Cell Th2 Cytokine Research Articles

Progranulin ameliorates coxsackievirus-B3-induced viral myocarditis by downregulating Th1 and Th17 cells

Viral myocarditis, which is caused by Coxsackievirus B3 (CVB3) infection, is a leading reason of sudden cardiac death in young adults. Progranulin (PGRN), a pleiotropic growth factor, has been shown to exert anti-inflammatory function in a variety of inflammatory diseases. However, the expression and function of PGRN in the pathogenesis of viral myocarditis remain largely unknown. In this study, we found that PGRN levels in plasma and cardiac tissues were significantly upregulated post CVB3 infection, and negative correlated with disease severity. PGRN deficiency significantly exacerbated, whereas recombinant PGRN treatment attenuated CVB3-induced myocarditis in mice. PGRN downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on viral myocarditis was Treg cell independent. Furthermore, PGRN regulated Th1 and Th17 cells differentiation through inhibition of the JAK/STAT pathway. Therefore, our findings reveal a critical role for PGRN in reducing CVB3-induced myocarditis and suggest that PGRN maybe a novel therapeutic treatment for viral myocarditis.

Gene Expression Analysis of the Effect of Microbial Tryptophan Metabolites on T‐cell Differentiation

The goal of this work is to elucidate the molecular basis underlying the effect of tryptophan‐derived microbiota metabolites on T‐cell differentiation and function. Naive T‐cells differentiate into various subsets with specialized functions, including pro‐tolerogenic regulatory T (Treg) cells and pro‐inflammatory T helper 17 (Th17) cells. An imbalance in the relative proportions of the different T‐cell subtypes is associated with a number of autoimmune and inflammatory diseases. While the role of host cytokines and growth factors in T‐cell differentiation are well established, recent studies have suggested that the gut microbiota metabolites also modulate T‐cell differentiation. Recent work from our laboratory has demonstrated that the microbiota metabolite indole, which has been previously shown to attenuate indicators of inflammation in intestinal epithelial cells, augments TGF‐β mediated Treg differentiation from naïve T‐cells as well as suppresses IL‐6 mediated Th17 differentiation, promoting an anti‐inflammatory phenotype. On the other hand, 5‐hydroxyindole (5HI) shows reciprocal effects, suppressing Treg differentiation and augmenting Th17 differentiation. However, the mechanisms by which indole and 5HI modulate T‐cell differentiation and their effects on function are unknown. Using microarrays, we identified 551 and 219 differentially expressed genes in indole treated Treg cells and 5‐HI treated Th17 cells, respectively, as compared to conventionally differentiated cells. Indole treatment resulted in a slight decrease in overall transcription, with 290 of the differentially expressed genes being upregulated, while 5HI increased overall transcription with 182 differentially expressed genes being upregulated. The differentially expressed genes in Treg cells with indole treatment was largely comprised of enzymes (14%), transcription factors (10%), and cytokines (7%), while 5HI resulted in differential regulation of enzymes (10%), cytokines (9%), and transmembrane receptors (5%) in Th17 cells. The glycine amidinotransferase (Gatm) gene that is involved in creatine biosynthesis and contains an Aryl Hydrocarbon Responsive Element II (AHRE‐II) in its 5’ regulatory region was up‐regulated 12‐fold in indole treated Treg cells, suggesting a role for the aryl hydrocarbon receptor (AhR) in indole signaling. The gene encoding the IL‐13 cytokine was the most strongly induced by indole treatment (82‐fold increase). IL‐13 is produced by Th2 cells and has both pro and anti‐inflammatory properties. Interestingly, other Th2 cytokines genes, Il4 and Il5, were also up‐regulated at 10‐ and 26‐fold, respectively. This unexpected pattern of signaling suggests that indole may induce the differentiation of a unique cell type with phenotypes characteristic of both Treg cells and Th2 cells. In 5HI treated Th17 cells, a 15‐ and 3‐fold increase in the expression of genes encoding the pro‐inflammatory cytokines IL‐22 and IFNg was observed. The gene for IL‐17, which is the characteristic cytokine of Th17 cells was upregulated 1.6 fold. These expression patterns support the induction of pro‐inflammatory signaling by 5HI. Overall, these results suggest that different tryptophan‐derived microbiota metabolites can have different effects on T‐cell differentiation and function. Further characterization of cell function and investigation into the role of the AhR the signaling of these metabolites is warranted.Support or Funding InformationNational Institutes of Health R01AI110642This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Treatment of experimental autoimmune myasthenia gravis rats with FTY720 and its effect on Th1/Th2 cells.

