IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential

2012 ◽  
Vol 122 (11) ◽  
pp. 487-511 ◽  
Author(s):  
Shu Zhu ◽  
Youcun Qian
Keyword(s):  
Autoimmune Diseases ◽  
Therapeutic Potential ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Subset ◽  
Interleukin 17 ◽  
T Helper 17 ◽  
Receptor System ◽  
Inflammatory Autoimmune Diseases

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.

scholarly journals Fenofibrate Inhibited the Differentiation of T Helper 17 CellsIn Vitro

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Zhou Zhou ◽  
Weiliang Sun ◽  
Ying Liang ◽  
Yanxiang Gao ◽  
Wei Kong ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Diseases ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Lipid Lowering ◽  
Interleukin 17 ◽  
T Helper ◽  
T Helper 17 ◽  
Th17 Differentiation

Uncontrolled activity of T cells mediates autoimmune and inflammatory diseases such as multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and atherosclerosis. Recent findings suggest that enhanced activity of interleukin-17 (IL-17) producing T helper 17 cells (Th17 cells) plays an important role in autoimmune diseases and inflammatory diseases. Previous papers have revealed that a lipid-lowering synthetic ligand of peroxisome proliferator-activated receptorα(PPARα), fenofibrate, alleviates both atherosclerosis and a few nonlipid-associated autoimmune diseases such as autoimmune colitis and multiple sclerosis. However, the link between fenofibrate and Th17 cells is lacking. In the present study, we hypothesized that fenofibrate inhibited the differentiation of Th17 cells. Our results showed that fenofibrate inhibited transforming growth factor-β(TGF-β) and IL-6-induced differentiation of Th17 cellsin vitro. However, other PPARαligands such as WY14643, GW7647 and bezafibrate did not show any effect on Th17 differentiation, indicating that this effect of fenofibrate might be PPARαindependent. Furthermore, our data showed that fenofibrate reduced IL-21 production and STAT3 activation, a critical signal in the Th17 differentiation. Thus, by ameliorating the differentiation of Th17 cells, fenofibrate might be beneficial for autoimmunity and inflammatory diseases.

scholarly journals Therapeutic Potential of IL-9 in Allergic and Autoimmune Diseases

2021 ◽  
Author(s):  
Ahmed Ummey Khalecha Bintha ◽  
Amani Souwelimatou Amadou ◽  
Mursalin Md Huzzatul ◽  
Muhammad Fauziyya
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Autoimmune Diseases ◽  
Therapeutic Potential ◽  
Cell Subset ◽  
Allergic Diseases ◽  
Helper T Cell ◽  
T Cell Subset ◽  
Interleukin 9

Interleukin-9 (IL-9) is a pleiotropic cytokine produced by several immune and epithelial cells. Recently, many studies have eluded the physiological and pathological roles of IL-9 and its lineage-specific helper T cell subset (Th9). In this chapter, we will focus on the immunological role of Interleukin 9 (IL-9) in allergy and autoimmunity. We will introduce the basics of IL-9 and describe the cells involved in the secretion, signaling, and regulation of IL-9. After establishing the background, we will discuss the pathogenesis and regulation of IL-9 in allergic and autoimmune diseases. We will conclude the chapter by providing an updated therapeutics that target IL-9 and their potential uses in autoimmune and allergic diseases.

scholarly journals TRAIL and FasL Functions in Cancer and Autoimmune Diseases: Towards an Increasing Complexity

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 639 ◽  
Author(s):  
Aurélie Rossin ◽  
Giorgia Miloro ◽  
Anne-Odile Hueber
Keyword(s):  
Tumor Necrosis Factor ◽  
Autoimmune Diseases ◽  
Tumor Necrosis ◽  
Fas Ligand ◽  
Current Knowledge ◽  
Receptor Gene ◽  
Critical Role ◽  
Effector Proteins ◽  
Immune Functions ◽  
Necrosis Factor

Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) and Fas Ligand (FasL/TNFSF6), two major cytokines of the TNF (Tumor Necrosis Factor) superfamily, exert their main functions from the immune system compartment. Mice model studies revealed that TRAIL and FasL-mediated signalling both control the homeostasis of the immune cells, mainly from the lymphoid lineage, and function on cytotoxic cells as effector proteins to eliminate the compromised cells. The first clues in the physiological functions of TRAIL arose from the analysis of TRAIL deficient mice, which, even though they are viable and fertile, are prone to cancer and autoimmune diseases development, revealing TRAIL as an important safeguard against autoimmunity and cancer. The naturally occurring gld (generalized lymphoproliferative disease) and lpr (lymphoproliferation) mutant mice develop lymphadenopathy and lupus-like autoimmune disease. The discovery that they are mutated in the fasl and the fas receptor gene, respectively, demonstrates the critical role of the FasL/Fas system in lymphocyte homeostasis and autoimmunity. This review summarizes the state of current knowledge regarding the key death and non-death immune functions that TRAIL and FasL play in the initiation and progression of cancer and autoimmune diseases.

scholarly journals Interplay between Mediterranean Diet and Gut Microbiota in the Interface of Autoimmunity: An Overview

