Zhu S, Qian Y.IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Clin Sci 122:487-511

The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Clinical Science (Impact Factor: 5.6). 06/2012; 122(11):487-511. DOI: 10.1042/CS20110496
Source: PubMed


IL-17 (interleukin-17), a hallmark cytokine of Th17 (T-helper 17) cells, plays critical roles in host defence against bacterial and fungal infections, as well as in the pathogenesis of autoimmune diseases. The present review focuses on current knowledge of the regulation, functional mechanisms and targeting strategies of IL-17 in the context of inflammatory autoimmune diseases. Evidence shows that IL-17 is highly up-regulated at sites of inflammatory tissues of autoimmune diseases and amplifies the inflammation through synergy with other cytokines, such as TNF (tumour necrosis factor) α. Although IL-17 was originally thought to be produced mainly by Th17 cells, a newly defined T-cell subset with a specific differentiation programme and tight regulation, several other cell types (especially innate immune cells) are also found as important sources for IL-17 production. Although IL-17 activates common downstream signalling, including NF-κB (nuclear factor κB), MAPKs (mitogen-activated protein kinases), C/EBPs (CCAAT/enhancer-binding proteins) and mRNA stability, the immediate receptor signalling has been shown to be quite unique and tightly regulated. Mouse genetic studies have demonstrated a critical role for IL-17 in the pathogenesis of variety of inflammatory autoimmune diseases, such as RA (rheumatoid arthritis) and MS (multiple sclerosis). Importantly, promising results have been shown in initial clinical trials of monoclonal antibodies against IL-17 or its receptor (IL-17R) to block IL-17-mediated function in treating autoimmune patients with psoriasis, RA and MS. Therefore targeting IL-17/IL-17R, IL-17-producing pathways or IL-17-mediated signalling pathways can be considered for future therapy in autoimmune diseases.

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    • "Furthermore, the production of IL17A is important for host defense against extracellular pathogens (fungi, viruses, bacteria, and parasites) assisting in neutrophils recruitment and activation and also promoting antimicrobial peptides [8] [9] [10] [11] [12]. Studies in mice [12] [13] [14] [15] and humans [16] [17] [18] highlighted the importance of IL17 expressing cells for immunity against several diseases, and low expression levels of IL17 and IL17RA make organisms more susceptible to disease, including those caused by extracellular pathogens such as Francisella tularensis. "
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    ABSTRACT: In leporids, IL17A had been implicated in the host defense against extracellular pathogens, such as Francisella tularensis that infects hares and rabbits and causes the zoonotic disease tularemia. Here, we studied IL17A from five lagomorphs, European rabbit, pygmy rabbit, brush rabbit, European brown hare, and American pika. We observed that this protein is highly conserved between these species, with a similarity of 97–99% in leporids and ~88% between leporids and American pika. The exon/intron structure, N-glycosylation sites, and cysteine residues are conserved between lagomorphs. However, at codon 88, one of the interaction sites between IL17A and its receptor IL17RA, there is an Arg>Pro mutation that only occurs in European rabbit and European brown hare. This could induce critical alterations in the IL17A structure and conformation and consequently modify its function. The differences observed between leporids and humans or rodents might also represent important alterations in protein structure and function. In addition, as for other interleukins, IL17A sequences of human and European rabbit are more closely related than the sequences of human and mouse or European rabbit and mouse. This study gives further support to the hypothesis that European rabbit might be a more suitable animal model for studies on human IL17.
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    • "Functionally, IL-17 is known to mediate pro-inflammatory responses, with certain differences depending on the type and site of inflammation (Jin and Dong, 2013). Since IL-17 has been also associated with autoimmune disorders (Codarri et al., 2011; Zhu and Qian 2012), the evidence emanating from such results including that of present study might shed light on the association of IL-17 with anxiety À depression. "
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    ABSTRACT: The present study compares the serum cytokine levels between adolescent depression patients and healthy controls and assesses correlation between depression, anxiety scores and serum levels of eight cytokines. Study also checked the variation in serum levels with medication status (medication free/naïve vs. patients on medication). Following clinical and psychometric assessment of 77 adolescent (aged 13-18 years) depression patients (49 males and 28 females; 56 medication free/naïve) and 54 healthy controls (25 males, 29 females), eight cytokines (IL-1β, IL-2, IL-6, IL-10, TNF-α, IFN-γ, TGF-β1 and IL-17A {denoted IL-17 throughout}) were measured in serum using ELISA. Depressed adolescents had significantly high levels of IL-2 (p<0.001) and IL-6 (p=0.03) as compared to controls. The female population skewed the result of one cytokine (IL-6) in patients. Anxiety scores showed positive correlation (only in female patients) with IL-1β, IL-10 and negative correlation with TGF-β1 and IL-17. The gender effect in relationship between anxiety and cytokines was not straightforward. On comparing study groups on the medication/naïve status, IL-2 and TGF-β1 showed significant difference between the groups (p<0.001, p=0.007 higher in medicated). Depression in adolescents was associated with elevation of proinflammatory serum cytokines with a gender bias for females. Anxiety scores correlated negatively with TGF-β1 and IL-17. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jun 2015
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    • "Calcitriol has some effects on the B cells, including inhibition of proliferation, differentiation and apoptosis of plasma and memory cells and decreasing of immunoglobulin production [10]. Th17A, a new class of inflammatory T helper cells produces IL-17 that plays critical role in autoimmune diseases, including rheumatoid arthritis, systemic Lupus erythematous and MS [11] [12]. This cytokine is produced by activated T cells and regulates activities of NF-KB and mitogen-activated protein kinases. "
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    ABSTRACT: Vitamin D regulates gene expression and affects target cell functions. IL-6 and IL-17A are pro-inflammatory cytokines associated with MS pathogenesis. The aim of this study was to investigate the vitamin D effects on the expression level of IL-6 and IL-17A in peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients. Also, we performed a correlation analysis between the gene expression and some clinical features such as serum level of vitamin D and the expanded disability status scale (EDSS). Significant up-regulation of IL-6 and IL-17A gene expression was shown under vitamin D treatment. Also, some gender specific correlations between the gene expression with vitamin D levels were detected in female RR-MS patients.
    Full-text · Article · Jun 2015 · International Immunopharmacology
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