Myasthenia gravis (MG) is an autoimmune neurological disease that is characterized by the expression of anti-acetylcholine receptor (AChR) antibodies. The immune response at AChRs of neuromuscular junction is disrupted in patients with MG, which manifests as skeletal muscle fatigue and is aggravated following periods of activity and alleviated following rest. Although a novel immune suppressant FTY720 drug, which exhibits strong immune suppression efficacy and minor adverse effects, is available, its role and mechanism in MG have not been elucidated. The aim of this study was to investigate the role of FTY720 in MG. A total of 60 healthy female Lewis rats were randomly assigned into 4groups: Control group, Model group of experimental autoimmune myasthenia gravis (EAMG), 0.5mg/kg FTY720-treatment EAMG group and 1.0mg/kg FTY720‑treatment EAMG group. Body weight and symptoms were examined; Lennon score was used to evaluate improvement of clinical symptoms. Reverse transcription‑quantitative polymerase chain reaction and ELISA were used to test the mRNA and protein expression levels, respectively, of the helper T (Th)1 and Th2 cell cytokines, including interleukin (IL)‑2, interferon (IFN)‑γ, IL‑4 and IL‑6 in thymus tissue and serum. FTY720 treatment improved rat MG symptoms, increased body weight and decreased Lennon score. FTY720 treatments also reduced tissue and serum levels of IL‑2, IFN‑γ and IL‑6, but not IL‑4 expression levels. FTY720 suppressed the inflammatory response and improved EAMG symptoms by inhibiting the secretion of inflammatory factors.

Cytokine expression and cytokine-based T-cell profiling in occupational medicamentosa-like dermatitis due to trichloroethylene

Early diagnosis and treatment of occupational medicamentosa-like dermatitis due to trichloroethylene (OMLDT) are absence of specific and reliable diagnostic/therapeutic biomarkers. This study was conducted on 30 cases of OMLDT, 58 workers exposed to trichloroethylene (TCE) and 40 unexposed controls in order to identify any cytokine signatures that give an index to CD4+T cell differential and serve as biomarkers of OMLDT. Expression profiles of Th1, Th2, Th17 and Treg cell type-specifying transcription factors and cytokines were analyzed using real time quantitative PCR (RT-qPCR) assay. To explore whether such expression profiles reflected their steady state plasma levels, a Luminex liquid fluorescence analysis was conducted. We found that the expression of transcription factors FoxP3 transcription factors (P = 0.006 and P < 0.0001) and IL-10 cytokine (P = 0.0008 and P < 0.0001) of the Treg subset were significantly higher in patients than TCE exposure workers and unexposed controls, suggesting that Treg cells were active after the occurrence of OMLDT. The transcript levels of IL-6 were significantly lower in the TCE exposure groups including patients and exposure workers as compared to the unexposed controls (P < 0.0001 and P = 0.0008). Circulating levels of assessed cytokines of IL-6 (P = 0.001 and P = 0.011) and TFN-α (P = 0.005 and P < 0.0001) were lower in the exposure groups than in the unexposed controls. Compared to the controls, the levels of IL-10 in patients were higher (P = 0.001 and P = 0.0008). There was a significantly positive correlation between the plasma levels IL-6 and IL-10 in TCE exposed workers. These alterations in the expression of transcription factors and cytokines highlight the underlying dysregulation of T cell subsets in OMLDT that reflect an immune tolerance or immune inhibition. Therefore, the elevation of IL-10 level may be a kind of pathogenesis indicator, and the decline in IL-6 level may be a kind of TCE exposure biomarker. These biomarkers need additional longitudinal follow-up studies to warrant to clinically useful biomarkers of OMLDT.

