Interleukin-17A (IL-17A, CTLA-8, and IL-17) is the prototypic member of the IL-17 family of cytokines. IL-17A plays a critical role in host defense and inflammation. IL-17A expression is most often associated with the T helper 17 (TH17) subset of CD4+ T cells, but has also been observed in CD8+ T cells, neutrophils, and gamma delta T cells upon stimulation with IL-1 and IL-23.
Structure of IL-17A
IL-17A is most similarly related to IL-17F with which it shares 50% sequence homology. Both IL-17A and IL-17F can exist as:
- Biologically active homodimers (IL-17AA and IL-17FF)
- Biologically active heterodimers (IL-17AF)
All three protein complexes are currently believed to signal through the same receptor complex (IL-17R) composed of the subunits IL-17RA and IL-17RC (IL-17RL), though they appear to have different biological functions.
It has been suggested that differential expression patterns of the IL-17R subunits could provide a tissue specific signaling mechanism for IL-17A and IL-17F. In humans, IL-17A binds to IL-17RA with high affinity and IL-17RC with lower affinity, while IL-17F responds in the exact opposite fashion. So cells with higher levels of IL-17RC expression are more responsive to IL-17F than to IL-17A, whereas cells with higher IL-17RA expression might respond better to IL-17RA stimulation. This is slightly skewed in mice where IL-17RA binds IL-17A and IL-17F equally, but IL-17RC only binds strongly to IL-17F. Accordingly, the signal elicited upon binding by either IL-17A or IL-17F is remarkably different with IL-17F showing a 10-30 fold weaker response in terms of downstream gene activation over IL-17A, while IL-17AF heterodimer elicits an intermediate response.
Role of IL-17A in Disease
The main function of IL-17A appears to be the regulation of local tissue inflammation via the coordinated expression of pro-inflammatory and neutrophil-mobilizing cytokines and chemokines that include IL-1, IL-6, IL-8, GM-CSF, G-CSF, TNF, CXCL1 (KC), CCL2 (MCP-1), CXCL2 (MIP-2), CCL7 (MCP-3) and CCL20 (MIP-3A).
Upon ligand/receptor interaction, IL-17A induces inflammatory cytokine production in epithelial cells, endothelial cells, and fibroblasts through NFkB signaling as well as the activation of many MAPK family members with the activation of AP-1 transcription factor proteins. Because of this, IL-17 family members have become important targets for drug discovery for the treatment of various forms of inflammatory disorders where IL-17 sera levels are elevated.
High concentrations of IL-17 are associated with autoimmunity and inflammatory diseases such as:
- rheumatoid arthritis
- multiple sclerosis
- transplant rejection
- inflammatory bowel disease (IBD)
Therapeutic monoclonal antibodies against human IL-17A have shown promise for the treatment of psoriasis, rheumatoid arthritis, and chronic non-infectious uveitis. This is very good news to the one-third of rheumatoid arthritis patients who do not respond to current TNF inhibition treatments and to the patients that lose the initially good response to TNF inhibition treatment.