3.3. Signalling pathways of Th17 cells
IL-17 acts as a cytokinine produced primarily by Th17, which signals
through the corresponding receptors and activates or depresses the
downstream pathway, including NF-κB, JAK/STAT, MAPKs (Figure 3). TGF-β
activates Smad2/3 transcription factors, whereas IL-6 signals mediate
STAT3 phosphorylation. Smad2/3 and STAT3, together with other
transcription factors activated by TCR signalling, induce the expression
of RORγt and Th17 differentiation. The downstream signal IL-17R
regulates the activation of NF-κB and proliferative protein kinase
(MAPK), resulting in the production of pro-inflammatory cytokines and
chemokines and subsequent recruitment of bone marrow cells to inflamed
tissue. Induces the release of certain chemokines (IL-8, CCL2, CCL7,
CCL20, CXCL1, CXCL2, CXCL5 and CXCL8) from mesenchymal and medullary
cells[34], cytokines(IL-6, IL-36, GM-CSF, G-CSF), matrix
metalloproteinases(MMPs)and antimicrobial peptides[35]. This leads
to the amplification and aggregation of neutrophils in the innate immune
system, and links the innate and adaptive immunity in the body. IL-17A
and IL-17F are the major cytokines secreted by Th17, and also the most
similar proteins in the IL-17 family[36]. On the other hand, IL-2
inhibits IL-6R expression and instead induces STAT5 phosphorylation,
which inhibits Th17 cell differentiation[37]. Both IL-4 and
interferon (IFN)-γ suppress RORC2 by upregulating GATA binding protein 3
(GATA-3) and the transcription factor T-bet, respectively, thereby
inhibiting Th17 differentiation[38]. The growth and development of
Th17 cells requires the support of IL-23 and TGF-β, both of which are
negatively regulated by IFN-γ and IL-4. Once mature, Th17 cells resist
the inhibitory effects of IFN-γ and IL-4[39].