IL-17 Exerts Anti-Apoptotic Effect via miR-155-5p Downregulation in Experimental Autoimmune Encephalomyelitis

Multiple sclerosis is an autoimmune, neurodegenerative disease, affecting mostly young adults and resulting in progressive disability. It is a multifactorial disorder, with important involvement of both cellular and epigenetic components. Among the epigenetic factors, microRNAs are currently intensively investigated in the context of multiple sclerosis. It has been shown that their biogenesis and function may be regulated by various cytokines. IL-17, a hallmark cytokine of Th17 cells, has been thought to function predominantly as a pro-inflammatory factor, leading to increased disease symptoms. However, there are several studies indicating its protective role during inflammatory process. In this work, we have assessed the impact of high-dose IL-17 administration on microRNAs’ expression profile during the preclinical stage of EAE. For selected microRNA, we have performed computational analysis of its potential target mRNAs and cellular pathways. Based on results obtained from in silico analysis, we have chosen genes from neurotrophin signaling pathway for further experiments—BDNF, HRAS, and BCL2. Results obtained in this study suggested that high dose of IL-17 exerts protective activity via miR-155-5p downregulation. Increased expression of all studied genes, especially BCL2, indicated a potential anti-apoptotic function of IL-17 during the preclinical phase of EAE.

Effects of neuro-immuno-modulation on healing of wound combined with local radiation injury in rats

PurposeTo investigate effects of neuro-immuno-modulation on wound healing by observing changes of cytokines and hypothalamic-pituitary-adrenal (HPA) axis hormones in acute stress reaction in rats with wound and combined local radiation injury. MethodsSixty female Wistar rats (weighting 200 ± 20 g) were randomly divided into normal control group, wound group and combined wound-local radiation (CWR) group (25 Gy local radiation post wound), 20 rats in each group. Contents of IL-1β, IL-6 and IFN-γ and IL-4 in serum were measured and changes of adrenocorticotropic hormone (ACTH) and glucocorticoid (GC) in serum were analyzed by using enzyme-linked immunosorbent assay and radioimmunologic assay, respectively at different time points post wound and radiation. Results(1) The level of IFN-γ, one of the Th1 cell cytokines increased significantly at 14 d post CWR, which was markedly higher than that in control group and wound group. However, the level of IL-4, IL-1β and IL-6, one of the Th2 cell cytokines, did not show obvious change. (2) Ratio of Th1/Th2 (IFN-γ/IL-4) in wound group and CWR group increased significantly at 7 d after wound and radiation, which suggested that Th1/Th2 balance drifted to Th1 immune response. The ratio of Th1/Th2 in wound group returned to the normal level up to 14 d after the wound and radiation, while the Th1/Th2 ratio in CWR group increased persistently and was much higher than that in control and wound groups. (3) Level of serous ACTH and GC in CWR group increased at 3 d post wound and radiation, and among them, level of GC showed statistically significant increase, which was much higher than that in control and wound groups. ConclusionLevel of serous neurohormone GC in rats increased significantly immediately after wound and radiation; while the level of IFN-γ showed significant increase only up to 14 d after wound and radiation, and the Th1/Th2 imbalance sustained till 28 d post wound and radiation. In order to reduce acute damage caused by CWR, organic immune system and nerve system showed up a marked regulate effects simultaneously and mutually. Nonetheless, the excessive stress induced by CWR causes disturbance of immunoregulation, which is one of the key reasons for delayed wound healing in CWR.

