Th2 Cytokine Inhibitor Research Articles

Suplatast tosilate reduces peripheral blood eosinophil levels in patients with eosinophilia: A real-world retrospective study

IntroductionEosinophilia is a rare disease characterized by an increase in eosinophils. Suplatast tosilate is a selective Th2 cytokine inhibitor that can reduce eosinophils. There is currently a lack of clinical studies of suplatast tosilate in the treatment of eosinophilia. Research objectiveTo explore whether suplatast tosilate can reduce blood eosinophil levels in eosinophilia and the factors that might influence the improvement. MethodsA real-world retrospective study of 20 patients with eosinophilia was conducted using electronic medical record information. The main outcome measure was the difference in peripheral blood absolute eosinophil count (AEC) and percentage (EOS%) before suplatast tosilate (baseline) and the lowest AEC during the 1-year period of suplatast tosilate treatment (post-treatment). Data on age, gender, disease duration, involved organs, and concomitant medication were collected, and subgroup analysis and linear regression analysis were performed. ResultsSubjects were predominantly male, with a mean age of 33 years and a disease duration of approximately 30 months. After treatment with suplatast tosilate, the patient's AEC (p ​= ​0.029) and EOS% (p ​= ​0.016) significantly decreased. The decline in eosinophils was more pronounced in patients who were male, age <33 years, disease duration <30 months and gastrointestinal system involvement. In addition, the shorter the course of the disease, the greater the relative decrease in eosinophils after suplatast tosilate treatment (β ​= ​−0.018, p ​< ​0.001). ConclusionsSuplatast tosilate is effective in reducing peripheral blood eosinophil levels in patients with eosinophilia. Large-scale prospective cohort studies are needed for further confirmation.

Preventive effects of Bifidobacterium lactis Probio-M8 on ovalbumin-induced food allergy in mice

Food allergy is a significant public health concern globally. Certain probiotics have been found to enhance food allergy by regulating immune-microbe interactions in animal models and patients. However, the effects of Bifidobacterium lactis Probio-M8 (Probio-M8) on food allergy have not been thoroughly investigated. The present study examined the anti-allergic properties of Probio-M8, particularly in relation to immune response and gut microbiota composition. Results demonstrate that oral administration of Probio-M8 effectively mitigated the allergy symptoms triggered by ovalbumin (OVA) by ameliorating the morphological damage in the jejunum, reducing OVA-specific IgE and histamine levels in the serum, and suppressing Th2 cytokines (interleukin (IL) 4 and IL-13) while increasing Th1 cytokines (interferon (IFN) γ) and regulatory T (Treg) cytokines (IL-10 and transforming growth factor (TGF) β1) in the culture supernatants of splenic cells. Furthermore, Probio-M8 effectively altered the diversity and composition of gut microbiota, particularly the relative abundances of Akkermansia_muciniphila in OVA-induced mice. Compared to the OVA group, the Probio-M8 group showed a decrease in the relative abundance of Akkermansia_muciniphila. In conclusion, Probio-M8 demonstrates the potential to alleviate food allergy by regulating the Th1/Th2 response and modulating gut microbiota, thereby offering a novel therapeutic strategy for patients with food allergy.

Impact of antigen loading in tolerogenic nanoparticles to mitigate Th2-mediated allergic lung inflammation.

Allergic disease is a major global health concern that imposes significant life-altering and economic burdens on affected individuals. However, there is still no cure. Polymer-based nanoparticles (NP) have shown the potential to induce antigen (Ag)-specific immune tolerance in various Th1/17 and Th2-mediated immune disorders including autoimmunity and allergy. Common methods by which Ags are associated with NPs are through surface conjugation or encapsulation. However, these Ag delivery strategies can be associated with several caveats that dampen their effectiveness such as uncontrolled Ag loading, a high Ag burst release, and an increased immune recognition profile. We previously developed Ag-polymer conjugate NPs (acNPs) to overcome those noted limitations, while allowing for controlled delivery of precise quantities of Ag to innate immune cells for Ag-specific CD4 T cell modulation. Here, we utilized ovalbumin (OVA) protein-poly(lactic-co-glycolic acid) (PLGA) conjugate NPs (acNP-OVA) to elucidate the impact of Ag loading on the induction of Th2 tolerance using a prophylactic and therapeutic OVA/ALUM-induced mouse model of allergic lung inflammation (ALI) in comparison to Ag-encapsulated PLGA NPs (NP(Ag)). We demonstrate that acNP-OVA formulations reduced OVA-specific IgE and inhibited Th2 cytokine secretions in an Ag loading-dependent manner when administered prophylactically. Administration of acNP-OVA to pre-sensitized mice did not affect OVA-specific IgE and Th2 cytokines tended to be reduced, however, there was no clear Ag loading dependency. acNP-OVA with medium-to-low Ag loadings were well tolerated, while formulations with high Ag loadings, including NP(Ag) resulted in anaphylaxis. Overall, our results clarify the relationship between Ag loading and Ag-specific IgE and Th2 cytokine responses in a murine model of ALI, which provides insight useful for future design of tolerogenic NP-based immunotherapies.