2020 ◽  
Author(s):  
Christina Tsigalou ◽  
Avgi Tsolou ◽  
Theoharis Konstantinidis ◽  
Efterpi Zafiriou ◽  
Dardiotis Efthimios ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Gut Microbiota ◽  
Autoimmune Diseases ◽  
Mediterranean Diet ◽  
Intestinal Microbiota ◽  
Unsaturated Fatty Acids ◽  
Current Knowledge ◽  
Critical Role ◽  
Mucosal Inflammation ◽  
Omega 3

The nutritional habits regulate the gut microbiota and may provoke and/or prevent autoimmune disease. Western diet is rich in sugars, meat and poly-unsaturated fatty acids, which lead to dysbiosis of intestinal microbiota, disruption of gut epithelial barrier and chronic mucosal inflammation. On the other hand, Mediterranean Diet (MedDiet) is rich in ω3 fatty acids, fruits and vegetables and has anti-inflammatory properties, which can restore gut eubiosis. The effect of MedDiet and its components in health and disease states have been thoroughly analyzed in several studies. Moreover, several studies have specifically investigated the association between MedDiet, microbiota and risk for autoimmune diseases. Furthermore, the MedDiet has been associated with lower risk of cardiovascular diseases, which plays a critical role in reducing mortality in patients suffering from autoimmune diseases with comorbidities. The aim of the present review is to specifically highlight current knowledge regarding possible interactions of MedDiet with the patterns of intestinal microbiota focusing on autoimmunity and a blueprint through dietary modulations for the prevention and management of diseases’s activity and progression.

scholarly journals NK Cells in Autoimmune Diseases: Protective or Pathogenic?

2021 ◽  
Vol 12 ◽  
Author(s):  
Meifang Liu ◽  
Shujuan Liang ◽  
Cai Zhang
Keyword(s):  
Immune System ◽  
Autoimmune Diseases ◽  
Nk Cells ◽  
Lupus Erythematosus ◽  
Nk Cell ◽  
Current Knowledge ◽  
Type I Diabetes ◽  
Cell Subset ◽  
Type I ◽  
Autoantibody Production

Autoimmune diseases generally result from the loss of self-tolerance (i.e., failure of the immune system to distinguish self from non-self), and are characterized by autoantibody production and hyperactivation of T cells, which leads to damage of specific or multiple organs. Thus, autoimmune diseases can be classified as organ-specific or systemic. Genetic and environmental factors contribute to the development of autoimmunity. Recent studies have demonstrated the contribution of innate immunity to the onset of autoimmune diseases. Natural killer (NK) cells, which are key components of the innate immune system, have been implicated in the development of multiple autoimmune diseases such as systemic lupus erythematosus, type I diabetes mellitus, and autoimmune liver disease. However, NK cells have both protective and pathogenic roles in autoimmunity depending on the NK cell subset, microenvironment, and disease type or stage. In this work, we review the current knowledge of the varied roles of NK cell subsets in systemic and organic-specific autoimmune diseases and their clinical potential as therapeutic targets.

Therapeutic potential of interleukin-17 in inflammation and autoimmune diseases

2013 ◽  
Vol 18 (1) ◽  
pp. 29-41 ◽  
Author(s):  
Jun-Wei Yan ◽  
Yu-Jie Wang ◽  
Wen-Jia Peng ◽  
Jin-Hui Tao ◽  
Ya-Nan Wan ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Therapeutic Potential ◽  
Interleukin 17

scholarly journals The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease

2019 ◽  
Vol 116 (37) ◽  
pp. 18528-18536 ◽  
Author(s):  
Christina Chang ◽  
Chin-San Loo ◽  
Xuan Zhao ◽  
Laura A. Solt ◽  
Yuqiong Liang ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Nuclear Receptor ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptor ◽  
Interleukin 17 ◽  
Orphan Nuclear Receptor ◽  
T Helper 17 ◽  
Autoimmune Encephalomyelitis

T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORγt. Here, we identify REV-ERBα (encoded byNr1d1), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt function in Th17 cells. REV-ERBα binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORγt-dependent genes includingIl17aandIl17f. Furthermore, elevated REV-ERBα expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE). These results suggest that modulating REV-ERBα activity may be used to manipulate Th17 cells in autoimmune diseases.

Interleukin-17 Antagonists in the Treatment of Psoriasis

2015 ◽  
Vol 19 (2) ◽  
pp. 109-114 ◽  
Author(s):  
Shivani Felicia Chandrakumar ◽  
Jensen Yeung
Keyword(s):  
Critical Role ◽  
Cell Subset ◽  
Severity Index ◽  
Unknown Etiology ◽  
Interleukin 17 ◽  
New Class ◽  
Immune Mediated ◽  
Sizable Proportion ◽  
Inflammatory Skin Disorder ◽  
Proinflammatory Role

Background Psoriasis is a chronic, immune-mediated inflammatory skin disorder of unknown etiology. Interleukin (IL)-17a, a key product of the recently identified Th17 cell subset, has been found to play a critical role in the immunopathogenesis of psoriasis. IL-17 antagonists are a new class of biological agent currently in development for psoriasis that selectively inhibit IL-17a activity. Objective This review aims to summarize the current efficacy data from phase II randomized controlled trials of the IL-17 antagonists brodalumab, ixekizumab, and secukinumab for the treatment of moderate to severe psoriasis. Conclusion Patients treated with IL-17 antagonists achieved marked reduction in psoriasis disease severity as demonstrated by the Psoriasis Area and Severity Index (PASI) 75 response rates. A sizable proportion of patients treated with brodalumab and ixekizumab achieved unprecedented clinical clearance of their psoriasis (PASI > 90). These encouraging results demonstrate the efficacy of these agents and validate the proinflammatory role of IL-17 in the pathophysiology of psoriasis.