Tim3/galectin-9 alleviates the inflammation of TAO patients via suppressing Akt/NF-kB signaling pathway

Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease. Studies showed that T helper 1 (Th1), Th2, and Th17 cells play important roles in the pathology of TAO. Tim-3 and its only known ligand Galectin-9 (Gal-9) is related to the suppression of Th1 and Th17 cytokine secretion. This study aims to investigate the role of Tim3/Gal-9 in the inflammatory response of TAO. In this study, the levels of Tim3, Gal-9, and cytokines of Th1 (TNF-α and IFN-γ), Th2 (IL-4), and Th17 (IL-17) cells were analyzed in the blood samples of TAO patients and healthy controls as well as in orbital fibroblasts. Tim3 overexpression and Gal-9 neutralizing antibody were used in TAO and LPS-stimulated control orbital fibroblasts to further investigate the role and mechanism of Tim3/Gal-9 on the inflammation of TAO. We found Tim3 and Gal-9 expression was significantly downregulated in TAO patients and further lower in active TAO than inactive TAO or controls. Th1, Th2, and Th17 cytokines were all increased in TAO patients. Th1 and Th17 cytokines were higher in active TAO patients than in inactive TAO patients, while Th2 cytokines were enhanced in inactive TAO. Tim3 overexpression decreased the levels of Th1 and Th17 cytokines, but not Th2 cytokine in TAO or LPS-stimulated control orbital fibroblasts. These effects were abrogated by Gal-9 neutralizing antibody. Moreover, Tim3 reduced the levels of p-Akt and p-p65 in TAO or LPS-induced control orbital fibroblasts that were reversed by Gal-9 blocking. In conclusion, Tim3/Gal-9 alleviates the inflammation of TAO patients via suppressing Akt/NF-κB signaling pathway.

Effect of Intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL)

BackgroundWomen with elevated natural killer (NK) cell frequency and function during pregnancy, suffer from recurrent pregnancy loss (RPL). In the present study, the possible effect of intravenous immunoglobulin (IVIG) administration on Th1 and Th2 cell frequency, cytokine secretion, and expression of transcription factors is compared between RPL patients and control group. Materials and methodsTotally, 44 women with a history of RPL (32 women as treated group and 12 as control group) were enrolled in the study. The frequency of Th1 and Th2 lymphocytes, the expression of transcription factors related to these cells and the serum levels of associated cytokines were assessed by flowcytometry, real-time PCR and ELISA, respectively. All, assessments were performed both before and after treatment with IVIG. ResultsA significant reduction in Th1 lymphocyte frequency, transcription factor expression and cytokine levels were observed in IVIG-treated group, while all the above parameters indicated a significant increase for Th2 lymphocytes. Th1/Th2 ratio decreased significantly (p value<0.0001) at the end of treatment and 28 out of 32 (87.5%) women in IVIG-treated group had live birth in comparison with 5 out of 12 (41.6%) in untreated group. ConclusionIVIG administration proves to be an efficient therapeutic strategy which is able to enhance the success rate of pregnancy through a shift in Th2 responses. Furthermore, IVIG presents efficacy for the treatment of reproduction failures especially in subjects with immune cell abnormalities and increased NK cell level and function.

Role of Th-1 cell cytokines, leukemia inhibitory factor and hoxA genes in women with recurrent pregnancy loss

Abstract Objective Immunological problems have been identified as a potential cause of recurrent pregnancy loss (RPL). The aim of this study was to investigate the effect of Th-1 cell cytokines, leukemia inhibitory factor and hoxA genes in women with RPL. Materials & methods A prospective, case-control study conducted in Assiut Women Health Hospital, Egypt included 37 women presented with a history of RPL. Samples of uterine flush and endometrial biopsy were taken during the implantation window from those confirmed as not pregnant. Cytokine (LIF and Th1 induced) levels were measured by ELISA, while hox A10 and hox A11 gene expression was evaluated by Taq-man Real Time PCR. Results Higher cytokine mean levels were seen in the RPL group when compared to the control group (TNF-α and LIF cytokines, p ≤ 0.001; INF-γ and IL2 cytokines, p ≤ 0.01). The opposite was true with regards to gene expression, with lower means in both sets found in the RPL group ( hox A11, p ≤ 0.000). A statistically significant positive correlation between INF-γ and TNF-α, hox A10 and hox A11, as well as between LIF and hox A11 was demonstrated. Conclusion This study suggests that women with a history of RPL can have abnormal cytokine and gene expression even when not pregnant. Our findings can be a basis for providing of future successful immunological therapy for women with RPL.