Effects of rosmarinic acid on immune response and intestinal microbiota in ovalbumin-induced intestinal allergy mice.

Rosmarinic acid (RA) is an active polyphenol that is widely found in various edible herbs. This study explored the potential anti-allergic activities and the underlying mechanisms of RA in ovalbumin (OVA)-induced intestinal allergic mice. Forty female BALB/c mice were randomly divided into five groups: control group, model group (OVA sensitized/challenged), RA-Low group (OVA sensitized/challenged, 30 mg kg-1 RA intervention), RA-Middle group (OVA sensitized/challenged, 90 mg kg-1 RA intervention) and RA-High group (OVA sensitized/challenged, 270 mg kg-1 RA intervention). RA effectively attenuated allergic reactions, including alleviating allergic symptoms and regulating the hypothermia of mice in the model group. Moreover, the anaphylactic mediator (OVA-specific IgE, histamine and mMCP-1) levels of OVA allergic mice were markedly decreased after RA intervention. Quantitative polymerase chain reaction analysis showed that RA significantly inhibited Th2 cytokine expression, while Th1 and Treg cytokines were markedly increased. 16S rRNA gene sequence analysis indicated that RA effectively regulated the richness and diversity of the intestinal microbiota in OVA allergic mice. At the phylum level, the relative abundance of Bacteroidetes and Firmicutes and the Firmicutes/Bacteroidetes ratio were altered by RA intervention. At the genus level, RA was found to regulate the disturbances in the relative abundance of Muribaculaceae, Lactobacillus and Prevotella. RA exhibited potential anti-allergic activity in OVA allergic mice by regulating hypersensitive immune responses and the intestinal microbiota structure. These results provide important evidence that RA can be developed into a novel functional food-derived ingredient against food allergy. © 2023 Society of Chemical Industry.

Mifepristone Modulates the Polarization of Th1/Th2 by Inducing the Mature of Monocyte‐Derived Dendritic Cells

AbstractAs an anti‐implantation contraception medicine, mifepristone can alter the development of the endometrium. In contrast, little research is performed to decipher the effect of mifepristone on Th1/Th2 immune homeostasis in the endometrium. CD14+ monocytes derived from healthy donors are cultured with interleukin (IL)‐4 and granulocyte macrophage‐colony stimulating factor to induce monocyte‐derived dendritic cells (DCs), which are further incubated with mifepristone. Mifepristone incubation could induce up‐regulated CD83 and major histocompatibility complex cell surface receptor staining on monocyte‐derived DCs. Functionally, mifepristone incubation could enhance the allostimulatory capacity of DCs to promote the proliferation of allogeneic T cells with up‐regulated Th1 cell proportion and down‐regulated Th2 cell proportion. On the other side, increased Th1 cytokines release (interferon‐γ, tumor necrosis factor α), inhibited Th2 cytokines release (IL‐10, IL‐4), promoted T‐Box transcription factor 21 transcription, and inhibited GATA binding protein 3 transcription are also identified. Mifepristone‐stimulated DCs could alter the Th1/Th2 transcription balance to favor Th1 skewing inflammatory environment.

