IL-10 signaling pathway
Interleukin-10 (IL-10) is a pleiotropic cytokine with
important immunoregulatory functions. Its actions influence activities of many of the
cell-types in the immune system. It is also a cytokine with potent anti-inflammatory
properties: it represses the expression of inflammatory cytokines, such as Tumor necrosis
factor-alpha (TNF-alpha), Interleukin-6 (IL-6) and
Interleukin-1 (IL-1 beta), in macrophages , .
Functional IL-10 receptor complex is a tetramer
consisting of two identical ligand-binding subunits (IL10RA)
and two identical accessory signaling subunits (IL10RB)
, , .
Binding of IL-10 to the extracellular domain of
IL-10 receptor activates phosphorylation of the
receptor-associated Janus kinase 1 (JAK1) and Tyrosine
kinase 2 (Tyk2). These kinases then phosphorylate specific
tyrosine residues on the intracellular domain of the IL-10
receptor. Once phosphorylated, these tyrosine residues serve as temporary
docking sites for the latent transcription factor, Signal transducer and activator of
transcription 3 (STAT3). STAT3
binds to these docking sites and is tyrosine-phosphorylated by the receptor-associated
JAK1 and Tyk2.
STAT3 then homodimerizes and translocates to the nucleus where it binds to
the promoters of various IL-10-responsive genes , , .
STAT3 regulates transcription of anti-apoptotic genes,
such as BCL2-like 1 (Bcl-XL) and B-cell CLL/lymphoma 2
(Bcl-2), and genes inhibiting cell cycle progression, such
as Cyclin-dependent kinase inhibitor 2D (p19) , , , , , , , , , , .
activation results in decreased expression of the inflammatory cytokines, such as
STAT3 also promotes transcription of Suppressor of
cytokine signaling 3 (SOCS3).
SOCS3 acts as a negative feedback regulator of
STAT3 signaling and inhibits endotoxin-inducible expression
of many inflammatory cytokines, including TNF-alpha, IL-6
and IL-1 beta , , , .
Interaction of IL-10 with IL-10
receptor also results in subsequent tyrosine-phosphorylation of
STAT1 and, in non-macrophage cells,
STAT5 , , , , . In myeloid cells, IL-10
predominantly activates STAT3 and activated
STAT3 is primarily involved in the negative regulation of
macrophage activation . The role of STAT1
and STAT5 in IL-10 signal
transduction remains unclear, although IL-10-induced CD14
up-regulation in monocytes is believed to be mediated by STAT1
IL-10 also stimulates tyrosine phosphorylation of Cysteine and glycine-rich protein 2
(CRP2), probably by JAK1,
followed by rapid translocation of CRP2 into the nucleus
where it up-regulates expression of the TIMP metallopeptidase inhibitor 1
(TIMP-1). TIMP-1 expression in
human prostate cancer cells can play a key role in inhibiting tumor growth, perhaps by
blocking tumor vascularization , .
IL-10 also activates another major survival pathway
consisting of Insulin receptor substrate 2 (IRS-2),
Phosphoinositide-3 kinase class IA (PI3K reg class IA/
PI3K cat class IA) and its downstream effectors
3-Phosphoinositide dependent protein kinase-1 (PDK (PDPK1)),
Ribosomal protein S6 kinase 70kDa polypeptide 1 (p70S6K) and
v-Akt murine thymoma viral oncogene homolog (AKT(PKB))
, , .
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