Interleukin-17 Axis Research Articles

Punicalagin alleviates the hyperproliferation of keratinocytes in psoriasis through inhibiting SKP2 expression.

Psoriasis is a chronic inflammatory skin disorder characterized by abnormal keratinocytes proliferation and multiple immune cells infiltration in the dermis and epidermis. Although most psoriasis-related researches have been concentrated on the interleukin-23 (IL-23)/interleukin-17 (IL-17) axis, new data suggest that keratinocytes also play a pivotal role in psoriasis. Previously, we found that punicalagin (PUN), a bioactive ellagitannin extracted from Pericarpium Granati (the pericarpium of Punica granatum L.), exerts a therapeutic effect on psoriasis. However, the underlying mechanism, especially its potential modulatory effect on keratinocytes, remains obscure. Our study aims to reveal the potential regulatory effect and its underlying cellular mechanism of PUN on the hyperproliferation of keratinocytes. We used tumor necrosis factor α (TNF-α), IL-17A and interleukin-6 (IL-6) to induce abnormal proliferation of HaCaT cells (Human Keratinocytes Cells) in vitro. Then, we evaluated the effects of PUN through MTT assay, EdU staining and cell cycle detection. Finally, we explored the underlying cellular mechanisms of PUN via RNA-sequencing, WB in vitro and in vivo. Here, we found that PUN can directly and dose-dependently decrease TNF-α, IL-17A and IL-6-induced abnormal proliferation of HaCaT cells in vitro. Mechanically, PUN suppresses the hyperproliferation of keratinocytes through repressing S-phase kinase-associated protein 2 (SKP2) expression in vitro and in vivo. Moreover, overexpression of SKP2 can partly abolish PUN-mediated inhibition of aberrantly proliferative keratinocytes. These results illustrate that PUN can reduce the severity of psoriasis through directly repressing SKP2-mediated abnormal proliferation of keratinocytes, which gives new insight into the therapeutic mechanism of PUN on psoriasis. Moreover, these findings imply that PUN might be a promising drug candidate for the treatment of psoriasis.

Trichinella pseudospiralis-secreted 53 kDa protein ameliorates imiquimod-induced psoriasis by inhibiting the IL-23/IL-17 axis in mice

Trichinella infection can experimentally ameliorate many autoimmune diseases. However, the immune mechanism of the amelioration and the identification of corresponding Trichinella-derived molecule(s) are still not fully elucidated. Fifty-three kDa excretory-secretory (ES) protein from Trichinella pseudospiralis (Tpp53) is a molecule like TsP53 reported as a protein exerting immune-inhibitory effect in T. spiralis. In this study, we investigated the immunomodulatory effect of Tpp53 using imiquimod (IMQ)-induced psoriasis-like dermatitis model, which is a mouse model of autoimmune disease with the pathogenic interleukin 17 (IL-17) producing CD4+ T cells (Th17) via IL-23/IL17 axis. Administrating the recombinant Tpp53 (rTpp53) mixed with IMQ cream on the skin of mice ameliorated psoriatic lesions, as revealed by the improvement of erythema, scaling, skin thickening, epidermis hyperplasia and parakeratosis, thickening of acanthosis cell layer, epidermal extension of dermis, less infiltration of inflammatory cells, and decreased expression of inflammatory marker. The increased expression of the factors related to the IL-23/IL-17 axis, including IL-17A, IL-6, Il17F and Il23a, in the skins of IMQ-treated mice was inhibited by rTpp53 treatment. Moreover, the expression of activated keratinocyte-produced cytokines, chemokines, and antimicrobial peptides in the skin was also down-regulated in rTpp53-treated IMQ-treated mice. Co-culture of splenocytes with rTpp53 inhibited IL-17A and treatment of macrophages with rTpp53 reduced IL-6 production. Overall, our study revealed that the Trichinella-secreted 53 kDa ES protein could ameliorate IMQ-induced psoriasis by inhibiting the IL-23/IL-17 axis, suggesting that Tpp53 might involve in regulating host Th17 for immune evasion and have an alternative potential for psoriasis therapy.

