Function Of Th17 Cells Research Articles

Innate-like Lymphocytes and Innate Lymphoid Cells in Asthma.

Asthma is a chronic pulmonary disease, highly associated with immune disorders. The typical symptoms of asthma include airway hyperresponsiveness (AHR), airway remodeling, mucus overproduction, and airflow limitation. The etiology of asthma is multifactorial and affected by genetic and environmental factors. Increasing trends toward dysbiosis, smoking, stress, air pollution, and a western lifestyle may account for the increasing incidence of asthma. Based on the presence or absence of eosinophilic inflammation, asthma is mainly divided into T helper 2 (Th2) and non-Th2 asthma. Th2 asthma is mediated by allergen-specific Th2 cells, and eosinophils activated by Th2 cells via the secretion of interleukin (IL)-4, IL-5, and IL-13. Different from Th2 asthma, non-Th2 asthma shows little eosinophilic inflammation, resists to corticosteroid treatment, and occurs mainly in severe asthmatic patients. Previous studies of asthma primarily focused on the function of Th2 cells, but, with the discovery of non-Th2 asthma and the involvement of innate lymphoid cells (ILCs) in the pathogenesis of asthma, tissue-resident innate immune cells in the lung have become the focus of attention in asthma research. Currently, innate-like lymphocytes (ILLs) and ILCs as important components of the innate immune system in mucosal tissues are reportedly involved in the pathogenesis of or protection against both Th2 and non-Th2 asthma. These findings of the functions of different subsets of ILLs and ILCs may provide clues for the treatment of asthma.

Zishen Tongluo formula ameliorates collagen-induced arthritis in mice by modulation of Th17/Treg balance.

Zishen Tongluo formula (ZTF) is simplified from the Qingluo Tongbi formula, which has been applied to treat rheumatoid arthritis (RA) in clinical practices for several decades. Our previous studies have verified the effects of ZTF on arthritis animal models. However, its mechanism of treating RA is not clear. The present study was designed to investigate the effects of ZTF on the Th17/Treg balance in RA mice and the role of the different herb groups with the effect of Zishen yangyin (YY), Huatan quyu (HT), or Qufeng chushi (QF) in ZTF. A mouse model of collagen-induced arthritis (CIA) was established. The animals were randomly divided into the normal, model, positive drug, YY, QF, HT, and the whole compound (ZTF) groups. After oral administration for one-month, cytokine levels in the plasma and histopathological changes of the joint were measured by ELISA and hematoxylin-eosin staining, respectively. Meanwhile, the balance of Th17/Treg cells in blood, spleen or lymph nodes was detected using flow cytometry and qPCR. ZTF or the different functional groups could improve the joint inflammation, decrease the levels of proinflammatory cytokines, restore the balance of Th17 and Treg cells in CIA mice. However, there were some differences in each functional group: YY mainly promoted the responses of Treg cells while QF inhibited the functions of Th17cells. Besides, HT regulated both Th17 and Treg cells to keep the immune balance. ZTF could notably ameliorate CIA mice by restoring the balance of Th17/Treg cells. Each functional group could target Th17 and/or Treg cells to produce synergistic/enhancement effects, and ZTF had a better holistic effect in RA treatment.

Pyrrothiogatain acts as an inhibitor of GATA family proteins and inhibits Th2 cell differentiation in vitro

The transcription factor GATA3 is a master regulator that modulates T helper 2 (Th2) cell differentiation and induces expression of Th2 cytokines, such as IL-4, IL-5, and IL-13. Th2 cytokines are involved in the protective immune response against foreign pathogens, such as parasites. However, excessive production of Th2 cytokines results in type-2 allergic inflammation. Therefore, the application of a GATA3 inhibitor provides a new therapeutic strategy to regulate Th2 cytokine production. Here, we established a novel high-throughput screening system for an inhibitor of a DNA-binding protein, such as a transcription factor, and identified pyrrothiogatain as a novel inhibitor of GATA3 DNA-binding activity. Pyrrothiogatain inhibited the DNA-binding activity of GATA3 and other members of the GATA family. Pyrrothiogatain also inhibited the interaction between GATA3 and SOX4, suggesting that it interacts with the DNA-binding region of GATA3. Furthermore, pyrrothiogatain significantly suppressed Th2 cell differentiation, without impairing Th1 cell differentiation, and inhibited the expression and production of Th2 cytokines. Our results suggest that pyrrothiogatain regulates the differentiation and function of Th2 cells via inhibition of GATA3 DNA binding activity, which demonstrates the efficiency of our drug screening system for the development of novel small compounds that inhibit the DNA-binding activity of transcription factors.

