Immune response - IL-17 signaling pathways

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IL-17 signaling pathway

The Interleukin-17 family consists of six cytokines in mammals. Among them, Interleukin 17A (IL-17) and Interleukin 17F (IL-17F) are produced by a distinct subset of CD4+ T helper (Th) cells called Th17 cells. IL-17 and IL-17F play a critical role in inflammation and pathogenesis of multiple autoimmune diseases [1], [2], [3], [4], [5].

Development and differentiation of Th17 cells requires a complex network of cytokines. In humans, Th17 differentiation is mediated by IL-23 and IL-6 released from myeloid dendritic cells, IL-1 beta and IL-6 derived from macrophages, as well as IL-21 produced by activated T cells [1], [6]. IL-17 released from Th17 cells affects different cell populations of the inflamed tissue, including fibroblasts, chondrocytes, osteoblasts, mast cells, neutrophils, airway epithelial cells and vascular endothelial cells [1], [7].

IL-17 acts through the Interleukin 17 receptor A (IL-17 receptor), which associates with Interleukin 17 receptor C (IL-17RC) to form a multimeric receptor complex [8]. IL-17RC binds both IL-17F and IL-17 [9]. Much is known regarding IL-17, but the understanding of IL-17 receptor signal transduction is still limited [10].

IL-17 receptor signaling induces activation of Nuclear factor kappa-B (NF-kB), Mitogen-activated protein kinase 3 and 1 (ERK1/2) and CCAAT-enhancer-binding proteins (C/EBPbeta and C/EBPdelta) followed by subsequent transcription of IL-17 target genes involved in inflammation and autoimmunity [1].

Among the main IL-17 target genes are: IL-6, which mediates inflammation and reinforces Th17 development; granulopoietic growth factors, such as Granulocyte colony-stimulating factor (G-CSF) and Granulocyte-macrophage colony-stimulating factor (GM-CSF); neutrophil-attracting CXC chemokines, such as CXCL1 chemokine ligand 1 (GRO-1), CXCL5 chemokine ligand 5 (ENA-78), CXCL6 chemokine ligand 6 (GCP2) and Interleukin 8 (IL-8); CC chemokines, such as CCL2, CCL7 and CCL20; Beta-defensin 2 (both CCL20 and Beta-defensin 2, which have antimicrobial activity and chemotactic activity to CCR6-positive dendritic and T cells [11], [12], [13]); the acute phase protein Lipocalin 2 (NGAL), which exhibits antibacterial activity; Intercellular adhesion molecule 1 (ICAM1); Prostaglandin-endoperoxide synthase 2 (COX-2), which catalyzes the biosynthesis of Prostaglandin E2 (PGE2), the mediator for pain and fever during inflammation; Nitric oxide synthase 2 (iNOS), which generates Nitric oxide (NO) during inflammation; mucus/gel-forming mucins, Mucin 5AC and Mucin 5B, which are secreted by airway cells (mucins contribute to mucociliary defense, but mucin overproduction leads to airway obstruction by mucus in chronic airway diseases, such as asthma and cystic fibrosis [14]); Tumor necrosis factor (ligand) superfamily, member 11 (RANKL), which promotes osteoclastogenesis and subsequent bone destruction in autoimmune diseases such as rheumatoid arthritis; and matrix metalloproteinases, such as MMP-1, MMP-3 (Stromelysin-1) and MMP-9, the major players in matrix destruction and tissue damage in arthritis [3], [10].

After stimulation with IL-17, TRAF3 interacting protein 2 (CIKS) is recruited to IL-17 receptor and triggers the activation of the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6), Mitogen-activated protein kinase kinase kinase 7 (TAK1) and Mitogen-activated protein kinase kinase kinase 14 (NIK(MAP3K14)) followed by downstream activation of transcription factor NF-kB [3], [15], [16], [17], [18].

Most IL-17-regulated genes contain crucial NF-kB sites in their promoters [10], [19]. However, IL-17 induces NF-kB activation only weakly. NF-kB can play an important but poorly understood role in controlling IL-17 target genes [20]. The transcription factors C/EBPbeta and C/EBPdelta are also responsible for cooperative enhancement of the promoters of IL-17 target genes [17], [19], [20], [21]. The upstream events that regulate C/EBPbeta and C/EBPdelta activation are poorly understood. C/EBPbeta and C/EBPdelta expression and activities are regulated by both transcriptional and posttranscriptional events. IL-17 has been found to up-regulate expression of C/EBPbeta and C/EBPdelta [17], [20], [21]. Their expression is dependent on CIKS, the NF-kB upstream activator in IL-17 receptor signaling [22]. IL-17 signaling can also regulate C/EBPbeta activity and subsequent expression of pro-inflammatory genes. The phosphorylation of two sites in the regulatory domains of C/EBPbeta by ERK1/2 and Glycogen synthase kinase 3 beta (GSK3 beta) inhibits C/EBPbeta activity [23].

IL-17 also activates Janus kinase 1 and 2 (JAK1 and JAK2) signaling [12], [24]. In human airway epithelial cells, IL-17 induces a JAK1/JAK2-associated Phosphoinositide-3-kinase (PI3K) signaling pathway independent from NF-kB activation. JAK1/JAK2 / PI3K reg class IA / PI3K cat class IA signaling results in an increase in lipid Phosphatidylinositol (3,4,5) (PtdIns(3,4,5)P3) and activation of V-akt murine thymoma viral oncogene homolog (AKT(PKB)) that, in turn, phosphorylates and inactivates GSK3 beta [18].

IL-17 also induces the phosphorylation and activation of mitogen-activated protein kinases MEK1 and MEK2, MEK3 and MEK6, and p38 MAPK. MEK1 and MEK2 can directly phosphorylate ERK1/2 and activate its signaling pathway, whereas MEK3 and MEK6 can phosphorylate and activate p38 MAPK [25]. p38 MAPK increases mRNA stability of multiple IL-17-induced transcripts, e.g. COX-2 [10].

In the airway epithelium, both IL-6 and IL-17 are involved in the expression of mucin genes, Mucin 5AC and Mucin 5B [26], [27]. Because IL-17 signaling results in the induction of IL-6, mucin expression is at least partly up-regulated by IL-17 through IL-6 by an autocrine/paracrine loop [26]. Expression of Mucin 5AC and Mucin 5B in response to IL-17 has been proposed to depend on ERK1/2 or JAK2/ ERK1/2 signaling [26], [27]. Several transcription factors such as c-Jun/c-Fos and SP1 can be involved in Mucin 5AC and Mucin 5B transcription [14], [28].


References

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