Anemia and thrombocytosis associated with erythrodermic psoriasis successfully treated with ixekizumab: A case report

Introduction: Erythrodermic psoriasis is a rare and potentially life-threatening subtype of psoriasis. It can be accompanied by systemic inflammatory disorders such as arthritic, hematologic, hemodynamic, and metabolic disturbances. We herein report a case involving a woman with erythroderma, joint deformities, anemia, and thrombocytosis who was diagnosed with erythrodermic psoriasis and psoriasis arthritis that were successfully treated with interleukin-17A antibody. Case presentation: A 35-year-old woman presented with an almost 20-year history of recurrent erythema and desquamation. She was diagnosed with plaque psoriasis and psoriatic arthritis and treated with acitretin, etanercept combined with methotrexate, and etanercept combined with cyclosporin, respectively. However, at the time of consultation, she was experiencing an episode of severe skin and joint inflammation. Routine laboratory evaluation revealed moderate microcytic hypochromic anemia, thrombocytosis, and increased serum cytokine concentrations. The patient was given the standard dose of ixekizumab, which resulted in clearance of her skin lesions with a Psoriasis Area and Severity Index 90 response at week 12. Her arthritic symptoms, including arthralgia and joint dysfunction, also improved. Moreover, her hemoglobin concentration, platelet count, and inflammatory markers reached the normal ranges. Discussion: Multiple cytokines participate in the pathogenesis of erythrodermic psoriasis, including interleukin-17A, interleukin-6, interleukin-1β, and interleukin-8. In the present case, treatment targeting the interleukin-23/interleukin-17 axis showed great efficacy not only for the skin lesions but also for systemic inflammatory comorbidities, such as arthritis, anemia, and thrombocytosis. Conclusion: Patients with systemic inflammatory disorders related to psoriasis, such as anemia and thrombocytosis, may benefit from anti-IL-17A treatment.

Balanced control of thermogenesis by nuclear receptor corepressors in brown adipose tissue

Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure require histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors (NCoRs) NCoR1 and NCoR2 (also known as silencing mediator of retinoid and thyroid receptors [SMRT]), but the functions of NCoR1/2 in BAT have not been established. Here we report that as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between NCoR1/2 BAT-dKO and HDAC3 BAT-KO mice. Despite these commonalities, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the interleukin-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA sequencing and chromatin immunoprecipitation sequencing data revealed that NCoR1/2 directly regulate Mmp9, which integrates extracellular matrix remodeling and inflammation. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, such that HDAC3-independent suppression of BAT inflammation counterbalances stimulation of HDAC3 activity in the control of thermogenesis.

Allergic airway inflammation induces upregulation of the expression of IL-23R by macrophages and not in CD3 + T cells and CD11c+F4/80− dendritic cells of the lung

Interleukin 23 and the interleukin 23 receptor (IL-23-IL23R) are described as the major enhancing factors for Interleukin 17 (IL-17) in allergic airway inflammation. IL-17 is considered to induce neutrophilic inflammation in the lung, which is often observed in severe, steroid-resistant asthma-phenotypes. For that reason, understanding of IL-23 and IL-17 axis is very important for future therapy strategies, targeting neutrophil pathway of bronchial asthma.This study aimed to investigate the distribution and expression of IL-23R under physiological and inflammatory conditions. Therefore, a house dust mite (HDM) model of allergic airway inflammation was performed by treating mice with HDM intranasally. Immunofluorescence staining with panel of antibodies was performed in lung tissues to examine the macrophage, dendritic cell, and T cell subpopulations. The allergic airway inflammation was quantified by histopathological analysis, ELISA measurements, and airway function.HDM-treated mice exhibited a significant allergic airway inflammation including higher amounts of NE+ cells in lung parenchyma. We found only a small amount of IL-23R positives, out of total CD3+T cells, and no upregulation in HDM-treated animals. In contrast, the populations of F4/80+ macrophages and CD11c+F4/80− dendritic cells (DCs) with IL-23R expression were found to be higher. But HDM treatment leads to a significant increase of IL-23R+ macrophages, only. IL-23R was expressed by every examined macrophage subpopulation, whereas only Mϕ1 and hybrids between Mϕ1 and Mϕ2 phenotype and not Mϕ2 were found to upregulate IL-23R. Co-localization of IL-23R and IL-17 was only observed in F4/80+ macrophages, suggesting F4/80+ macrophages express IL-23R along with IL-17 in lung tissue.The study revealed that macrophages involving the IL-23 and IL-17 pathway may provide a potential interesting therapeutic target in neutrophilic bronchial asthma.