AGE-RELATED ELEVATED CD4+ T HELPER 17 CELL RESPONSE PROMOTES PROSTATE CANCER CELL GROWTH, MIGRATION, AND INVASION

Age is the most important risk factor for prostate cancer (PCa). But, how age contributes to PCa remains unknown. Interleukin-17 (IL-17) -producing CD4+ T helper 17 (Th17) cells play a critical role in inflammatory diseases. It is often elevated in aging humans and mice, however, whether aging affects Th17 cell function and subsequent PCa risk increase is unclear. In this study, we investigated the role of CD4+ T cells in PCa cell growth during the aging process. Splenic T cells were isolated and purified into CD4+CD25- T cells from young and old mice, then cultured in the presence of plate-bound anti-CD3/anti-CD28. Four days later, the cells were re-stimulated with PMA and ionomycin in the presence of brefeldin A for 4 hours and then were collected and used for flow cytometry and/or qPCR. The supernatant (conditioned media) from young and old cultures was collected and used in subsequent experiments. Flow and qPCR results showed that 17-producing T cells and associated cytokines were significantly increased in old mice compared to young mice. When PCa cell lines (LNCaP, DU-145, and PC3) were treated by the conditioned media for 48 and 72 hours. The cell proliferation, migration, and invasion, as well as the activation of NF-B signaling in PCa cells, were significantly increased after exposure to the conditioned media from aged mice, compared to that from young mice. These results indicated that age-related CD4+ Th17 cell responses are elevated in mice in the aging process and play an important role in PCa growth.

NFAT-Specific Inhibition by dNP2-VIVIT Ameliorates Autoimmune Encephalomyelitis by Regulation of Th1 and Th17

Nuclear factor of activated T cells (NFATs) is an important transcription factor for T cell activation and proliferation. Recent studies have highlighted the role of NFATs in regulating the differentiation of effector CD4 T helper (Th) subsets including Th1 and Th17 cells. Because controlling the effector T cell function is important for the treatment of autoimmune diseases, regulation of NFAT functions in T cells would be an important strategy to control the pathogenesis of autoimmune diseases. Here, we demonstrated that an NFAT inhibitory peptide, VIVIT conjugated to dNP2 (dNP2-VIVIT), a blood-brain barrier-permeable peptide, ameliorated experimental autoimmune encephalomyelitis (EAE) by inhibiting Th1 and Th17 cells, but not regulatory T (Treg) cells. dNP2-VIVIT negatively regulated spinal cord-infiltrating interleukin-17A (IL-17A) and interferon (IFN)-γ-producing CD4+ T cells without affecting the number of Foxp3+ CD4+ Treg cells, whereas dNP2-VEET or 11R-VIVIT could not significantly inhibit EAE. In comparison with cyclosporin A (CsA), dNP2-VIVIT selectively inhibited Th1 and Th17 differentiation, whereas CsA inhibited the differentiation of all T cell subsets including that of Th2 and Treg cells. Collectively, this study demonstrated the role of dNP2-VIVIT as a novel agent for the treatment of autoimmune diseases such as multiple sclerosis by regulating the functions of Th1 and Th17 cells.

