Hanyang Med Rev.  2013 Feb;33(1):17-26. 10.7599/hmr.2013.33.1.17.

Targeting Interleukin-17 and Th17 in Immune Inflammatory Diseases

• Cho MR

• KMID: 2168216
• DOI: http://doi.org/10.7599/hmr.2013.33.1.17

Abstract

Th17 cells (Th17) are a distinct lineage of CD4+ T cells that secrete high amounts of IL-17 under orphan nuclear receptor retinoic acid receptor-related orphan receptor gammat (RORgammat) which is a lineage-specific transcription factor. TGF-beta and inflammatory cytokines, such as IL-6, IL-21, IL-1beta, and IL-23, play central roles in the generation of Th17 cells. Th17 cells and their effector molecules, such as IL-17A, IL-17F, IL-21, IL-22, and CCL20, contribute to the progression and pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease and systemic lupus erythematosus. Studies of Th17 development and the effects of IL-17 signaling in autoimmune responses suggest a high potential for targeting this pathway in immune pathologies. In this review, we discuss Th17 biology in relation to autoinflammatory disorders and the various therapeutic strategies under investigation which target the IL-17-Th17 cell pathway in chronic inflammatory autoimmune disorders.

Keyword

Th17 Cells; Receptors, Interleukin-17; Autoimmune Diseases; Therapeutics

MeSH Terms

Arthritis, Rheumatoid
Autoimmune Diseases
Autoimmunity
Biology
Child
Child, Orphaned
Cytokines
Humans
Inflammatory Bowel Diseases
Interleukin-17
Interleukin-23
Interleukin-6
Interleukins
Lupus Erythematosus, Systemic
Multiple Sclerosis
Psoriasis
Receptors, Interleukin-17
T-Lymphocytes
Th17 Cells
Transcription Factors
Transforming Growth Factor beta
Tretinoin
Cytokines
Interleukin-17
Interleukin-23
Interleukin-6
Interleukins
Receptors, Interleukin-17
Transcription Factors
Transforming Growth Factor beta
Tretinoin

Figure

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  Fig. 1 Differentiation of Th17 cells in mouse and human. TGF-β and IL-6/21, or TGF-β3 and IL-6 required to induce the development of Th17 cells in mice. TNF and IL-1 are found to enhance TGF-mediated and IL-6-mediated differentiation of Th17 cells. Th17 cell differentiation was proposed to comprise three different stages (differentiation, amplification and stabilization). TGF-β, IL-21, IL-1, IL-6, and IL-23 are sufficient to induce the differentiation of human Th17 cells from naïve T cells. IL-1 and IL-6 are important for enhancing the expansion of differentiated and memory Th17 cells. IL, interleukin; Th17, IL-17-producing T helper; TGF-β, transforming growth factor beta; TNFα, tumour necrosis factor alpha; ROR, retinoic-acid-receptor-related orphan receptor; RORγt, ROR gamma t; RORα, ROR alpha; IRF4, interferon regulatory factor 4; STAT3, signal transducers and activators of transcription 3; APC, antigen presenting cell.

• 

  Fig. 2 IL-17 receptors and IL-17 signaling. (A) IL-17RA forms a complex with IL-17RB or IL-17RE to create the receptor for IL-17E (IL-25) and IL-17C, respectively.IL-17B and IL-17D bind to the monomeric receptors IL-17RB, while the receptor(s) for IL-17D has not yet been identified. (B) The IL 17R complex is composed of IL-17RA and IL-17RC. IL-17A or IL-17F homodimer or heterodimer can bind to IL-17R (the heterodimer of IL-17RA and IL-17RC). Binding of IL-17 to its receptor recruits adaptor protein ACT1. ACT1 is required for recruitment of TRAF6, which are essential upstream activators of NF-κB pathway. IL-17RA/ACT1/TRAF6 complex lead to the activation of NF-κB, and C/EBP. Also, ACT1-independent ERK activation contributes to IL-17R signaling. IL-17RA signaling can be negatively regulated by TRAF3, USP25 or SCFβ-TrCP. IL, interleukin; SCFβ-TrCP, SKP1-Cullin1-F-box beta-transducin repeat containing protein; TRAF, TNF-receptor-associated factor; ACT1, actin related gene 1; ERK, extracellular signal-regulated kinase; C/EBP, CCAAT/enhancer binding protein; NF-κB, nuclear factor kappa B; USP25, ubiquitin-specific protease 25.

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  Fig. 3 Key functions of Th17 cytokines. Th17 cells produce several effector molecules, such as IL-17A, IL-17F, IL-21, IL-22, and CCL20. IL-17A and IL-17F play a role in the recruitment, activation, and migration of neutrophils and can target nonimmune cells, such as fibroblasts, endothelial cells, and epithelial cells, to induce pro-inflammatory mediators. IL-22 induces antimicrobial agents in keratinocytes and promotes epidermal hyperplasia. IL-21 stimulates proliferation/differentiation of CD8 T cells, and differentiate/antibody class switching of B cells. Also IL-21 induces differentiation and cytotoxic program of NK and NKT cells, and IL-8 production from DCs and macrophages. CCL20 regulate recruitment of Th17 cells to inflamed tissues. IL, interleukin; TH17, IL-17-producing T helper; ACT1, actin related gene 1; TRAF, TNF-receptor-associated factor; STAT3, signal transducers and activators of transcription 3; NF-κB, nuclear factor kappa B; MAPK, mitogen-activated protein kinase; EpC, epithelial cell; EC, endothelial cell; FB, fibroblast; MØ, macrophage; NK, natural killer; DC, dendritic cell; CCL, CC chemokine ligand; CCR6, CC chemokine receptor 6; JAK, janus kinase; MMPs, matrix metalloproteinases; NO, nitric oxide; GC, germinal center; Bcl-6, B-cell CLL/lymphoma 6; IgG, immunoglobulin G.

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  Fig. 4 The role of IL-17 in autoimmune arthritis. IL-17 leads to inflammation, cartilage damage and bone erosion in arthritis. In synovial fibroblast and macrophage, IL-17 induces pro-inflammatory cytokines such as IL-6, IL-8, TNF, IL-1β or MMPs. When acting on monocytes, IL-17 contributes to inflammation by increasing the production of pro-inflammatory cytokines. IL-17 activates the production and function of matrix metalloproteinases. IL-17 increases the expression of RANKL in osteoblasts, which leads to increased RANK signalling in osteoclasts. IL-17 produced by Th17 cells influences the activity of various cell types, and consequently leads to the development of features characteristic of rheumatoid arthritis including inflammation and destruction of cartilage and bone. IL, interleukin; Th17, IL-17-producing T helper; TNF, tumour necrosis factor; RANK, receptor activator NF kappa B; RANKL, RANK ligand; MMPs, matrix metalloproteinases.

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  Fig. 5 Targeting of Th17 cells. There are several ways in which members of the IL-17 protein and receptor family can be targeted. Various therapeutic tools include blocking the differentiation and amplification of Th17 cells, inhibiting or neutralizing the cytokines of Th17 cells, and suppressing the transcription factors specific for Th17 cells. IL, interleukin; Th17, IL-17-producing T helper; STAT3, signal transducers and activators of transcription 3; ROR, retinoic-acid-receptor-related orphan receptor.

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