Effects of Vitamin D Supplementation on CD4+ T Cell Subsets and mTOR Signaling Pathway in High-Fat-Diet-Induced Obese Mice.

Obesity is associated with an impaired balance of CD4+ T cell subsets. Both vitamin D and obesity have been reported to affect the mTOR pathway. In this study, we investigated the effects of vitamin D on CD4+ T cell subsets and the mTOR pathway. Ten-week-old male C57BL/6 mice were divided into four groups and fed diets with different fat (control or high-fat diets: CON or HFD) and vitamin D contents (vitamin D control or supplemented diets: vDC or vDS) for 12 weeks. T cells purified by negative selection were stimulated with anti-CD3/anti-CD28 mAbs and cultured for 48 h. The percentage of CD4+IL-17+ T cells was higher in the vDS than vDC groups. The CD4+CD25+Foxp3+ T cells percentage was higher in HFD than CON groups. The phospho-p70S6K/total-p70S6K ratio was lower in vDS than vDC, but the phospho-AKT/total-AKT ratio was higher in vDS than vDC groups. Hif1α mRNA levels were lower in vDS than vDC groups. These findings suggest HIF1α plays an important role in vitamin-D-mediated regulation of glucose metabolism in T cells, and dietary vitamin D supplementation may contribute to the maintenance of immune homeostasis by regulating the mTOR pathway in T cells.

Chemical profiling and anti-psoriatic activity of marine sponge (Dysidea avara) in induced imiquimod-psoriasis-skin model.

Since Marine sponge Dysidea avara is regarded as a source of anti-inflammatory compounds, we decided to evaluate its potential anti-psoriatic activity in a psoriasis Imiquimod-induced in the mouse model. Psoriatic mice were treated with three different methanolic extracts of Dysidea avara compared with betamethasone-treated mice in in- vivo studies. Clinical skin severity was assessed with the psoriasis area index (PASI), whilst ELISA detected the expression of TNF-α, IL-17A, and IL-22. Dysidea avara activity was studied by employing GC-MS (to distinguish compounds), HPTLC (for skin permeation and accumulation), and SEA DOCK to predict single compound potential anti-inflammatory activity. After 7 days of treatment, mice treated with Dysidea avara displayed a dose-dependent, statistically significant improvement compared to controls (p< 0.001). In line with the clinical results, ELISA revealed a statistically significant decrease in IL-22, IL-17A, and TNF-α after treatment; the same SEA DOCK analysis suggests a possible anti-psoriatic activity of the extracts.

Melatonin attenuates microbiota dysbiosis of jejunum in short-term sleep deprived mice.

Our study demonstrated that sleep deprivation resulted in homeostasis disorder of colon. Our study goes deeper into the positive effects of melatonin on small intestinal microbiota disorder caused by sleep deprivation. We successfully established a multiplatform 72 h sleep deprivation mouse model with or without melatonin supplementation, and analyzed the change of small intestinal microbiota using high-throughput sequencing of the 16S rRNA. We found melatonin supplementation suppressed the decrease of plasma melatonin level in sleep deprivation mice. Meanwhile, melatonin supplementation improved significantly the reduction in OTU numbers and the diversity and richness of jejunal microbiota and the abundance of Bacteroidaeae and Prevotellaceae, as well as an increase in the Firmicutes-to-Bacteroidetes ratio and the content of Moraxellaceae and Aeromonadaceae in the jejunum of sleep deprived-mice. Moreover, melatonin supplementation reversed the change of metabolic pathway in sleep deprived-mice, including metabolism, signal transduction mechanisms and transcription etc, which were related to intestinal health. Furthermore, melatonin supplementation inverted the sleep deprivation-induced a decline of anti-inflammatory cytokines (IL-22) and an increase of the ROS and proinflammatory cytokines (IL-17) in jejunum. These findings suggested that melatonin, similar to a probiotics agent, can reverse sleep deprivation-induced small intestinal microbiota disorder by suppressing oxidative stress and inflammation response.