Reprograming of peripheral Foxp3+ regulatory T cell towards Th17-like cell in patients with active systemic lupus erythematosus

Treg is essential to limit the extend and duration of the immune response, but its stability is still under debate. Here we demonstrate that IL-17-producing Treg cells (Th17-like cells) increased in peripheral blood of patients with Systemic Lupus Erythematosus (SLE). Notably, the Th17-like cells from patient with active SLE were characterized with some phenotype and function of Th17 cells. Upon stimulation, Helios-Foxp3 + CD4+ T cells decrease Foxp3 expression but increase expression of IL-17 and RORγt. Damage associated molecule pattern and inflammatory cytokines are important for induction of IL-17 expression in Treg cells. The Th17-like cells from patients with active SLE lose suppressive function and have robust response to stimulation of autoantigens. We also observed that the level of Th17-like cells in peripheral blood is closely associated with the clinical index of SLE. These findings suggest that instability of Treg plays a critical role in pathogenesis of autoimmune diseases.

Variation at DENND1B and Asthma on the Island of Tristan da Cunha.

A high prevalence of asthma has been documented among the inhabitants of Tristan da Cunha, an isolated island in the South Atlantic. The population derives from just 28 founders. We performed lung function testing, including methacholine inhalation challenge, allergen skin prick testing, and collected DNA from essentially all of the current island population (269 individuals), and genotyped a panel of 43 single-nucleotide polymorphisms (SNPs) reported as associated with asthma and atopy. We carried out a mixed-model association analysis using the known pedigree. There were 96 individuals diagnosed as asthmatic (36%), and heritability estimates were similar to those from nonisolated population samples (multifactorial threshold model, h2 = 48%). The first component from a genetic principal components analysis using the entire SNP panel was nonlinearly associated with asthma, with the maximum risk to those intermediate to reference (Human Genome Diversity Project) European and African samples means. The single most strongly associated SNP was rs2786098 (p = 5.5 × 10-5), known to regulate the gene DENND1B. This explained approximately one-third of the trait heritability, with an allelic odds ratio for the A allele of 2.6. Among A/A carriers, 10 out of 12 individuals were asthmatic. The rs2786098*A variant was initially reported to decrease the risk of childhood (atopic) asthma in European but slightly increase the risk in African-descended populations, and does significantly alter Th2 cell function. Despite an absence of overall association with this variant in recent asthma genome wide association studies meta-analyses, an effect may exist on the particular genetic background of the Tristan da Cunha population.

Mangiferin suppresses allergic asthma symptoms by decreased Th9 and Th17 responses and increased Treg response

Mangiferin is the major bioactive ingredient in the leaves of Mangifera indica L., Aqueous extract of such leaves have been traditionally used as an indigenous remedy for respiratory diseases including cough and asthma in Traditional Chinese Medicine. Mangiferin was shown to exert its anti-asthmatic effect by modulating Th1/Th2 cytokines imbalance via STAT6 signaling pathway. However, compelling evidence indicated that subtypes of T helpers and regulatory T cells other than Th1/Th2 were also involved in the pathogenesis of asthma. In current study, we investigated the effects of mangiferin on the differentiation and function of Th9, Th17 and Treg cells in a chicken egg ovalbumin (OVA)-induced asthmatic mouse model. Mangiferin significantly attenuated the symptoms of asthma attacks, reduced the total number of leukocytes, EOS and goblet cells infiltration in lung. Simultaneously, treatment with mangiferin remarkably decreased the proportion of Th9 and Th17 cells; reduced the levels of IL-9, IL-17A; inhibited the expression of PU.1 and RORγt in lung. However, the proportion of Treg cells, the expression of IL-10, TGF-β1 and Foxp3 were increased by mangiferin. Our data suggest that mangiferin exerted anti-asthmatic effect through decreasing Th9 and Th17 responses and increasing Treg response in OVA-induced asthmatic mouse model.

Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase II randomized clinical trial

