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Review
. 2010 May;7(3):164-74.
doi: 10.1038/cmi.2010.21. Epub 2010 Apr 12.

Interleukin-17 and its expanding biological functions

Sheng Xu  1 , Xuetao Cao
Affiliations
Review

Interleukin-17 and its expanding biological functions

Sheng Xu et al. Cell Mol Immunol. 2010 May.

Abstract

Interleukin-17 (IL-17) and IL-17-producing cells have been shown to play important roles in inflammation and the immune response. IL-17 is believed to be mainly produced by T helper 17 (Th17) cells, a unique helper T-cell subset different from Th1 and Th2 cells. Other subsets of T cells such as gammadeltaT and natural killer T (NKT) cells have also been found to produce IL-17 in response to innate stimuli. IL-17 acts as a proinflammatory cytokine that can induce the release of certain chemokines, cytokines, matrix metalloproteinases (MMPs) and antimicrobial peptides from mesenchymal and myeloid cells. This leads to the expansion and accumulation of neutrophils in the innate immune system and links innate and adaptive immunity in vivo. Furthermore, increasing evidence indicates that IL-17 and IL-17-producing cells are involved in the pathogenesis of various diseases such as allergies, autoimmune diseases, allograft transplantation and even malignancy. They may also play protective roles in host defense against infectious diseases and promote induction of cytotoxic T lymphocyte (CTL) responses against cancer. Targeting of the IL-17 axis is under investigation for the treatment of inflammatory disorders.

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Figures

Figure 1
Figure 1
Helper T-cell subsets in host defense and immune responses. After being activated by antigen-presenting cells, naive CD4 T cells undergo clonal expansion and differentiate into different subsets of functional effector Th cells. IL-12 initiates the differentiation of Th1 cells, which is characterized by high production of IFN-γ, which act on macrophages and CTLs and are indispensable for cellular immunity and clearing intracellular pathogens. IL-4 triggers the differentiation of Th2 cells, which is characterized by production of IL-4, IL-5 and IL-13, which act on B cells, eosinophils and mast cells, and are responsible for humoral immunity and clearing of parasites. Recently, TGF-β plus IL-6 was demonstrated to initiate the programming of the third Th cell subset, Th17 cells, which are characterized by the production of IL-17A/F, IL-21 and IL-22. Th17 cytokines can stimulate the expansion and recruitment of PMN, and are critical in autoimmune diseases such as MS and RA and in host defenses against fungi and some extracellular pathogens. CTL, cytotoxic T lymphocyte; IFN, interferon; MS, multiple sclerosis; PMN, polymorphonuclear leukocytes; RA, rheumatoid arthritis; TGF, transforming growth factor; Th, T helper.
Figure 2
Figure 2
Signal pathways of IL-17. The IL-17R complex is composed of two IL-17RA and one IL-17RC; both subunits encode SEFIR domains. After activation, the intracellular IL-17 signaling includes ACT1-dependent and -independent downstream pathways. Left: the ACT1-dependent pathway: IL-17RA engages its SEFIR domain to recruit the adaptor protein ACT1. ACT1 contains a TRAF6-binding motif and can bind TRAF6, TRAF3 and TAK1, which subsequently leads to activation of the canonical NF-κB pathway. ACT1 is also required for the activation of MAPK p38, and this pathway leads to the stabilization of mRNAs, particularly those encoding chemokines and cytokines. Right: the ACT1-independent pathway involves JAK1 and PI3K, followed by subsequent inactivation of GSK-3β. Both ACT1-dependent and -independent pathways contribute to the activation of transcription factors C/EBP-β and C/EBP-δ. ACT1, nuclear factor-κB activator 1; C/EBP, CCAAT/enhancer-binding protein; GSK-3β, glycogen synthase kinase-3β JAK1, Janus kinase 1; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; PI3K, phosphatidylinositol 3-kinase; SEFIR, SEF/IL-17R; TAK1, TGF-β-activated kinase 1; TRAF6, tumor-necrosis factor receptor-associated factor 6.
Figure 3
Figure 3
Biological activities of IL-17. Th17, γδT, NKT, CD8 T, and LTi cells are cellular sources of IL-17. IL-17, in turn, can induce the production of various molecules (including chemokines, cytokines, growth factors, antimicrobial peptides and tissue remodeling enzymes) in epithelial cells, endothelial cells, fibroblasts, osteoblasts, macrophages and DCs. IL-17 can also exert its functions on B and T cells. For B cells, IL-17 can promote the survival and expansion of B cells and the differentiation of B cells into antibody producing plasma cells. IL-17 can also inhibit IFN-γ production by targeting T-bet expression. COX2, cyclooxygenase 2; DC, dendritic cell; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; IFN, interferon; iNOS, inducible nitric oxide synthase; LTi, lymph tissue inducer; MMP, matrix metalloproteinase; NKT, natural killer T; Th, T helper; TNF, tumor-necrosis factor.
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