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IL-17 / Interleukin 17
Interleukin 17 (IL-17) family, a type of interleukins, is a recently identified group of cytokines sharing homology in amino acid sequences with highly conserved cysteine residues critical to their 3-dimensional shape. To date, there are six IL-17 family ligands [IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F], and five receptors (IL-17RA, IL-17RB/IL-25R, IL-17RC, IL-17RD/SEF and IL-17RE). Interleukin-17A (hereafter referred to as IL-17) is the most intensively studied, but interest in the rest of the family is growing. Originally IL-17 was thought to be produced exclusively by T cells, but it is now known to be secreted by a variety of innate cells including macrophages, dendritic cells (DC), natural killer, natural killer T, lymphoid tissue inducer and γδ-T cells.
Roles of IL-17 / IL-17 Function
The interleukin-17 (IL-17) cytokines, IL-17A to IL-17F, are emerging as critical players in host defence responses and inflammatory diseases. Substantial data support the role of these proteins in innate and adaptive immunity. Of these family members, IL-17A, IL-17F and IL-17E have been the best studied. Both IL-17A and IL-17F contribute to the host response to extracellular bacteria and fungi, and IL-17E has been shown to play a role in parasitic infections. In addition, numerous pre-clinical and clinical studies link these proteins to the pathogenesis of inflammatory diseases, and a number of therapeutic programmes targeting these family members are in clinical development. This review will highlight the cellular sources, receptors/target cells, and role in inflammation of these and the less-characterized family members, IL-17B, IL-17C and IL-17D.
IL-17 Family Ligand
IL-17 Family Receptor
IL-17 Family Signaling Related Molecules
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IL-17 Receptor
The IL-17 receptor family represent a unique group of proteins that share minimal structural homology and signal transduction properties with other receptors. Each chain is composed of a single transmembrane domain, an extracellular-fibronectin III-like (FnIII) domain and an intracellular similar expression to FGF genes (SEF)/IL-17R (SEFIR) domain. Membrane-bound and soluble versions of the receptors have been described, the latter resulting from alternative splicing events. While the SEFIR domain resembles the Toll-/IL-1R (TIR) domains found in receptors of the innate immune system, structural differences between the proteins preclude association of the SEFIR domains with signalling components of the TIR pathways. Upon ligand binding, the SEFIR domains within the IL-17 receptors associate with other SEFIR-containing proteins to initiate signalling cascades.
Protumor and Antitumor Functions of Interleukin 17
Protumor functions of IL-17
IL-17 signaling induces the production of both proangiogenic and protumor factors from fibroblasts. IL-17 induces VEGF, which in turn induces TGF-β and, thereby, VEGF-mediated angiogenesis. TGF-β enhances the VEGF receptivity by increasing VEGF receptor expression. IL-17 also induces IL-6 expression in fibroblasts. Although IL-17-mediated IL-6 expression is regulated primarily by NF-κB, the same cytokine can further stimulate NF-κB-mediated transcription of its own. The increased production of IL-6 and TGF-β further amplifies Th17 differentiation and creates a sustained chronic inflammatory state that can favor tumor growth and metastasis. (Figure 1, A)
Antitumor functions of IL-17
Dendritic cells acquire, process tumor-associated or tumor Ags, and present epitopes to both CD4+ and CD8+ T cells, leading to differentiation of Th17 cells and effector CTLs. The differentiated Th17 cells can have multiple antitumor functions. Th17 cells potentiate effector functions of both CTLs and innate effectors such as NK cells and neutrophils. Th17 cells stimulate the secretion of IL-12 from macrophages that leads to CTL activation. Th17 cells also regulate DC maturation and effective T cell priming. (Figure 1, B)
References
- Gopal M. et al. (2009) Protumor vs Antitumor Functions of IL-17. The Journal of Immunology. 183(7): 4169-4175.
- Reiko M Onishi et al. (2010) Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology. 129(3): 311–321.
- Seon Hee Chang and Chen Dong. (2011) Signaling of Interleukin-17 family cytokines in immunity and inflammation. Cell Signal. 23(7): 1069–1075.
- Rajita P. et al. (2011) The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases. Immunology. 134(1): 8–16.
- Keiji H. et al. (2012) Regulation and function of innate and adaptive interleukin-17-producing cells. EMBO Rep. 13(2): 113–120.
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