BackgroundRIF is clinically defined as the failure of good quality embryos to implant into the uterus following at least three cycles of In Vitro Fertilization/Embryo Transfer (IVF/ET). During human pregnancy, a genetically different fetus is allowed to survive within the uterus despite the maternal recognition of fetal alloantigens. Compared with normal pregnant women, early loss of embryo is associated with systemic lower levels of Treg cells in IVF. Moreover, several lines of evidence have indicated that differentiation of naive T cells into Th17 is deleterious for normal pregnancy and may cause implantation failure. Sirolimus as the most common mTOR (mammalian target of Rapamycin) inhibitor is able to effectively prevent allograft rejection. Here we aimed to evaluate Sirolimus effects on Th17/Treg axis and subsequently on pregnancy outcome. Methods and materials121 patients with a history of at least 3 implatation failures were selected and enrolled in this clinical trial. Blood was drawn between days 5 and 10 of the cycle prior to the index IVF/ET cycle to assess baseline value of Th17 cells and regulatory T cells ratios using flowcytometry. A Th17/Treg cell ratio equal or >0.74 was considered to be the elevated Th17/Treg cell ratio. In 76 patients with elevated Th17/Treg ratios, 43 individuals were treated with Sirolimus and 33 remained untreated. ResultsOur results demonstrated that Sirolimus treatment led to an increase in Treg cells number and function in treated group and reduced the frequency and function of Th17 cells. Moreover Th17/Treg cell ratio, significantly reduced from 1.18 ± 0.46% to 0.9 ± 0.45% following Sirolimus intervention (P = 0.024). In contrast, no significant difference in Th17 and Treg cell frequencies and Th17/Treg cell ratio was observed in untreated control subjects before and after ET. Finally our data showed a significantly higher clinical pregnancy rate (55.81%) in Sirolimus-treated patients compared with control group (24.24%) (P < 0.0005). We also found a significantly increased live birth rate (48.83%) in RIF women who received Sirolimus compared with control group (21.21%) (P < 0.0001). ConclusionThe findings of the current study revealed the fact that Sirolimus exhibit potent immunosuppressive effects by blocking intracellular immune responses downstream of co-stimulatory signals, also is able to improve reproductive outcome in RIF women with imbalanced Th17/Treg ratio by modulate of Th17 /Treg axis, thus representing a new approach for the potential treatment of patients with embryo implantation failure.

Mechanism of action of celastrol against rheumatoid arthritis: A network pharmacology analysis

Network pharmacology uses bioinformatics to broaden our understanding of drug actions and thereby to advance drug discovery. Here we apply network pharmacology to generate testable hypotheses about the multi-target mechanism of celastrol against rheumatoid arthritis. We reconstructed drug–target pathways and networks to predict the likely protein targets of celastrol and the main interactions between those targets and the drug. Then we validated our predictions of four candidate targets (IKK-β, JNK, COX-2, MEK1) by performing docking studies with celastrol. The results suggest that celastrol acts against rheumatoid arthritis by regulating the function of several signaling proteins, including MMP-9, COX-2, c-Myc, TGF-β, c-JUN, JAK-1, JAK-3, IKK-β, SYK, MMP-3, JNK and MEK1, which regulate the functions of Th1 and Th2 cells, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Celastrol is predicted to affect networks involved mainly in cancer, connective tissue disorders, organismal injury and abnormalities, tissue development, cell death and survival. This network pharmacology strategy may be useful for discovery of multi-target drugs against complex diseases.

Ablation of RhoA impairs Th17 cell differentiation and alleviates house dust mite-triggered allergic airway inflammation

Asthma is a heterogeneous chronic airway inflammation in which Th2 and Th17 cells are key players in its pathogenesis. We have reported that RhoA of Rho GTPases orchestrated glycolysis for Th2 cell differentiation and allergic airway inflammation by the use of a conditional RhoA-deficient mouse line. However, the role of RhoA in Th17 cells remains to be elucidated. In this study, we investigated the effects of RhoA deficiency on Th17 cells in the context of ex vivo cell culture systems and an in vivo house dust mites (HDM)-induced allergic airway inflammation. We found that RhoA deficiency inhibited Th17 differentiation and effector cytokine secretion, which was associated with the downregulations of Stat3 and Rorγt, key Th17 transcription factors. Furthermore, loss of RhoA markedly suppressed Th17 and neutrophil-involved airway inflammation induced by HDM in mice. The infiltrating inflammatory cells in the lungs and bronchoalveolar lavage (BAL) fluids were dramatically reduced in conditional RhoA-deficient mice. Th17 as well as Th2 effector cytokines were suppressed in the airways at both protein and mRNA levels. Interestingly, Y16, a specific RhoA inhibitor, was able to recapitulate the most phenotypes of RhoA genetic deletion in Th17 differentiation and allergic airway inflammation. Our data demonstrate that RhoA is a key regulator of Th17 cell differentiation and function. RhoA might serve as a potential novel therapeutic target for asthma and other inflammatory disorders.