The Role of Interleukin-23 Inhibition in the Treatment of Psoriatic Arthritis

Psoriatic arthritis is a chronic inflammatory autoimmune disease with varied manifestations, including functional limitation and reduced quality of life. Improved understanding of the immunopathogenesis of psoriatic arthritis, particularly the role of the interleukin-23 and interleukin-17 axis, has led to the development of therapeutic targets to alter the natural history of the condition. In this article, we review the role of monoclonal antibodies targeting the p19 subunit of interleukin-23 in the treatment of psoriatic arthritis.

Interleukin-17 axis in the modulation of cortical and subcortical synaptic plasticity across disease stages in experimental multiple sclerosis

Interleukin-17A (IL-17) is known to be deeply involved in the immunopathogenesis of multiple sclerosis (MS), but recent reports suggest that it may also participate in synaptic modulation. The aim of our study was to explore the role exerted by IL-17 axis in the regulation of hippocampal and striatal synaptic plasticity in physiological conditions and across different stages of experimental MS.

Complexity of enthesitis and new bone formation in ankylosing spondylitis: current understanding of the immunopathology and therapeutic approaches.

Despite increasing availability of treatments for spondyloarthritis (SpA) including tumour necrosis factor (TNF) and interleukin-17 (IL-17) inhibitors, there is no established treatment that abates new bone formation (NBF) in ankylosing spondylitis (AS), a subset of SpA. Recent research on TNF has revealed the increased level of transmembrane TNF in the joint tissue of SpA patients compared to that of rheumatoid arthritis patients, which appears to facilitate TNF-driven osteo-proliferative changes in AS. In addition, there is considerable interest in the central role of IL-23/IL-17 axis in type 3 immunity and the therapeutic potential of blocking this axis to ameliorate enthesitis and NBF in AS. AS immunopathology involves a variety of immune cells, including both innate and adoptive immune cells, to orchestrate the immune response driving type 3 immunity. In response to external stimuli of inflammatory cytokines, local osteo-chondral progenitor cells activate intra-cellular anabolic molecules and signals involving hedgehog, bone morphogenetic proteins, receptor activator of nuclear factor kappa-B ligand, and Wnt pathways to promote NBF in AS. Here, we provide an overview of the current immunopathology and future directions for the treatment of enthesitis and NBF associated with AS.

Psychiatric aspects of spondyloarthritis

Spondyloarthritis refers to immune-mediated inflammatory rheumatic diseases characterized by the most pronounced pain, inflammatory activity and disability of patients of working age. One of the most frequent comorbid to spondy-loarthritis diseases that weigh down the course and outcomes are anxiety-depressive spectrum disorders. Chronic inflammation with hyperproduction of cytokines of the interleukin-23/interleukin-17 axis and violation of intracellular signaling of these cytokines, developing against the background of a violation of the stress and immune response, is a key pathogenetic mechanism that combines spondyloarthritis and anxiety-depressive spectrum disorders, and dictates approaches to their therapy. The article discusses the current understanding of the prevalence of mental disorders among patients with spondyloarthritis and their negative impact on the course and outcomes of the rheumatic disease, the common pathogenesis and provoking factors, the influence of antidepressants on spondyloarthritis outcomes and anti-inflammatory drugs, primarily interleukin-17 inhibitors and tumor necrosis factor alpha inhibitors on the symptoms of anxiety-depressive spectrum disorders.