Herbal Combinational Medication of Glycyrrhiza glabra, Agastache rugosa Containing Glycyrrhizic Acid, Tilianin Inhibits Neutrophilic Lung Inflammation by Affecting CXCL2, Interleukin-17/STAT3 Signal Pathways in a Murine Model of COPD.

Chronic obstructive pulmonary disease (COPD) is caused by exposure to toxic particles, such as coal fly ash (CFA), diesel-exhaust particle (DEP), and cigarette smoke (CS), leading to chronic bronchitis, mucus production, and a subsequent lung dysfunction. This study, using a mouse model of COPD, aimed to evaluate the effect of herbal combinational medication of Glycyrrhiza glabra (GG), Agastache rugosa (AR) containing glycyrrhizic acid (GA), and tilianin (TN) as active ingredients. GA, a major active component of GG, possesses a range of pharmacological and biological activities including anti-inflammatory, anti-allergic, anti-oxidative. TN is a major flavonoid that is present in AR. It has been reported to have anti-inflammatory effects of potential utility as an anti-COPD agent. The COPD in the mice model was induced by a challenge with CFA and DEP. BALB/c mice received CFA and DEP alternately three times for 2 weeks to induce COPD. The herbal mixture of GG, AR, and TN significantly decreased the number of neutrophils in the lungs and bronchoalveolar lavage (BAL) fluid. It also significantly reduced the production of C-X-C motif chemokine ligand 2 (CXCL-2), IL-17A, CXCL-1, TNF-α, symmetric dimethylarginine (SDMA) in BALF and CXCL-2, IL-17A, CXCL-1, MUC5AC, transient receptor potential vanilloid-1 (TRPV1), IL-6, COX-2, NOS-II, and TNF-α mRNA expression in the lung tissue. Notably, a combination of GG and AR was more effective at regulating such therapeutic targets than GG or AR alone. The histolopathological lung injury was alleviated by treatment with the herbal mixture and their active ingredients (especially TN). In this study, the herbal combinational mixture more effectively inhibited neutrophilic airway inflammation by regulating the expression of inflammatory cytokines and CXCL-2 by blocking the IL-17/STAT3 pathway. Therefore, a herbal mixture of GG and AR may be a potential therapeutic agent to treat COPD.

Interleukin-17A Is Associated With Alveolar Inflammation and Poor Outcomes in Acute Respiratory Distress Syndrome.

OBJECTIVE: Interleukin-17A is a proinflammatory cytokine known to play a role in host defense and pathologic inflammation in murine models of lung injury. The relationship between interleukin-17A and inflammation in human lung injury is unknown. Our primary objective was to determine whether interleukin-17A levels are associated with alveolar measures of inflammation and injury in patients with acute respiratory distress syndrome. Our secondary objective was to test whether interleukin-17A levels are associated with acute respiratory distress syndrome-related outcomes. DESIGN: Observational study. SETTING: Six North American medical centers. PATIENTS: We studied two groups of patients with acute respiratory distress syndrome: 1) patients previously enrolled in a placebo-controlled clinical trial of omega-3 fatty acids performed at five North American medical centers (n = 86, acute respiratory distress syndrome 1), and 2) patients with systemic inflammatory response syndrome admitted to an ICU who developed acute respiratory distress syndrome (n = 140, acute respiratory distress syndrome 2). In acute respiratory distress syndrome 1, we used paired serum and bronchoalveolar lavage fluid samples obtained within 48 hours of acute respiratory distress syndrome onset, whereas in acute respiratory distress syndrome 2, we used plasma obtained within the first 24 hours of ICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured circulating interleukin-17A in acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2. We also measured interleukin-17A, neutrophil counts, and total protein in bronchoalveolar lavage fluid from acute respiratory distress syndrome 1. We found that bronchoalveolar lavage interleukin-17A was strongly associated with higher bronchoalveolar lavage percent neutrophils (p < 0.001) and bronchoalveolar lavage total protein (p < 0.01) in acute respiratory distress syndrome1. In both acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2, elevated interleukin-17A was associated with higher Sequential Organ Failure Assessment scores (p < 0.05). CONCLUSIONS: Elevated circulating and alveolar levels of interleukin-17A are associated with increased percentage of alveolar neutrophils, alveolar permeability, and organ dysfunction in acute respiratory distress syndrome.