Regulation of TH17 Cells and Associated Cytokines in Wound Healing, Tissue Regeneration, and Carcinogenesis.

Wound healing is a crucial process which protects our body against permanent damage and invasive infectious agents. Upon tissue damage, inflammation is an early event which is orchestrated by a multitude of innate and adaptive immune cell subsets including TH17 cells. TH17 cells and TH17 cell associated cytokines can impact wound healing positively by clearing pathogens and modulating mucosal surfaces and epithelial cells. Injury of the gut mucosa can cause fast expansion of TH17 cells and their induction from naïve T cells through Interleukin (IL)-6, TGF-β, and IL-1β signaling. TH17 cells produce various cytokines, such as tumor necrosis factor (TNF)-α, IL-17, and IL-22, which can promote cell survival and proliferation and thus tissue regeneration in several organs including the skin, the intestine, and the liver. However, TH17 cells are also potentially pathogenic if not tightly controlled. Failure of these control mechanisms can result in chronic inflammatory conditions, such as Inflammatory Bowel Disease (IBD), and can ultimately promote carcinogenesis. Therefore, there are several mechanisms which control TH17 cells. One control mechanism is the regulation of TH17 cells via regulatory T cells and IL-10. This mechanism is especially important in the intestine to terminate immune responses and maintain homeostasis. Furthermore, TH17 cells have the potential to convert from a pro-inflammatory phenotype to an anti-inflammatory phenotype by changing their cytokine profile and acquiring IL-10 production, thereby limiting their own pathological potential. Finally, IL-22, a signature cytokine of TH17 cells, can be controlled by an endogenous soluble inhibitory receptor, Interleukin 22 binding protein (IL-22BP). During tissue injury, the production of IL-22 by TH17 cells is upregulated in order to promote tissue regeneration. To limit the regenerative program, which could promote carcinogenesis, IL-22BP is upregulated during the later phase of regeneration in order to terminate the effects of IL-22. This delicate balance secures the beneficial effects of IL-22 and prevents its potential pathogenicity. An important future goal is to understand the precise mechanisms underlying the regulation of TH17 cells during inflammation, wound healing, and carcinogenesis in order to design targeted therapies for a variety of diseases including infections, cancer, and immune mediated inflammatory disease.

Innate activation of Th17 cells triggers IL-26 release

Abstract IL-26 is a Th17 cell cytokine with both pro-inflammatory effects and direct antimicrobial activity. We investigated the role of IL-26 in the host response to infection by studying leprosy as a model, finding that IL-26 had direct antimicrobial activity against Mycobacterium leprae. IL-26 mRNA and protein expression was greater in skin lesions from patients with self-limited versus progressive infection, although IL-17 was weakly expressed. To determine the mechanism for IL-26 induction, we examined the kinetics of IL-26 secretion by PBMCs exposed to Mycobacterium leprae sonicate, which revealed induction at 3 hours suggesting activation of the innate response. IL-26 was secreted from PBMCs in response to a variety of pattern recognition receptor (PRR) ligands, correlating with IL-1β release. In PBMCs, IL-1β stimulated IL-26 secretion and blocking IL-1β with either antibodies or depletion of CD14+ cells after PRR ligand stimulation lead to reduction in IL-26 secretion. IL-1β also stimulated IL-26 secretion by both CD4+ and CD8+ T cells, and within the CD4+ compartment IL-26 secretion was limited to memory T cells. Only CD4+ memory Th17 cells, not Th1 or Th2, produced IL-26 in response to IL-1β, and expressed higher amounts of surface IL-1R1. Memory CD4+ T cells stimulated with IL-1β or αCD3/αCD28 secreted IL-26, but only cells stimulated with αCD3/αCD28 secreted IL-17 and IFN-γ. These studies suggest that Th17 cells play a role in the innate immune response by selectively secreting the antibacterial and pro-inflammatory cytokine IL-26 in response to IL-1β.