Phillyrin attenuates airway inflammation and Th2 cell activities in a mouse asthma model

ABSTRACT Phillyrin is isolated from the fruit of Forsythia suspensa, and exhibits multiple pharmacological effects, including anti-tumor, anti-inflammation, and anti-oxidation activities. Here, we investigated whether phillyrin could alleviate airway hyperresponsiveness (AHR) and eosinophil infiltration in the lungs of asthmatic mice, and mitigate inflammatory responses in tracheal epithelial BEAS-2B cells. IL-4/TNF-α-stimulated BEAS-2B cells were treated with various phillyrin doses. Female BALB/c mice were sensitised and challenged with ovalbumin (OVA), and then treated with intraperitoneal injection different phillyrin doses. In IL-4/TNF-α-stimulated BEAS-2B cells, phillyrin effectively reduced proinflammatory cytokines, chemokines, and eotaxin (CCL11) levels. In the lungs of asthmatic mice, phillyrin treatment relieved AHR, airway inflammation, eosinophil infiltration, and goblet cell hyperplasia. Phillyrin also reduced serum OVA-IgE, and Th2-associated cytokine levels in splenocyte culture medium, and in bronchoalveolar lavage fluid of asthmatic mice. Our results indicate that phillyrin attenuated airway inflammation and eosinophil infiltration in asthmatic mice by suppressing Th2 cytokine production.

GABA and Combined GABA with GAD65-Alum Treatment Alters Th1 Cytokine Responses of PBMCs from Children with Recent-Onset Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic cells. There is a need for the development of novel antigen-specific strategies to delay cell destruction, including combinatorial strategies that do not elicit systemic immunosuppression. Gamma-aminobutyric acid (GABA) is expressed by immune cells, β-cells, and gut bacteria and is immunomodulatory. Glutamic-acid decarboxylase 65 (GAD65), which catalyzes GABA from glutamate, is a T1D autoantigen. To test the efficacy of combinatorial GABA treatment with or without GAD65-immunization to dampen autoimmune responses, we enrolled recent-onset children with T1D in a one-year clinical trial (ClinicalTrials.gov NCT02002130) and examined T cell responses. We isolated peripheral blood mononuclear cells and evaluated cytokine responses following polyclonal activation and GAD65 rechallenge. Both GABA alone and GABA/GAD65-alum treatment inhibited Th1 cytokine responses over the 12-month study with both polyclonal and GAD65 restimulation. We also investigated whether patients with HLA-DR3-DQ2 and HLA-DR4-DQ8, the two highest-risk human leukocyte antigen (HLA) haplotypes in T1D, exhibited differences in response to GABA alone and GABA/GAD65-alum. HLA-DR4-DQ8 patients possessed a Th1-skewed response compared to HLA-DR3-DQ2 patients. We show that GABA and GABA/GAD65-alum present an attractive immunomodulatory treatment for children with T1D and that HLA haplotypes should be considered.

The small molecule inhibitor BX-795 uncouples IL-2 production from inhibition of Th2 inflammation and induces CD4+ T cells resembling iTreg.

Treg cells have been shown to be an important part of immune-homeostasis and IL-2 which is produced upon T cell receptor (TCR)-dependent activation of T lymphocytes has been demonstrated to critically participate in Treg development. To evaluate small molecule inhibitors (SMI) for the identification of novel IL-2/Treg enhancing compounds. We used TCR-dependent and allergen-specific cytokine secretion of human and mouse T cells, next generation messenger ribonucleic acid sequencing (RNA-Seq) and two different models of allergic airway inflammation to examine lead SMI-compounds. We show here that the reported 3-phosphoinositide dependent kinase-1 (PDK1) SMI BX-795 increased IL-2 in culture supernatants of Jurkat E6-1 T cells, human peripheral blood mononuclear cells (hPBMC) and allergen-specific mouse T cells upon TCR-dependent and allergen-specific stimulation while concomitantly inhibiting Th2 cytokine secretion. RNA-Seq revealed that the presence of BX-795 during allergen-specific activation of T cells induces a bona fide Treg cell type highly similar to iTreg but lacking Foxp3 expression. When applied in mugwort pollen and house dust mite extract-based models of airway inflammation, BX-795 significantly inhibited Th2 inflammation including expression of Th2 signature transcription factors and cytokines and influx into the lungs of type 2-associated inflammatory cells such as eosinophils. BX-795 potently uncouples IL-2 production from Th2 inflammation and induces Th-IL-2 cells, which highly resemble induced (i)Tregs. Thus, BX-795 may be a useful new compound for the treatment of allergic diseases.

Prevention of Renal Interstitial Fibrosis by Suplatast in a Mouse Model.

