Immune response IL-9 signaling pathway
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 typesassociated with allergic inflammation. IL-9 stimulates the growth andproliferation of T cells, enhances the production of IgE from B cells, and promotes theproliferation and differentiation of mast cells and hematopoietic progenitors [1], [2]. Besides the role of IL-9 during immune responses, itsgrowth factor and antiapoptotic activities on multiple transformed cells suggest itspotential role in tumorigenesis [3].
IL-9 binds to the heterodimeric receptor ( IL-9 receptor ) comprising aspecific chain ( IL9R ) and gamma chain ( IL-2R gamma chain ). IL-2Rgamma chain is shared by the receptors for Interleukins IL-2, IL-4, IL-7, IL-15 andIL-21.
IL-9 receptor ligation results in auto and/or trans-phosphorylation of Januskinases 1 and 3 ( JAK1 and JAK3 ), phosphorylation of the receptor, andactivation of the pathways involved in IL-9 signaling. These pathways includeSignal transducer and activator of transcription 1, 3 and 5 ( STAT1, STAT3and STAT5 ), Insulin receptor substrate 1 and 2 ( IRS-1 and IRS-2 )/Phosphoinositide-3-kinase ( PI3K reg class IA/ PI3K cat class IA ) andExtracellular signal regulated kinases 1 and 2 ( ERK1/2 ) [3].
In response to IL-9, transcriptional activities of STAT1 andSTAT3 are more related to differentiation processes, whereas STAT5, or bothSTAT1 and STAT3, are more related to the protection against apoptosis andcell proliferation [4].
STAT1 and STAT3, activated by IL-9, up-regulate thetranscription of Interleukin-22 ( IL-22 ), an inducible cytokine belonging to theIL-10 family that is involved in the generation of inflammatory and allergic responses[5].
IL-9 induces the expression of three cytokine signal inhibitors, Cytokineinducible SH2-containing protein (CISH), Suppressors of cytokine signaling 2 and 3 (SOCS2 and SOCS3 ). However, only SOCS3 exerts a negative effect onIL-9 activities, such as STAT3 activation and protection against apoptosis[6], [7].
IL-9 also induces B-cell CLL/lymphoma 3 ( Bcl-3 ) transcription bySTAT1 and STAT3 in T cells and mast cells. Bcl-3 expression isfollowed 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 [8]. Tumornecrosis factor alpha ( TNF-alpha ), a proinflammatory cytokine, induces NF-kBp50/p65 transcriptional activity via Tumor necrosis factor receptor superfamilymember 1A ( TNF-R1 )/ TNFRSF1A-associated via death domain ( TRADD )/ TNFreceptor-associated factor 2 ( TRAF2 )/ Mitogen-activated protein kinase kinasekinase 14 ( NIK(MAP3K14 )/ NF-kB inhibitor kinase complex ( IKK (cat) )/NF-kB inhibitor ( I-kB ) signaling pathway, leading to the expression of NF-kBp50/p65 target genes [9], [10]. IL-9 via Bcl-3expression specifically down-regulates a particular set of genes induced by NF-kBp50/p65 in response to TNF-alpha [8].
IL-9 can induce the phosphorylation of ectopically expressed IRS-1 in Tcells and of endogenous IRS-2 in other hematopoietic cells. After tyrosinephosphorylation, IRS-1 and IRS-2 interact with SH2-containing signalingproteins, such as PI3K reg class IA, SHC transforming protein 1 ( Shc )and Growth factor receptor-bound protein 2 ( GRB2 ) [3].
Positioned downstream of the PI3K reg class IA/ PI3K cat class IAsignaling, the v-Akt murine thymoma viral oncogene homolog (AKT(PKB)) does not seem to bethe main effector of IL-9 -activated IRS-1 and IRS-2 [11], [12].
A pathway that occurs downstream of Shc/ GRB2 signaling involvesstimulation of Son of sevenless homologs ( SOS )/ v-Ha-ras Harvey rat sarcomaviral 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 andMEK2 )/ ERK1/2/ Ribosomal protein S6 kinase 90kDa polypeptide 1 (p90RSK1 ). This pathway leads to growth stimulation of hematopoietic cell lines[13], [3].
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