Leptin Enhances TH2 and ILC2 Responses in Allergic Airway Disease

Abstract Allergic asthma and obesity are the leading health problems in the world. Many studies have shown that obesity is a risk factor of development of asthma. However, the underlying mechanism has not been well established. In this study, we demonstrate that leptin, an adipokine elevated in obese individuals, promoted proliferation and survival of pro-allergic type 2 helper T cells and group 2 innate lymphoid cells and production of type 2 cytokines, which together contribute to allergic responses. Leptin activates mTORC1, MAPK and STAT3 pathways in TH2 cells. The effects of leptin on TH2 cell proliferation, survival and cytokine production are dependent on the mTORC1 and MAPK pathways as revealed by specific inhibitors. In vivo, leptin-deficiency led to attenuated experimental allergic airway inflammation. Our results thus support that obesity associated elevation of leptin contributes to the increased susceptibility of asthma via modulation of pro-allergic lymphocyte responses.

Lumican Inhibits the pathogenicity of murine encephalitic TH17 cells

Abstract TH17 cells play an essential role in the development of both human multiple sclerosis and animal experimental autoimmune encephalomyelitis (EAE). Nevertheless, it is not well understood how the pathogenicity of TH17 cells is controlled in the autoimmune neuro-inflammation. In vitro, we found Lumican (Lum), an extracellular matrix (ECM) protein, is selectively expressed by TH17 cells among tested murine TH subsets. Lum-deficiency leads to earlier onset and enhanced severity of experimental autoimmune encephalomyelitis. This enhanced disease in Lum-deficient mice is associated with increased production of IL-17 and IL-21 and decreased TH17 cell apoptosis. Dysregulation in cytokine production appears to be specific to TH17 cells as TH1 and TH2 cell polarization and/or cytokine production were unaltered. Furthermore, adoptive transfer of MOG-specific TH17 cells derived from Lum-deficient mice led to earlier onset and increased severity of disease compared to controls highlighting a TH17 cell-intrinsic effect of Lum. Taken together, our results suggest that Lum negatively regulates encephalitic TH17 cells, implicating a potential therapeutic pathway in TH17 cell-mediated autoimmune and inflammatory diseases.

Biological evaluation of the MILLIPLEX® map Mouse High Sensitivity T Cell Panel

Abstract Low levels of inflammation are involved in many clinical and sub-clinical disease states like autoimmune diseases. Measuring picogram levels of cytokines is critical for understanding their pathogenesis. Model organisms, such as mice, offer unique challenges of sample availability and detection of low levels of cytokines. We recently developed a Mouse High Sensitivity T Cell Panel multiplex assay for simultaneous measurement of 18 mouse cytokines using Luminex xMAP® technology. In this study, we analyzed mouse cytokine secretions both in vitro, with PMA-, PHA-, LPS-, Con-A, or calcium ionophore-challenged PBMC samples, and in vivo, using LPS-challenged mice and an aged-mouse model. Typically, the response of mouse PBMCs to in vitro stimulants is difficult to study due to low levels of cytokine secretion. Using the MILLIPLEX® map Mouse High Sensitivity T Cell Panel, distinctly different stimulant-dependent cytokine responses were observed. PMA and LPS induced the secretion of IL-1β, IL-5, IL-10, LIX, MCP-1, MIP-2 and LPS. IL-6 was secreted in response to LPS but not PMA. Th17 cell cytokine IL-17A was secreted in response to PHA and Con A but not LPS. Interestingly, low levels of secretion were seen in response to the combination of all stimulants for GM-CSF, IFNγ, IL-1α and IL-2. The in vivo challenge of LPS significantly increased mouse plasma levels of fourteen cytokines. Small increases were also seen for GM-CSF and IL-2, while IL-5 and IL-12 (p70) trended higher. In a mouse model of aging, sex-specific changes of plasma levels were observed for IL-1, IL-5, IL-10, GM-CSF, IFNγ, KC and MIP-2. Thus, the MILLIPLEX® MAP Mouse High Sensitivity T Cell Panel is a useful tool to study low levels cytokines in mouse models of disease and inflammation.