Pathophysiological relevance of macrophage subsets in atherogenesis

2017 ◽  
Vol 117 (01) ◽  
pp. 07-18 ◽  
Author(s):  
Luca Liberale ◽  
Franco Dallegri ◽  
Federico Carbone ◽  
Fabrizio Montecucco
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Plaque Rupture ◽  
Current Knowledge ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Multiple Phenotypes ◽  
Adenosine Receptor Agonist ◽  
Macrophage Subsets

SummaryMacrophages are highly heterogeneous and plastic cells. They were shown to play a critical role in all stages of atherogenesis, from the initiation to the necrotic core formation and plaque rupture. Lesional macrophages primarily derive from blood monocyte, but local macrophage proliferation as well as differentiation from smooth muscle cells have also been described. Within atherosclerotic plaques, macrophages rapidly respond to changes in the microenvironment, shifting between pro- (M1) or anti-inflammatory (M2) functional phenotypes. Furthermore, different stimuli have been associated with differentiation of newly discovered M2 subtypes: IL-4/IL-13 (M2a), immunecomplex (M2b), IL-10/glucocorticoids (M2c), and adenosine receptor agonist (M2d). More recently, additional intraplaque macrophage phenotypes were also recognized in response to CXCL4 (M4), oxidized phospholipids (Mox), haemoglobin/haptoglobin complexes (HAmac/M(Hb)), and heme (Mhem). Such macrophage polarization was described as a progression among multiple phenotypes, which reflect the activity of different transcriptional factors and the cross-talk between intracellular signalling. Finally, the distribution of macrophage subsets within different plaque areas was markedly associated with cardiovascular (CV) vulnerability. The aim of this review is to update the current knowledge on the role of macrophage subsets in atherogenesis. In addition, the molecular mechanisms underlying macrophage phenotypic shift will be summarised and discussed. Finally, the role of intraplaque macrophages as predictors of CV events and the therapeutic potential of these cells will be discussed.

Interleukin 17 in the tumor microenvironment: A potent target for anticancer immunotherapy?

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 115-115
Author(s):  
Joseph Fabre ◽  
Jérôme Giustiniani ◽  
Stéphanie Servagi-Vernat ◽  
Christian Garbar ◽  
Yacine Merrouche ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Critical Role ◽  
Breast Cancer Cell Lines ◽  
Interleukin 17 ◽  
Growth Factor Signaling ◽  
Breast Cancer Patients ◽  
T Helper 17 ◽  
Proinflammatory Mediators

115 Background: Inflammation has been known to play a critical role in cancer for decades. Tumors build up on the “inflammatory soup” in the surrounding microenvironment to progress, grow, metastasize and evade immune response. Since its discovery in the nineties, interleukin-17 (IL-17A), a proinflammatory cytokine mainly secreted by T helper 17 cells, has been extensively studied in chronic inflammatory diseases like psoriasis or rheumatoid arthritis. In solid malignancies, there is growing evidence that IL-17 enhances cancer cells’ capacity of division, invasion and chemotherapy resistance. Methods: Based on our team's experience and publications, we systematically reviewed the existing literature about the role of IL-17 in cancers, in aim to discuss if developing IL-17 pathway-targeting strategies could be effective. Results: Data from several preclinical studies indicated tumor-promoting effects of IL-17 on diverse cancer models, cellular or murine. In clinical studies, detection of high levels of IL-17 in patients’ blood or tumors was correlated to bad prognosis. Concordantly, we reported recently in triple negative breast cancer cell lines that IL-17A and IL-17E promoted resistance to Docetaxel and failed to induce apoptosis as previously observed for IL-17E by other authors. Interestingly, we also revealed that both cytokines induced the generation of tumorigenic low molecular weight forms of cyclin E (LMW-E), which high levels correlated strongly with a poor survival in breast cancer patients. Lastly, we reported a crosstalk between IL-17E and epidermal growth factor signaling, which confers in vitro resistance to EGFR-targeted therapies. In opposition, a few studies observed that IL-17 inhibited tumor grafts development and metastasis in rodent possibly through the expression of other proinflammatory mediators such as IL-1β, TNFα, IL-6 or GM-CSF and the recruitment of neutrophils to the tumor site. Conclusions: Most of the literature supports a critical role of IL-17 in cancer promotion and development. These results encourage us to present the IL-17 family members and their receptors as potent targets for anticancer biotherapy.

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