The role of ixekizumab in non-radiographic axial spondyloarthritis

Among patients with axial spondyloarthritis (axSpA), non-radiographic axial spondyloarthritis (nr-axSpA) is distinguished from ankylosing spondylitis (AS) by a lack of obvious radiographic changes in the sacroiliac joint. Tumor necrosis factor inhibitor (TNFi) has been used as a highly effective treatment in patients with AS and has shown good efficacy and safety in clinical trials in patients with nr-axSpA. As the pathophysiological mechanism for axSpA has started to become better recognized, various drugs other than TNFi, all of which are related to the interleukin-17 (IL-17) axis, are being evaluated in patients with axSpA. IL-17 inhibitors, such as secukinumab and ixekizumab, are effective drugs for patients with AS. A recent clinical trial reported that ixekizumab, a monoclonal antibody against IL-17A, was also effective in patients with nr-axSpA. In a COAST-X study, ixekizumab was superior to a placebo for improving signs and symptoms in patients with nr-axSpA at weeks 16 and 52. The adverse events were no different from those found in previous ixekizumab studies, and no new safety signals were identified. However, when considering several IL-17 inhibitors, it is necessary to obtain sufficient data to identify the exacerbation of extra-articular manifestation. In terms of effectiveness and safety, ixekizumab may be an appropriate alternative to TNFi in nr-axSpA patients.

The Role of the Interleukin-17 Axis and Neutrophils in the Pathogenesis of Endemic and Systemic Mycoses.

Systemic and endemic mycoses are considered life-threatening respiratory diseases which are caused by a group of dimorphic fungal pathogens belonging to the genera Histoplasma, Coccidioides, Blastomyces, Paracoccidioides, Talaromyces, and the newly described pathogen Emergomyces. T-cell mediated immunity, mainly T helper (Th)1 and Th17 responses, are essential for protection against these dimorphic fungi; thus, IL-17 production is associated with neutrophil and macrophage recruitment at the site of infection accompanied by chemokines and proinflammatory cytokines production, a mechanism that is mediated by some pattern recognition receptors (PRRs), including Dectin-1, Dectine-2, TLRs, Mannose receptor (MR), Galectin-3 and NLPR3, and the adaptor molecules caspase adaptor recruitment domain family member 9 (Card9), and myeloid differentiation factor 88 (MyD88). However, these PRRs play distinctly different roles for each pathogen. Furthermore, neutrophils have been confirmed as a source of IL-17, and different neutrophil subsets and neutrophil extracellular traps (NETs) have also been described as participating in the inflammatory process in these fungal infections. However, both the Th17/IL-17 axis and neutrophils appear to play different roles, being beneficial mediating fungal controls or detrimental promoting disease pathologies depending on the fungal agent. This review will focus on highlighting the role of the IL-17 axis and neutrophils in the main endemic and systemic mycoses: histoplasmosis, coccidioidomycosis, blastomycosis, and paracoccidioidomycosis.

The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside.

Interleukin-17 (IL-17) is an essential proinflammatory cytokine, which is mainly secreted by the CD4+ helper T cells (Th17 cells) and subsets of innate lymphoid cells. IL-17A is associated with the pathogenesis of inflammatory diseases, including psoriasis, atopic dermatitis, hidradenitis suppurativa, alopecia areata, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Interleukin-23 (IL-23) plays a pivotal role in stimulating the production of IL-17 by activating the Th17 cells. The IL-23/IL-17 axis is an important pathway for targeted therapy for inflammatory diseases. Emerging evidence from clinical trials has shown that monoclonal antibodies against IL-23, IL-17, and tumor necrosis factor are effective in the treatment of patients with psoriasis, atopic dermatitis, hidradenitis suppurativa, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Here, we summarize the latest knowledge about the biology, signaling, and pathophysiological functions of the IL-23/IL-17 axis in inflammatory skin diseases. The currently available biologics targeting the axis is also discussed.