Distinct Expression of Inflammatory Features in T Helper 17 Cells from Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). T helper (Th) 17 lymphocytes play a role in the pathogenesis of MS. Indeed, Th17 cells are abundant in the cerebrospinal fluid and peripheral blood of MS patients and promote pathogenesis in the mouse model of MS. To gain insight into the function of Th17 cells in MS, we tested whether Th17 cells polarized from naïve CD4 T cells of healthy donors and MS patients display different features. To this end, we analysed several parameters that typify the Th17 profile during the differentiation process of naïve CD4 T cells obtained from relapsing-remitting (RR)-MS patients (n = 31) and healthy donors (HD) (n = 28). Analysis of an array of cytokines produced by Th17 cells revealed that expression of interleukin (IL)-21, tumour necrosis factor (TNF)-β, IL-2 and IL-1R1 is significantly increased in Th17 cells derived from MS patients compared to healthy donor-derived cells. Interestingly, IL-1R1 expression is also increased in Th17 cells circulating in the blood of MS patients compared to healthy donors. Since IL-2, IL-21, TNF-β, and IL-1R1 play a crucial role in the activation of immune cells, our data indicate that high expression of these molecules in Th17 cells from MS patients could be related to their high inflammatory status.

Artocarpus tonkinensis Protects Mice Against Collagen-Induced Arthritis and Decreases Th17 Cell Function.

Artocarpus tonkinensis (Moraceae) is a tree that grows in north Vietnam whose leaf decoction is used as a traditional remedy by the Hmong ethnic group to treat arthritis and backache. Our study evaluated the decoction’s efficacy and mechanism of action in DBA/1J mice with collagen-induced arthritis (CIA). Mice treated with the decoction (At) either from the first collagen immunization or after CIA development experienced significantly less joint edema and inflammatory infiltration, whereas CIA-induced cartilage damage could only be prevented by early At treatment. Autoimmune gene expression profiles showed that Th17 cell-associated chemokine CCL20 and cytokines IL-6, IL-17, and IL-22 were strongly downregulated by At. Reduced expression of IL-2, IL-17, IL-22, and FasL in lymph node cells from At-treated mice was further confirmed by real-time PCR. The decoction also inhibited polarization of Th17 cells from CD4+ splenic T cells according to levels of IL-17 and RORC, a Th17 cell-specific transcription factor. Chromatographic analysis identified At’s major component as maesopsin-β-D-glucoside, which could inhibit in vitro differentiation of Th17 cells. The decoction significantly alleviated the signs and symptoms of CIA and inhibited the development and function of Th17 cells, highlighting its potent anti-inflammatory activity.

LncRNAs associated with multiple sclerosis expressed in the Th1 cell lineage.

Multiple sclerosis (MS) is a type of inflammatory and demyelinating disorder of the central nervous system in which immune-mediated inflammatory processes are elicited by secreted cytokines from T helper (Th)-1 and Th17 cells. While some protein-coding genes expressed in T cell types have established involvement in MS disease progression, little is understood about the roles of long noncoding RNAs (lncRNAs) within the disease landscape. LncRNAs, noncoding RNAs longer than 200 nucleotides, likely control gene expression and function of Th1 cells, and offer the potential to act as therapeutic and biomarker candidates for MS. We identified lncRNAs in Th1 cells linked to MS. Expression levels of candidate lncRNAs and genes were evaluated in 50 MS patients and 25 healthy controls using quantitative real-time polymerase chain reaction, and their correlations were assessed. LncRNAs encoded by AC007278.2 and IFNG-AS1-001 showed significantly higher expression in relapsing Phase MS patients whereas IFNG-AS1-003 was elevated in patients in the remitting phase compared with relapsing patients. Collectively, these misregulated lncRNAs may provide valuable tools to understand the relationships between lncRNAs and MS, and possibly other related disorders.

