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 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 [1], [2]. 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 [3].

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) [3].

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 [4].

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 [5].

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 [6], [7].

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 [8]. 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 [9], [10]. 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 [8].

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) [3].

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 [11], [12].

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 [3], [13].

References:

1. 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
2. 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
3. Knoops L, Renauld JC
   IL-9 and its receptor: from signal transduction to tumorigenesis. Growth factors (Chur, Switzerland) 2004 Dec;22(4):207-15
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. Baud V, Karin M
    Signal transduction by tumor necrosis factor and its relatives. Trends in cell biology 2001 Sep;11(9):372-7
11. 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
12. 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
13. 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