Actualización en terapia biológica para psoriasis y artritis psoriática (parte II): agentes biológicos (inhibidores IL-23)

Psoriasis is a chronic, inflammatory skin disease, associated with cardiovascular comorbidities, metabolic syndrome, neoplasia, psychiatric impairment and arthritis (among others), which affect patients' quality of life, as well as their life expectancy. Even though it is a multifactorial process of unknown causes, its relationship to class 1 HLA alleles and their polymorphisms has been described. Its physiopathology involves a dysregulation of the systemic inflammatory response, mediated by T Helper lymphocytes, dermal cells, cytokines and interleukins, and their interactions with keratinocytes and sinovial cells. This triggers a differentiation of lymphocytes towards a Th 17 phenotype, which activates inflammatory processes mediated mainly by interleukin 17 (IL-17), with the subsequent proliferation of keratinocytes and inflammatory and angiogenic mediators, resulting in the typical cutaneous and osteoarticular clinical features. Biological agents are recombinat proteins produced in different cell lines aimed at interrupting inflammatory pathways in psoriasis and psoriatic arthritis, specifically, immune or genetic mediators involved in the progression of these diseases, ultimately targeting the IL-23/IL-17 axis. The following article includes the most recent clinical trials regarding the use of biological agents, in particular, IL-23 inhibitors in the treatment of psoriasis and psoriatic arthritis.

Role of interleukin-23/interleukin-17 axis in T-cell-mediated actions in hypertension.

Current knowledge suggests that hypertension is in part mediated by immune mechanisms. Both interleukin (IL)-23 and IL-17 are up-regulated in several experimental hypertensive rodent models, as well as in hypertensive humans in observational studies. Recent preclinical studies have shown that either IL-23 or IL-17A treatment induce blood pressure elevation. However, the IL-23/IL-17 axis has not been a major therapeutic target in hypertension, unlike in other autoimmune diseases. In this review, we summarize current knowledge on the role of these cytokines in immune mechanisms contributing to hypertension, and discuss the potential of IL-23/IL-17-targeted therapy for treatment of hypertension.

Nutrition and Psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α/interleukin-23/interleukin-17 axis, hyperproliferation and abnormal differentiation of epidermal keratinocytes. Psoriasis patients are frequently associated with obesity, diabetes, dyslipidemia, cardiovascular diseases, or inflammatory bowel diseases. Psoriasis patients often show unbalanced dietary habits such as higher intake of fat and lower intake of fish or dietary fibers, compared to controls. Such dietary habits might be related to the incidence and severity of psoriasis. Nutrition influences the development and progress of psoriasis and its comorbidities. Saturated fatty acids, simple sugars, red meat, or alcohol exacerbate psoriasis via the activation of nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 inflammasome, tumor necrosis factor-α/interleukin-23/interleukin-17 pathway, reactive oxygen species, prostanoids/leukotrienes, gut dysbiosis or suppression of regulatory T cells, while n-3 polyunsaturated fatty acids, vitamin D, vitamin B12, short chain fatty acids, selenium, genistein, dietary fibers or probiotics ameliorate psoriasis via the suppression of inflammatory pathways above or induction of regulatory T cells. Psoriasis patients are associated with dysbiosis of gut microbiota and the deficiency of vitamin D or selenium. We herein present the update information regarding the stimulatory or regulatory effects of nutrients or food on psoriasis and the possible alleviation of psoriasis by nutritional strategies.

