitor kinase complex (IKK (cat))/ NF-kB inhibitor
(I-kB) signaling pathway, leading to the expression of
NF-kB p50/p65 target genes , . IL-9 via Bcl-3
expression specifically down-regulates a particular set of genes induced by
NF-kB p50/p65 in response to
IL-9 can induce the phosphorylation of ectopically
expressed IRS-1 in T cells and of endogenous
IRS-2 in other hematopoietic cells. After tyrosine
phosphorylation, IRS-1 and IRS-2
interact with SH2-containing signaling proteins, such as
PI3K reg class IA, SHC transforming protein 1
(Shc) and Growth factor receptor-bound protein 2
Positioned downstream of the PI3K reg class IA/
PI3K cat class IA signaling, the v-Akt murine thymoma viral
oncogene homolog (AKT(PKB)) does not seem to be the main effector of
IL-9-activated IRS-1 and
IRS-2 , .
A pathway that occurs downstream of Shc/
GRB2 signaling involves stimulation of Son of sevenless
homologs (SOS)/ v-Ha-ras Harvey rat sarcoma viral oncogene
homolog (H-Ras)/ v-Raf-1 murine leukemia viral oncogene
homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase
1 and 2 (MEK1 and MEK2)/
ERK1/2/ Ribosomal protein S6 kinase 90kDa polypeptide 1
(p90RSK1). This pathway leads to growth stimulation of
hematopoietic cell lines , .
- Demoulin JB, Renauld JC
Interleukin 9 and its receptor: an overview of structure and function.
International reviews of immunology 1998;16(3-4):345-64
- Levitt RC, McLane MP, MacDonald D, Ferrante V, Weiss C, Zhou T, Holroyd KJ, Nicolaides NC
IL-9 pathway in asthma: new therapeutic targets for allergic inflammatory disorders.
The Journal of allergy and clinical immunology 1999 May;103(5 Pt 2):S485-91
- Knoops L, Renauld JC
IL-9 and its receptor: from signal transduction to tumorigenesis.
Growth factors (Chur, Switzerland) 2004 Dec;22(4):207-15
- Demoulin JB, Van Roost E, Stevens M, Groner B, Renauld JC
Distinct roles for STAT1, STAT3, and STAT5 in differentiation gene induction and apoptosis inhibition by interleukin-9.
The Journal of biological chemistry 1999 Sep 3;274(36):25855-61
- Dumoutier L, Louahed J, Renauld JC
Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9.
Journal of immunology (Baltimore, Md. : 1950) 2000 Feb 15;164(4):1814-9
- Lejeune D, Demoulin JB, Renauld JC
Interleukin 9 induces expression of three cytokine signal inhibitors: cytokine-inducible SH2-containing protein, suppressor of cytokine signalling (SOCS)-2 and SOCS-3, but only SOCS-3 overexpression suppresses interleukin 9 signalling.
The Biochemical journal 2001 Jan 1;353(Pt 1):109-116
- Demoulin JB, Van Snick J, Renauld JC
Interleukin-9 (IL-9) induces cell growth arrest associated with sustained signal transducer and activator of transcription activation in lymphoma cells overexpressing the IL-9 receptor.
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 2001 Mar;12(3):169-74
- Richard M, Louahed J, Demoulin JB, Renauld JC
Interleukin-9 regulates NF-kappaB activity through BCL3 gene induction.
Blood 1999 Jun 15;93(12):4318-27
- Hsu H, Xiong J, Goeddel DV
The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation.
Cell 1995 May 19;81(4):495-504
- Baud V, Karin M
Signal transduction by tumor necrosis factor and its relatives.
Trends in cell biology 2001 Sep;11(9):372-7
- Xiao H, Yin T, Wang XY, Uchida T, Chung J, White MF, Yang YC
Specificity of interleukin-2 receptor gamma chain superfamily cytokines is mediated by insulin receptor substrate-dependent pathway.
The Journal of biological chemistry 2002 Mar 8;277(10):8091-8
- Fujitsu Y, Fukuda K, Kimura K, Seki K, Kumagai N, Nishida T
Protection of human conjunctival fibroblasts from NO-induced apoptosis by interleukin-4 or interleukin-13.
Investigative ophthalmology & visual science 2005 Mar;46(3):797-802
- Demoulin JB, Louahed J, Dumoutier L, Stevens M, Renauld JC
MAP kinase activation by interleukin-9 in lymphoid and mast cell lines.
Oncogene 2003 Mar 27;22(12):1763-70