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].