Physiopathologie du rhumatisme psoriasique

Psoriatic arthritis is a common and complex form of chronic arthritis with significant impact on individual patients. Recent progress in understanding the pathophysiology of the disease has well aligned with the development and validation of new therapies that offer unprecedented options for the patients. Key cytokines in the disease process are tumor necrosis factor (TNF) and the interleukin-23–interleukin-17 axis. Other studies have pointed towards biomechanical stress as factors important both in the development of the disease as well as in the skeletal outcomes. Despite this progress, many questions and challenges remain. Interactions between laboratory science and clinical observations will remain key to solve the psoriatic arthritis puzzle.

Actualización en terapia biológica para psoriasis y artritis psoriática (parte I): moléculas pequeñas, inhibidores de JAK y agentes biológicos (inhibidores IL-17)

Psoriasis is a chronic, inflammatory skin disease associated with cardiovascular comorbidities, metabolic syndrome, neoplasms, psychiatric impairment, and arthritis, among others, which affect patients’ quality of life, as well as their life expectancy. Even though it is a multifactorial process of unknown causes, its relationship to class 1 HLA alleles and their polymorphisms has been described. Its physiopathology involves a dysregulation of the systemic inflammatory response —mediated by T Helper lymphocytes, dermal cells, cytokines, and interleukins—, as well as their interactions with keratinocytes and synovial cells. This triggers differentiation of lymphocytes towards a Th 17 phenotype, which activates inflammatory processes mediated mainly by interleukin 17 (IL-17), with the subsequent proliferation of keratinocytes and inflammatory and angiogenic mediators, resulting in the typical cutaneous and osteoarticular clinical features. Biological agents are recombinant proteins produced in different cell lines aimed at interrupting inflammatory pathways in psoriasis and psoriatic arthritis, specifically, immune or genetic mediators involved in the progression of these diseases, ultimately targeting the IL-23 / IL-17 axis. This review aims to discuss the most recent literature regarding the use of small molecules, JAK inhibitors, and biological agents (IL-17 inhibitors) in the treatment of psoriasis and psoriatic arthritis, mainly referring to their efficacy and safety. Using these molecules means a fundamental change in the approach to patients with psoriasis and psoriatic arthritis. As a specific mediator-targeted therapy, it enhances effectiveness, and at the same time, reduces the associated adverse effects. Therefore, it is essential to know how they work from a physiopathological point of view, as well as assessing their effectiveness in humans through randomized clinical trials. Current knowledge allows us to conclude that despite biological agents being the best treatment option in psoriasis as well as in psoriatic arthritis, comparative studies —among drugs of the same group and groups— are still required. Besides, their high price is another problem to solve before they can be massively used in these patients.

Salvianolic Acid B in Microemulsion Formulation Provided Sufficient Hydration for Dry Skin and Ameliorated the Severity of Imiquimod-Induced Psoriasis-Like Dermatitis in Mice.

Psoriasis is a chronic inflammatory skin disorder with a pathogenesis involving the interleukin-23/interleukin-17 axis. Salvianolic acid B exerts several pharmacological effects, such as antioxidation, anti-inflammation, and antitumor effects. The anti-psoriatic effects of salvianolic acid B have not been reported. In this study, we aimed to determine the optimum vehicle for salvianolic acid B, investigate its therapeutic effect on psoriatic-like skin conditions, and explore its underlying mechanisms of action. BALB/c mice were administered topical imiquimod to induce psoriasis-like skin and were then randomly assigned to control, vehicle control, salvianolic acid B in vehicles, and 0.25% desoximetasone ointment treatment groups. Barrier function, cytokine expression, histology assessment, and disease severity were evaluated. The results showed that salvianolic acid B-containing microemulsion alleviated disease severity, reduced acanthosis, and inhibited interleukin-23/interleukin-17 (IL-23/IL-17) cytokines, epidermal proliferation, and increased skin hydration. Our study suggests that salvianolic acid B represents a possible new therapeutic drug for the treatment of psoriasis. In addition, such formulation could obtain high therapeutic efficacy in addition to providing sufficient hydration for dry skin.

