Interleukin-17 family members in health and disease

Abstract

The interleukin-17 (IL-17) family consists of six family members (IL-17A-IL-17F) and all the corresponding receptors have been identified recently. This family is mainly involved in the host defense mechanisms against bacteria, fungi and helminth infection by inducing cytokines and chemokines, recruiting neutrophils, inducing anti-microbial proteins and modifying T-helper cell differentiation. IL-17A and some other family cytokines are also involved in the development of psoriasis, psoriatic arthritis and ankylosing spondylitis by inducing inflammatory cytokines and chemokines, and antibodies against IL-17A as well as the receptor IL-17RA are being successfully used for the treatment of these diseases. Involvement in the development of inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and tumors has also been suggested in animal disease models. In this review, we will briefly review the mechanisms by which IL-17 cytokines are involved in the development of these diseases and discuss possible treatment of inflammatory diseases by targeting IL-17 family members.

Keywords: IL-17 family; IL-17 receptor; antibodies against IL-17 and the receptors; autoimmune disease; psoriasis.

Graphical Abstract

Fig. 1.

The IL-17 family, its receptors and the downstream signaling pathways (1, 3, 4, 6). The IL-17 family consists of six family members. IL-17A and IL-17F form homodimers and heterodimers, whereas IL-17B, IL-17C and IL-17E form homodimers. Upon ligand binding, IL-17 receptors form dimers except for the IL-17D receptor CD93. IL-17A/A, IL-17A/F and IL-17F/F can induce the formation of IL-17RA/RC and IL-17RC/RC. In addition, IL-17A/A binds IL-17RA/RD. Dimer formation of receptors induces signal transduction by recruiting the ubiquitin ligase Act1 to the SEFIR domain and activates the TRAF6–TAK1–NF-κB pathway downstream. Activation of the C/EBP and MAPK pathways also occurs. The intracellular domain of CD93 is cleaved upon stimulation and functions as a transcription factor. The dotted lines show unconfirmed pathways.