Interleukin 5 (colony-stimulating factor, eosinophil)
(IL-5) is produced by Th2 cells and mast cells after
activation by mitogens or antigens . IL-5 is
capable to induce the survival, growth and differentiation of eosinophils and B-cells
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) , .
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) , , , , , , .
Actvated JAK2 phosphorylates
STAT1, STAT3 and
STAT5, JAK1 also phosphorylates
STAT5 , , .
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), , , , . Pim-1 and
c-Myc play role in cell proliferation and survival processes
, , . STAT5
activity is necessary for cell differentiation . Phosphorylation of
STAT3 leads to increase of Cyclin D3
JAK2 also phosphorylates IL-5
receptor that leads to different signal pathways , .
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) , , , . 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 , . 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) , .
ITGB2 directly binds to intercellular adhesion molecule 1
Activation of ERK1/2 also leads to anti-apoptosis .
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) , that induces binding of
CrkL to STAT5 .
CrkL activates Rap guanine nucleotide exchange factor
(GEF) 1 (C3G). This leads to induction of RAP1A, member of
RAS oncogene family (RAP-1A) .
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) . 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 . This cascade
possibly plays an important role in inhibition of apoptosis .
PI3K reg class IA (p85) also binds
to Protein kinase C, delta (PKC-delta) . Activated PKC-delta takes part in regulation of
Ras/MEK/ERK pathway by interacting with c-Raf-1.
This also induces integrin adhesion .
PKC-delta activates NADPH-oxidase that leads to oxygen
generation and oxidative stress .
IL-5 through IL-5 receptor
enhances expression of v-Fos FBJ murine osteosarcoma viral oncogene
homolog (c-Fos) and Jun oncogene
IL-5 increases expression of B-cell CLL/lymphoma 2
(Bcl-2) and jun B proto-oncogene
(JunB) providing inhibition of apoptosis , .
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