MiR-383 inhibits cell growth and promotes cell apoptosis in hepatocellular carcinoma by targeting IL-17 via STAT3 signaling pathway

ObjectivesEmerging microRNAs (miRNAs) are validated to take part in pathological processes, including numerous carcinomas. Currently, we focused on the functional role of miR-383 and interleukin-17 (IL-17) in hepatocellular carcinoma (HCC), and the underlying molecular mechanisms were also the emphases in our research. MethodsWe used reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to measure the expression levels of miR-383 in 45 paired tumor tissues and adjacent non-tumor tissues extracted from patients with hepatocellular carcinoma. These tissues were also stained for IL-17 using immunohistochemical staining. Western blot was performed to detect the protein expressions of following protein-coding genes, including p-Stat3, Stat3 and GAPDH. A dual-luciferase activity was carried out to determine whether IL-17 was the downstream gene of miR-383 in hepatocellular carcinoma development. The colony assay, CCK8 assay, and apoptosis assay were used to explore the detailed regulatory effects of miR-383/IL-17 axis in the cellular processes of hepatocellular carcinoma separately. ResultsmiR-383 was down-regulated significantly in tumor tissues, while IL-17 was up-regulated. IL-17 was certificated to act as the downstream gene of miR-383. Furthermore, overexpression of miR-383 suppressed cell proliferation and promoted apoptosis in hepatocellular carcinoma. However, the raised IL-17 attenuated the inhibition effect of miR-383 in hepatocellular carcinoma. In addition, we found that p-Stat3 was repressed by miR-383, and the up-regulation of IL-17 reversed the suppression effect in hepatocellular carcinoma. ConclusionsmiR-383 may play a anti-tumor role in the pathogenesis of hepatocellular carcinoma by targeting IL-17 through STAT3 signaling pathway. miR-383/IL-17 axis maybe a potent target for the clinical diagnosis and treatment of hepatocellular carcinoma.

NLRP3 inflammasome activates interleukin-23/interleukin-17 axis during ischaemia-reperfusion injury in cerebral ischaemia in mice

AimsNLRP3 inflammasome has been reported associated with some inflammatory and autoimmune diseases. We previously researches showed that interleukin-23 (IL-23) and interleukin-17 (IL-17) aggravates the ischaemic injury of the brain tissue. However, it is poorly understood whether the NLPR3 inflammasome was involved in regulating and activating the IL-23/IL-17 axis in ischaemic stroke. We aimed to delineate whether the NLRP3 inflammasome signalling provokes the IL-23/IL-17 axis and interleukin-23 receptor (IL-23R) inducing the ischaemia-reperfusion injury of the brain in mice. Main methodsThe male C57/BL6 mice with experimental transient middle cerebral artery occlusion (tMCAO) were established for cerebral ischaemia-reperfusion injury. MCC950 was utilized as a selective NLRP3 inflammasome inhibitor. NLRP3 inflammasome associated protein, IL-23/IL-17 and IL-23R were detected to investigate their changes in the brain tissue after tMCAO. Key findingsMCC950 inhibited the NLRP3 inflammasome, which alleviated the neurological ischaemia-reperfusion injury. Inhibition the NLRP3 inflammasome signalling by treatment with MCC950 decreased the activation of IL-23/IL-17 axis and the expression of IL-23R. SignificanceThe NLRP3 inflammasome facilitated the injury effect of the IL-23/IL-17 axis, which contributed to the cerebral ischaemia-reperfusion injury. This process was associated with IL-23R. Furthermore, this indicated that the NLRP3 inflammasome, as an important therapeutic target for ischaemic stroke, involves multiple mechanisms in ischaemia-reperfusion injury, and MCC950 is a promising way for clinical treatment.