Anti-inflammatory effects of rosmarinic acid-4-O-β-D-glucoside in reducing acute lung injury in mice infected with influenza virus

Rosmarinic acid-4-O-β-D-glucoside (RAG) is a dicaffeoyl phenolic compound isolated from Sarcandra glabra (Thunb.) Nakai. Preliminary studies show that RAG has significant anti-inflammatory properties and can alleviate ear swelling in mice and the paw swelling in rats. Here, the anti-influenza effects of RAG were investigated in mice infected with A/FM/1/47 H1N1 virus. The survival rate and body weight were observed, the lung edema, virus copies, inflammatory cytokines (including IL-4, IL-5, TNF-α and IFN-γ) and oxidative damage indexes (including SOD, MDA, NO, and CAT) were measured. Moreover, immune cell recruitment in alveoli was measured with white blood cells and differential counts. Therapeutic RAG concentrations substantially improve the symptoms, mitigate body weight loss and alleviate lung edema induced by virus, thus improve survival protection effects. Furthermore, RAG was shown to regulate influenza virus-induced inflammatory cytokine expression, specifically by downregulating the Th1 cell cytokines IFN-γ, TNF-α and upregulating the Th2 cell cytokines IL-4, IL-5. Cell migration and infiltration were also diminished after RAG administration.

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

While Th17 cells can protect against colonization by pathogenic organisms, they also have the potential to become pathogenic and promote autoimmune and inflammatory diseases. Mechanisms that control their pathogenic potential remain poorly understood. Here we show that Ndfip1, a co-activator of the E3 ubiquitin ligase Itch, restricts the frequency and pathogenicity of Th17 cells. Mice lacking Ndfip1 have increased numbers of Th17 cells, and this increase is cell intrinsic. We found that Ndfip1 restricts production of the proinflammatory cytokines in Th17 cells. Increased cytokine production correlated with reduced degradation and accumulation of RORγT. When transferred in vivo, Th17 cells lacking Ndfip1 were more likely to maintain their ability to make IL-17, were more potent proinflammatory cytokine producers, and were powerful inducers of colitis. Together our data support an essential role for Ndfip1 in degrading RORγT and suppressing Th17 lineage stability, proinflammatory cytokine production, and pathogenicity.

Cutaneous Lichen Planus Induced by Secukinumab

Lichen planus (LP) is a chronic mucocutaneous disease, characterised by an inflammatory immune response with sub-epithelial infiltration of T lymphocytes causing basal epithelial cell damage. Secukinumab is a monoclonal antibody that blocks IL-17A; which is the primary cytokine of Th17 cells involved in the aetiology of inflammatory skin diseases such as psoriasis. Secukinumab has been linked to induction of oral LP, but never directly to cutaneous LP. We report the first case of drug-induced cutaneous LP in the setting of secukinumab for treatment of chronic plaque psoriasis. A 56-year-old man with chronic plaque psoriasis presented with a 2-month history of violaceous and pruritic, thickened plaques on his bilateral lower limbs and buttocks in the setting of secukinumab use for psoriasis. Histological analysis showed a band-like lymphocyte inflammatory infiltrate just beneath the epithelium and was consistent with cutaneous LP. He was treated with topical betamethasone dipropionate cream with moderate effect. Initial laboratory tests including hepatitis and inflammatory screens were within normal limits. We hypothesise that this causal association may be due to a microbial trigger, activating a T-cell mediated immunologic response in CD8+ T-cells and dendritic cells, causing activation of type I interferons and an inflammatory skin response consistent with LP. Clinicians should monitor patients for mucosal and cutaneous LP when using secukinumab or other biologic modulators of IL-17 for extended periods with psoriasis.

Proinflammatory Cytokine IL-17 Shows a Significant Association with Helicobacter pylori Infection and Disease Severity.

