IL-22 signaling pathway
Interleukin-22 (IL-22) is a member of the IL-10 family of
cytokines. The major sources of IL-22 are activated T cells,
especially upon type 1 polarization, and natural killer (NK) cells , .
IL-22 acts via a heterodimeric receptor complex
(IL-22 receptor) consisting of Interleukin 22 receptor,
alpha 1 subunit (IL22RA1) and Interleukin 10 receptor, beta
subunit (IL10RB). Neither resting, nor activated immune
cells express IL22RA1, or respond to
IL-22. In contrast, tissue cells at outer body barriers,
i.e., of the skin, kidney, and the digestive and respiratory systems are targets of this
cytokine. IL-22 produced by immune cells regulates tissue
protection and homeostasis by promoting the anti-microbial defense, protecting against
damage, and reorganizing non-immune tissues , .
In addition to the cell surface associated IL-22 receptor
complex, there is a secreted ('soluble'), single-chain Interleukin 22 receptor, alpha 2
(IL-22RA2). IL-22RA2 prevents
binding of IL-22 to the functional cell surface
IL-22 receptor and neutralizes
IL-22 activity. IL-22RA2 also
blocks induction of the Suppressor of cytokine signaling-3
(SOCS3) gene expression by IL-22
IL-22 is expressed in T cells activated by either T cell
receptor (TCR alpha/beta) stimulation in response to antigen
presentation by Major histocompatibility complex, class II (MHC class
II), or stimulation with other cytokines, e.g., Interleukin-9 (IL-9)
, , . IL-22
expression is markedly enhanced in Th1 polarized populations of T cells rather than Th2
CD4 cells . IL-22 is also expressed by Th17
cells, a distinct lineage of effector CD4+ T cells characterized by their production of
Interleukin-17 (IL-17). IL-22 synergizes with IL-17 to
regulate genes associated with skin innate immunity .
Interleukin-2 (IL-2) and Interleukin-12
(IL-12) secreted by CD4+ T cells and antigen-presenting
cells, respectively, act on NK cells that can produce IL-22
in response to IL-2 and IL-12
. IL-2 signaling pathway
includes IL-2 receptor/ Janus kinases 1 and 3
(JAK1 and JAK3)/ Signal
transducers and activators of transcription 5 (STAT5)
activation. IL-12 signaling pathway involves activation of
IL-12 receptor/ Janus kinase 2 and Tyrosine kinase 2
(JAK2 and Tyk2)/ Signal
transducer and activator of transcription 4 (STAT4) , , .
Although activated CD4+ T cells and NK cells secrete
IL-22, this cytokine acts exclusively on certain tissue
cells. If the production occurs in the lymph nodes, the cytokine binds to
IL-22RA2 constitutively expressed by the lymph nodes and
probably acts as a carrier for IL-22 to transport this
cytokine to its target cells .
The IL-22 that is produced in infected tissues mostly
acts directly on the adjacent tissue cells. IL-22 binding to
IL-22 receptor complex leads to the activation of the
receptor-associated Janus kinases JAK1 and
Tyk2, followed by activation of transcription factors
STAT3, and often STAT1 and/or
STAT5. These molecules are then phosphorylated by
JAK1 and Tyk2 to form
homodimers that immigrate into the nucleus to induce the expression of specific genes and
therefore modulate the cell activities , , .
STAT3 induces expression of
SOCS3, which can negatively regulate
JAK1/ STAT3 signaling . STAT3 also up-regulates expression of a variety
of anti-apoptotic (e.g., B-cell CLL/lymphoma 2 (Bcl-2),
BCL2-like 1 (Bcl-XL), Myeloid cell leukemia sequence 1
(Mcl-1)) and mitogenic (e.g., v-Myc myelocytomatosis viral
oncogene homolog (c-Myc))
In addition to JAK/STAT signaling, activation of the three major MAP kinase pathways
(Mitogen-activated protein kinases 8-10 (JNK(MAPK8-10)),
Mitogen-activated protein kinases 11-14 (p38 MAPK) and
Mitogen-activated protein kinases 3 and 1 (ERK1/2)) is also
required for maximum IL-22-induced transactivation of STAT3
by yet unknown mechanism, and is possibly required for activation of Activating protein 1
(c-Jun/c-Fos), heterodimeric transcription factor consisting
of Jun oncogene (c-Jun) and v-Fos FBJ murine osteosarcoma
viral oncogene homolog (c-Fos), to elicit expression of
proinflammatory cytokines , , .
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