Cytokines of the IL-17 family include IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. All members of the IL-17 family have a similar protein structure, with four highly conserved cysteine residues critical to their 3-dimensional shape. Cytokines of IL-17 family are all well conserved in mammals, with as much as 62–88% of amino acids conserved between the human and mouse homologs.
IL-17 family of cytokines have been reported to function in numerous immune processes. Most notably, IL-17 is involved in inducing and mediating proinflammatory responses. This proinflammatory activity is exemplified by their involvement in pulmonary inflammatory responses. Both IL-17A and IL-17F are involved in the recruitment of neutrophils, and IL-17E is able to induce Th2 cytokine production and eosinophilia.
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The IL-17 is a family of pro-inflammatory cytokines implicated in a variety of immune responses and is composed of six members, from IL-17A to IL-17F. They bear greatest similarity within the C terminal 70 amino acids and have 4 well conserved cysteines.
The 4 conserved cysteines in the C-terminal half of the IL-17F sequence are shown to form a cystine knot in the crystal structure, this cystine knot structure is similar to a common structural motif seen in several growth factors, such as bone morphogenic proteins, TGF-β, nerve growth factor, and platelet-derived growth factor. In addition, IL-17F is believed to form disulfidebonded homodimers, whereas other members of the IL-17 family are expressed as tightly associated dimers.
IL-17 family cytokines must depend on cell surface IL-17 receptors (IL17Rs) for signalling. IL17RA and IL17RC are well-studied members of the IL-17 receptor family in human and mouse models.
As IL-17 receptor proteins possess an intracellular SEFIR domain, upon IL17 ligands binding, this conserved domain directly interacts with Act1 adaptor/ubiquitin ligase to initiate signalling cascades, activating other inflammatory cytokines and chemokines that are usually associated with innate immune responses.
The special capacity for IL-17/IL-17 receptor family members to cooperate with cytokines of innate immunity to promote inflammation implies that they might act as a bridge between innate and adaptive immune systems.
IL-17 family has been shown to activate many common downstream signaling pathways, including NF-κB, the MAPKs (mitogen-activated protein kinases) JNK (c-Jun N-terminal kinase), p38 and ERK (extracellular-signalregulated kinase), C/EBPs (CCAAT/enhancer-binding proteins), PI3K (phosphoinositide 3-kinase) and JAK (Janus kinase)/STATs.
All of the IL-17 receptors recruit Act1 as an adaptor molecule for downstream signaling. IL-17A and IL-17F signals through the IL-17RA-RC complex, triggering TRAF6-dependent target gene transcription and TRAF6-independent IKKi-dependent mRNA stabilization, both of which are important for host defense and contributes to the pathogenesis of autoimmune diseases and cancer.