Background The pro- and anti-inflammatory cytokines play an important role in the immune response against H. pylori infection. The proinflammatory cytokines of Th17 cells have been suggested to play a major role in H. pylori infection and resulting gastric inflammation. Objective The objective of this study was to compare the expression of selected inflammatory cytokines (IL-10, IL-17, IL-21, IL-23, and TNF-α) in H. pylori-infected patients and healthy controls and to understand their association with H. pylori infection and disease severity. Results The expression levels of IL-17 and IL-23 were significantly higher in H. pylori-infected patients. The expression of IL-21 was also higher in H. pylori-positive patients but there was no significant association with infection. IL-17 expression showed a significant increase with the severity of chronic gastritis. Conclusion The proinflammatory cytokine, IL-17, shows a significant association with H. pylori infection and disease severity in a Sri Lankan dyspeptic patient population.

Berberine exerts an anti-inflammatory role in ocular Behcet's disease.

Behcet's disease is a multi-system inflammatory disorder, and ocular Behcet's disease (OBD) is one of the most common causes of uveitis in China. A number of studies have indicated that Th17 cells, a subset of interleukin-17 (IL-17)-producing CD4+ T-helper cells, serve important roles in the pathogenesis of OBD. Berberine (BBR) is an isoquinoline derivative alkaloid isolated from Chinese herbs, and has been used traditionally for the treatment of gastrointestinal disorders. The aim of the present study was to investigate the effect of BBR on Th17 cell proliferation and cytokine secretion, and the expression and activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor in OBD in vitro. Blood samples were obtained from healthy controls and patients with active ocular Behcet's disease. Peripheral blood mononuclear cells (PBMCs) or CD4+ T cells were cultured for three days with or without BBR and in the presence of anti-CD3 and anti-CD28 antibodies. IL-17 expression in cell sample supernatants was determined by enzyme-linked immunosorbent assay, and cell viability was measured using the Cell Counting kit-8 assay. The number of CD4+IL-17+ cells and the expression level of phosphorylated (p)-STAT3 in CD4+ T cells was determined using flow cytometry analysis. The expression of IL-17 was increased in patients with active OBD following the activation of PBMCs and CD4+ T cells with anti-CD3 and anti-CD28 antibodies when compared with healthy controls. However, no significant difference in cell viability following exposure to BBR was observed in PBMCs derived from healthy controls or patients with OBD. Following incubation with BBR, the expression of IL-17 was reduced and the number of CD4+IL-17+ cells was decreased in patients with active OBD and healthy controls. Furthermore, the expression of p-STAT3 was significantly decreased in the presence of BBR in healthy controls. In conclusion, the results of the present study demonstrate that BBR may suppress the Th17 response in patients with OBD by reducing STAT3 phosphorylation. BBR may be a potential therapeutic agent for the treatment of OBD.

Lumican negatively controls the pathogenicity of murine encephalitic TH17 cells.

TH17 cells play an essential role in the development of both human multiple sclerosis and animal experimental autoimmune encephalomyelitis (EAE). Nevertheless, it is not well understood how the pathogenicity of TH17 cells is controlled in the autoimmune neuroinflammation. In vitro, we found Lumican (Lum), an extracellular matrix (ECM) protein, is selectively expressed by TH17 cells among tested murine TH subsets. Lum deficiency leads to earlier onset and enhanced severity of EAE. This enhanced disease in Lum-deficient mice is associated with increased production of IL-17 and IL-21 and decreased TH17 cell apoptosis. Dysregulation in cytokine production appears to be specific to TH17 cells as TH1 and TH2 cell polarization and/or cytokine production were unaltered. Furthermore, adoptive transfer of myelin oligodendrocyte glycoprotein specific TH17 cells derived from Lum-deficient mice led to earlier onset and increased severity of disease compared to controls highlighting a TH17-cell-intrinsic effect of Lum. Taken together, our results suggest that Lum negatively regulates encephalitic TH17 cells, implicating a potential therapeutic pathway in TH17 cell mediated autoimmune and inflammatory diseases.