[Effects of different doses of 1,25-(OH)2D3 on expression of HMGB1 and IL-17 in the lungs of asthmatic mice].

OBJECTIVE: To study the effects of 1,25-(OH)(2)D(3) on airway remodeling and expression of high mobility group box 1 (HMGB1) and IL-17 in asthmatic mice. METHODS: Fifty female mice were randomly divided into 5 groups: control, asthma, low-dose, middle-dose, and high-dose intervention groups (n=10 each). Asthma was induced by intraperitoneal injections of ovalbumin (OVA) and aerosol inhalation of OVA solution. The low-dose, middle-dose, and high-dose intervention groups were administered with 1,25-(OH)(2)D(3) solution at the dosage of 1, 4 and 10 µg/kg respectively by intraperitoneal injections before asthma challenge. The airway structural changes were assessed by hematoxylin and eosin staining. mRNA expression levels of HMGB1 and IL-17 in the lung tissues were evaluated by RT-PCR. The protein levels of HMGB1 and IL-17 in the lung tissues were observed by immunohistochemistry. RESULTS: The airway wall thickness, protein and mRNA expression levels of HMGB1 and IL-17 were higher in the untreated asthma group than in the control group (P<0.05). The airway wall thickness, protein and mRNA expression levels of HMGB1 and IL-17 were lower in the middle-dose and low-dose intervention groups than in the untreated asthma group, and the middle-dose intervention group demonstrated lower airway wall thickness, protein and mRNA expression levels of HMGB1 and IL-17 than in the low-dose intervention group (P<0.05). However, the airway wall thickness, protein and mRNA expression levels of HMGB1 and IL-17 in the high-dose intervention group were higher than in the untreated asthma group (P<0.05). CONCLUSIONS: HMGB1 and IL-17 may be involved in the airway remodeling process in asthmatic mice. A moderate amount of HMGB1 and IL-17 may be involved in the airway remodeling process in asthmatic mice. A moderate amount of 1,25-(OH)(2)D(3) can improve the airway remodeling, but a higher dose of 1,25-(OH)(2)D(3) may affect adversely the airway remodeling process.

Clinical and immunological responses in ocular demodecosis.

The purpose of this study was to investigate clinical and immunological responses to Demodex on the ocular surface. Thirteen eyes in 10 patients with Demodex blepharitis and chronic ocular surface disorders were included in this study and treated by lid scrubbing with tea tree oil for the eradication of Demodex. We evaluated ocular surface manifestations and Demodex counts, and analyzed IL-1ß, IL-5, IL-7, IL-12, IL-13, IL-17, granulocyte colony-stimulating factor, and macrophage inflammatory protein-1ß in tear samples before and after the treatment. All patients exhibited ocular surface manifestations including corneal nodular opacity, peripheral corneal vascularization, refractory corneal erosion and infiltration, or chronic conjunctival inflammatory signs before treatment. After treatment, Demodex was nearly eradicated, tear concentrations of IL-1ß and IL-17 were significantly reduced and substantial clinical improvement was observed in all patients. In conclusion, we believe that Demodex plays an aggravating role in inflammatory ocular surface disorders.

Amelioration of rat collagen-induced arthritis through CD4+ T cells apoptosis and synovial interleukin-17 reduction by indoleamine 2,3-dioxygenase gene therapy.

