H-Ras, p90RSK1, NF-kB p50/p65, IL-2R gamma chain, CISH, STAT1, IL-22, IRS-1, JAK1, GRB2, PI3K cat class IA, Shc, IL-9, NIK(MAP3K14), SOCS3, SOS, JAK3, IL-9 receptor, TRADD, MEK2, IL9R, PI3K reg class IA, IKK (cat), TRAF2, TNF-alpha, c-Raf-1, IRS-2, STAT3, ERK1/2, STAT5, MEK1, TNF-R1, Bcl-3, NF-kB p50/p50, I-kB, SOCS2
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 .
STAT1 and 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 TNF-alpha .
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 ( GRB2 ) .
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 , .