Mediators of the homeostasis and effector functions of memory Th2 cells as novel drug targets in intractable chronic allergic diseases.

Allergic patients have life-long chronic inflammatory diseases with repeated relapses and exacerbations. Currently used allergy therapeutics have some limitations, which warrants a search for novel drug targets for allergy treatment. The studies on conventional allergic disease therapeutics have been focused on the pathology of allergy involving effector type 2 helper T cells (Th2). However, it has been suggested that allergen-specific memory Th2 cells are developed after the initial allergen exposure, which may play a critical role in the allergic relapses. Here, we discuss the contribution of memory Th2 cells to allergic diseases and the microenvironmental factors for chronic allergic disease persistence. Since most allergy drugs are prescribed to suppress symptoms of the diseases, targeting the different types of cells or factors contributing to allergic diseases persistence may cure the disease.

Generation of a novel GATA3 reporter and inducible deletion system to study GATA3hi Th2 and ILC2 cells in vivo

Abstract GATA3 is an important transcription factor for the development of CD4 T cells and innate lymphoid cells (ILCs); it is also essential for the differentiation and function of Th2 cells and ILC2s. To understand the physiological role of GATA3 in these cells particularly in vivo, we have generated a novel GATA3 reporter mouse strain by inserting the ZsGreen-T2A cassette in front of the translation initiation site of the Gata3 allele already carrying two loxp sites which allow inducible Gata3 deletion when it is crossed to the CreERT2 transgenic mouse strain. Our initial experiments with this mouse line showed that the reporter expression faithfully reflects the GATA3 protein expression in both in vitro differentiated Th subsets and in vivo isolated T cells and ILCs. Furthermore, the reporter expression was still observed even when the Gata3 exon 4 (encoding zinc fingers) was deleted by tamoxifen treatment. Thus, this novel mouse model will allow us to separate GATA3-deficient “Th2” cells and “ILC2s” during in vivo immune responses. We are now using this reporter system to explore the role of GATA3 in various cells types generated in vivo by comparing GATA3-sufficient and GATA3-deficient reporter positive cells.

Egr2 deficiency significantly impairs the development of pathogenic TH17 cells

Abstract TH17 cells have critical functions in host defense at mucosal barriers, but they can also be the key drivers of immunopathology. Since their discovery, multiple transcription factor networks have been described that direct Th17 lineage commitment; however, molecular switches that control the development of “pathogenic” versus “non-pathogenic” TH17 cells remain largely unknown. In this study, we have identified the transcription factor Egr2 as a critical regulator of the TH17 pathogenic program. When ectopically expressed under TH17-polarizing conditions, Egr2 significantly enhanced the expression of TH17 signature genes in a RORγt-dependent manner. Although Egr2-deficient CD4+ T cells could be polarized in vitro into TH17 cells, these cells lacked the pathogenic potential in a TH17-dependent disease model, experimental autoimmune encephalomyelitis (EAE). In both active EAE and passive EAE, Egr2-deficeint TH17 cells failed to induce neuroinflammatory response in the CNS. Analysis of CNS infiltrates revealed reduced accumulation of IL-17A-producing CD4+ T cells and impaired recruitment of monocytes and myeloid dendritic cells in mice with T cell-specific loss of Egr2. Most importantly, transcriptional analysis of ex vivo isolated Egr2-deficient CD4+ T cells revealed that Egr2 controlled the expression of pathogenicity-associated genes in TH17 cells in the CNS. We further show that Egr2 deficiency did not affect the effector function of protective TH17 cells at mucosal barriers in Citrobacter rodentium and Candida albicans infections, suggesting that Egr2 is an attractive candidate for the therapeutic targeting of pathogenic TH17 cells while preserving tissue-protective functions of TH17 cells at barrier sites.