Indoleamine 2,3-dioxygenase (IDO) has been known as an emerging therapeutic target in autoimmunity-related arthritis. The treatment responses of adenoviral vectors encoding IDO (AdIDO) gene therapy in rat collagen-induced arthritis (CIA) were examined in this study. The therapeutic effects on ankle circumference, articular index, and radiographic and histological scores were evaluated in AdIDO-injected ankle joints. We further determined CD4+ T-cell numbers and their apoptotic status, CD68(+) macrophage numbers, kynurenine (a downstream tryptophan metabolite) concentrations, interleukin-17 (IL-17) levels, and retinoic acid-related orphan receptor γt (RORγt) expression in synovial tissues of CIA rats receiving AdIDO treatment. Reduction of ankle circumference, articular index, and radiographic and histological scores were noted in AdIDO-treated ankles, as compared with those receiving injection of control vectors. Furthermore, IDO gene transfer led to decreased infiltrating CD4+ T cells with enhanced apoptosis, reduced CD68+ macrophage numbers, increased kynurenine levels, lower IL-17 concentrations, and decreased RORγt expression within the ankle joints. In addition, such a therapy diminished type II collagen-specific IL-17 production and RORγt expression in CD4+ T cells from draining lymph nodes of CIA rats. Our results demonstrate for the first time that intra-articular delivery of IDO gene ameliorated ankle arthritis of CIA rats by induction of CD4+ T-cell apoptosis and reduction of synovial IL-17 production through the supplement of kynurenine. Taken together, these findings implicate the novel strategy of using IDO gene as a therapeutic approach in treating patients with rheumatoid arthritis.

Therapeutic effects of TACI-Ig on rat with adjuvant arthritis.

Transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig) is a human fusion protein that binds and neutralizes both B lymphocyte stimulator (BLyS), a cytokine shown to be a key regulator of B cell maturation, proliferation and survival, and a proliferation-inducing ligand (APRIL). Rat adjuvant arthritis (AA) is an experimental animal model of rheumatoid arthritis (RA), which is mainly dependent on T cells and neutrophil-mediated cytokine production. The purpose of the present study was to investigate the effects of TACI-Ig on rat AA. Rat AA was induced by intradermal injection of 0·1 ml complete Freund's adjuvant (CFA). TACI-Ig (0·7, 2·1 and 6·3 mg/kg), recombinant human tumour necrosis factor-α receptor (rhTNFR) : Fc (2·8 mg/kg) and IgG-Fc (6·3 mg/kg) were administered subcutaneously every other day from days 16 to 34 after immunization. Arthritis was evaluated by arthritis global assessment and swollen joint count (SJC). The ankle joint and spleen were harvested for histopathological examination. Spleen index and thymus index were calculated. The levels of BLyS, interleukin (IL)-17, interferon (IFN)-γ, IgG1, IgG2a and IgM in AA rat spleen were measured by enzyme-linked immunosorbent assay. Administration of TACI-Ig significantly reduced the arthritis global assessment and SJC, decreased spleen index and ameliorated histopathological manifestations of rat AA. Suppressing the levels of BLyS, IL-17, IFN-γ and Ig in AA rat spleen were observed after administration of TACI-Ig. These results showed that TACI-Ig significantly inhibited the degree of rat AA, and the inhibitory effects might be associated with its ability to reduce BLyS, proinflammatory cytokines and Ig levels in spleen.

Clinical and Immunological Responses in Ocular Demodecosis

The purpose of this study was to investigate clinical and immunological responses to Demodex on the ocular surface. Thirteen eyes in 10 patients with Demodex blepharitis and chronic ocular surface disorders were included in this study and treated by lid scrubbing with tea tree oil for the eradication of Demodex. We evaluated ocular surface manifestations and Demodex counts, and analyzed IL-1beta, IL-5, IL-7, IL-12, IL-13, IL-17, granulocyte colony-stimulating factor, and macrophage inflammatory protein-1beta in tear samples before and after the treatment. All patients exhibited ocular surface manifestations including corneal nodular opacity, peripheral corneal vascularization, refractory corneal erosion and infiltration, or chronic conjunctival inflammatory signs before treatment. After treatment, Demodex was nearly eradicated, tear concentrations of IL-1beta and IL-17 were significantly reduced and substantial clinical improvement was observed in all patients. In conclusion, we believe that Demodex plays an aggravating role in inflammatory ocular surface disorders.