Immune response - IL-5 signalling

IL-5 signaling

Interleukin 5 (colony-stimulating factor, eosinophil) (IL-5) is produced by Th2 cells and mast cells after activation by mitogens or antigens [1]. IL-5 is capable to induce the survival, growth and differentiation of eosinophils and B-cells [2].

IL-5 receptor is composed of two polypeptide chains: alpha and beta subunits. Both subunits contain extracellular domains. The alpha and beta subunits are associated only in the presence of ligand. Alpha-subunit is ligand-specific and beta subunit is shared with the receptors for Interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating-factor (GM-CSF) [3], [4].

Following IL-5 -induced hetero-dimerization, IL-5 receptor binds to multiple signal-transducing proteins, which include Janus kinase 1 (JAK1) and 2 (JAK2), v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn), spleen tyrosine kinase (Syk) and SHC transforming protein 1 (Shc). Lyn additionally phosphorylates Syk and Bruton agammaglobulinemia tyrosine kinase (Btk) [5], [6], [7], [8], [9], [10], [11].

Actvated JAK2 phosphorylates STAT1, STAT3 and STAT5, JAK1 also phosphorylates STAT5 [9], [12], [13]. Phosphorylated STAT5 and STAT3 translocate to the nucleus and activates transcription of different genes, including Pim-1 oncogene (Pim-1) and v-myc myelocytomatosis viral oncogene homolog (avian) (c-Myc), [13], [14], [15], [16]. Pim-1 and c-Myc play role in cell proliferation and survival processes [13], [17], [18]. STAT5 activity is necessary for cell differentiation [19]. Phosphorylation of STAT3 leads to increase of Cyclin D3 expression [13].

JAK2 also phosphorylates IL-5 receptor that leads to different signal pathways [7], [20].

Upon IL-5 stimulation, the adaptor molecule Shc is rapidly phosphorylated and associates with the phosphorylated IL-5 receptor. IL-5 stimulation also results in the activation of GRB2 and protein tyrosine phosphatase, non-receptor type 11 (SHP-2) which associates with Shc and form a complex with Son of sevenless homologs (SOS) [7], [21], [22], [23]. SOS promotes 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 pathway [24], [25]. ERK1/2 activates phospholipase A2, group IV (cPLA2) that catalyses modification of Platelet activating factor to Lyso-PAF. Lyso-PAF enhances eosinophil adhesion through interacting with Integrin, alpha M (ITGAM) and Integrin, beta 2 (ITGB2) [26], [27]. ITGB2 directly binds to intercellular adhesion molecule 1 (ICAM1) [26].

Activation of ERK1/2 also leads to anti-apoptosis [25].

IL-5 induces not only JAK-dependent activation of STAT5, but a JAK-independent too. Shc binds to v-crk sarcoma virus CT10 oncogene homolog (avian)-like (CrkL) [28], that induces binding of CrkL to STAT5 [29].

CrkL activates Rap guanine nucleotide exchange factor (GEF) 1 (C3G). This leads to induction of RAP1A, member of RAS oncogene family (RAP-1A) [29].

Under IL-5 action, Lyn induces Phosphoinositide-3-kinase regulatory subunits (PI3K reg class IA (p85))/ Phosphoinositide-3-kinase catalytic subunits (PI3K cat class A1) [30]. PI3K cat class A1 catalyses PtdIns(3,4,5)P3 formation that leads to activation of v-akt murine thymoma viral oncogene homologs (AKT(PKB)) by direct interaction with PtdIns(3,4,5)P3 as well as by interaction with 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) induced by PtdIns(3,4,5)P3 [31]. This cascade possibly plays an important role in inhibition of apoptosis [20].

PI3K reg class IA (p85) also binds to Protein kinase C, delta (PKC-delta) [32]. Activated PKC-delta takes part in regulation of Ras/MEK/ERK pathway by interacting with c-Raf-1. This also induces integrin adhesion [33]. PKC-delta activates NADPH-oxidase that leads to oxygen generation and oxidative stress [34].

IL-5 through IL-5 receptor enhances expression of v-Fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) and Jun oncogene (c-Jun) [35].

IL-5 increases expression of B-cell CLL/lymphoma 2 (Bcl-2) and jun B proto-oncogene (JunB) providing inhibition of apoptosis [18], [36].

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