A directly GP130-targeting small molecule ameliorates collagen-induced arthrites by inhibiting IL-6/GP130 signalling and Th17 differentiation

Abstract Rheumatoid arthritis is a chronic inflammatory disease that is characterized by joint destruction and inflammation by T helper 17 (Th17) cells. Interleukin-6 (IL-6) is secreted in cells such as macrophage or synovial fibroblast and induces the differentiation and function of Th17 cells that increase lymphocytic infiltration in the joint. LMT-28 suppresses IL-6 signaling through direct binding to glycoprotein-130, and alleviates inflammatory disease (such as rheumatoid arthritis, inflammatory bowel disease) in previous study. The purpose of this study is to assess whether LMT-28 would potently inhibit Th17 differentiation, and the mechanism of LMT-28 that attenuates rheumatoid arthritis through IL-6 signaling pathway. LMT-28 reduced the arthritis score and showed protective effects against bone and cartilage destruction in collagen induced arthritis (CIA) mice. In mice with CIA, LMT-28 markedly decreased the serum levels of IL-6, TNF, and IL-1β compared with each vehicle treated group. Moreover, LMT-28 attenuated Th17 cell activation in lymph nodes of CIA mice. We demonstrated that LMT-28 suppressed differentiation of Th17 in mouse splenocytes and human PBMCs. Additionally, LMT-28 inhibited the phosphorylation of GP130, STAT3, and ERK induced by Hyper IL-6 in human fibroblast-like synoviocytes(FLS). Collectively, these results suggested that LMT-28 inhibits differentiated/activated-Th17 cells in rheumatoid arthritis by blocking activation of the STAT3 pathway.

Periodontal disease: from infection to autoimmunity

Abstract Five decades of publications have been necessary to document the relationship between immune response and tissue injury in periodontitis. Multiple mechanisms have been implicated in the progression of tissue damage, including the controversial mechanisms of autoimmunity. The aim of this paper is the development of the theories that considered periodontal disease as an autoimmune entity with a historical narrative and descriptive view. Diverse theories have been referenced involving the innate and acquired immunity: generation of anti-neutrophil cytoplasmic antibodies (ANCA), Th17 cell function and IL-17, auto-antibodies to collagen and epithelial components of the periodontium, the role of NK cells T lymphocytes and T CD5, development of molecular mimicry, among others. In conclusion, it’s still difficult to classify periodontal disease as an stabilshed autoimmune disease, because its multifactorial nature makes it difficult to understand. However, the evidence is clear and comprehensive showing related autoimmune mechanisms, which could eventually explain the progression and its relation to systemic events such as cardiovascular disease and atherosclerosis.

Expression and function of IL-1 receptor type 2 (IL-1RII) regulating human Th17 responses

Abstract Th17 cells are a unique subset of proinflammatory cells conferring protection against extracellular bacteria and fungi, but have been also implicated in the pathogenesis of many autoimmune diseases. IL-1β is critical for the differentiation, expansion, in vivo survival, and effector function of Th17 cells. Among components of IL-1 receptor (IL-1R), decoy IL-1RII is a negative regulator of functional IL-1RI-mediated IL-1β signaling. Given its preferential expression on Treg cells, IL-1RII has been suggested to play a role for controlling the Th17 and Treg balance. However, little is known about a molecular mechanism underlying IL-1RII expression and its contribution to modulation of Th17 responses. Here, we found that IL-1RI and IL-1RII expression were rapidly induced by memory CD4+ T cells after stimulation with TCR alone. Cyclosporin A reduced IL-1RII expression, whereas an augmented FOXP3 was associated with enhanced IL-1RII expression. This finding was corroborated by in vitro assays using NFAT inhibitor, dNP2-VIVIT and an inhibitor of FOXP3/NFAT1 interaction, peptide FOXP3 393–403. Moreover, reporter assay suggests that NFAT/FOXP3 binding sites in IL-1RII promoter are critical for its transcription. At day 2 post-stimulation, there were three distinct subsets; IL-1RI+IL-1RII−, IL-1RI+IL-1RII+, and IL- 1RI−IL-1RII− CD4+ T cells, having unique features including cytokine production profile, the expression of Tregassociated genes, and responsiveness to IL-1β, suggesting a pivotal regulatory role of IL-1RII for human Th17 responses. Our findings will be beneficial to understanding a modulatory mechanism on Th17 response and IL- 1β-mediated IL-1R signaling contributing to pathogenesis of autoimmune diseases.