Suplatast is a T helper 2 (Th2) cytokine inhibitor. Here, we tested its therapeutic effects using a mouse model of renal interstitial fibrosis caused by unilateral ureteral obstruction (UUO). In this model, suplatast was found to prevent the induced fibrosis in the obstructed kidney when given in the drinking water at 100 mg/kg/d. Mechanistically, suplaplast inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) that was otherwise increased by UUO. Similarly, suplaplast reduced the increased accumulation of KIM-1, transforming growth factor β (TGF-β), type I collagen, interleukin-4 (IL-4), janus kinase (JAK)1 and signal transducer and activator of transcription (STAT)3 mRNA seen in the kidneys of UUO-treated mice. Furthermore, STAT3 phosphorylation, which was stimulated by UUO, was also significantly decreased by suplatast. Collectively, these data show that suplatast reduces UUO-induced renal interstitial fibrosis via mechanisms including a reduction of phosphorylation of ERK and JAK/STAT pathway signaling.

Angiotensin converting enzyme 2 activation improves allergic rhinitis and suppresses Th2 cytokine release.

Allergic rhinitis (AR) is primarily regulated by type I hypersensitivity, with Th2 and immunoglobulin E (IgE) playing essential roles. This study aimed to determine whether angiotensin converting enzyme (ACE)2 could participate in the regulation of AR. Nasal mucosal tissues of AR patients were collected to determine ACE2 levels. Following AR mouse models were established, ACE2 levels in nasal mucosa were determined. Then the influences of diminazene aceturate (ACE2 agonist) on AR symptoms, pathology, specific antibodies, histamine, and interleukins (ILs) release in vivo were evaluated. Afterward, human nasal mucosa epithelial cells were exposed to IL-13, and the impacts of ACE2 overexpression on the secretion of pro-inflammatory factors in vitro were assessed. ACE2 levels significantly declined in nasal mucosa both in patients and mouse models (p < .001). Diminazene aceturate treatment elevated the ACE2 level in mice (p < .01), accompanied by reduced frequency of nasal spray and nasal friction, decreased eosinophils and goblet cells (p < .001) according to histopathological staining. Furthermore, lgE, lgG1, histamine, and IL levels in mice were also decreased (p < .05). In vitro experiments revealed that ACE2 overexpression suppressed the secretion of pro-inflammatory factors (p < .001). Together, ACE2 activation can alleviate the symptoms of AR in mice and inhibit the release of Th2 cytokines. Activating ACE2 is a promising therapeutic approach for AR.

Isosorbide Fatty Acid Diesters Have Synergistic Anti-Inflammatory Effects in Cytokine-Induced Tissue Culture Models of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic disease in which epidermal barrier disruption triggers Th2-mediated eruption of eczematous lesions. Topical emollients are a cornerstone of chronic management. This study evaluated efficacy of two plant-derived oil derivatives, isosorbide di-(linoleate/oleate) (IDL) and isosorbide dicaprylate (IDC), using AD-like tissue culture models. Treatment of reconstituted human epidermis with cytokine cocktail (IL-4 + IL-13 + TNF-α + IL-31) compromised the epidermal barrier, but this was prevented by co-treatment with IDL and IDC. Cytokine stimulation also dysregulated expression of keratinocyte (KC) differentiation genes whereas treatment with IDC or IDL + IDC up-regulated genes associated with early (but not late) KC differentiation. Although neither IDL nor IDC inhibited Th2 cytokine responses, both compounds repressed TNF-α-induced genes and IDL + IDC led to synergistic down-regulation of inflammatory (IL1B, ITGA5) and neurogenic pruritus (TRPA1) mediators. Treatment of cytokine-stimulated skin explants with IDC decreased lactate dehydrogenase (LDH) secretion by more than 50% (more than observed with cyclosporine) and in vitro LDH activity was inhibited by IDL and IDC. These results demonstrate anti-inflammatory mechanisms of isosorbide fatty acid diesters in AD-like skin models. Our findings highlight the multifunctional potential of plant oil derivatives as topical ingredients and support studies of IDL and IDC as therapeutic candidates.

Seabuckthorn juice alleviates allergic symptoms in shrimp-induced food allergy mice

Tropomyosin (TM) in shrimp is one of the predominant causes of food allergy around the world. In the present study, the effect of seabuckthorn juice against TM -induced shrimp allergy was investigated in BALB/c mice. Allergic symptoms, spleen index, intestinal section and diarrhea were measured in shrimp allergy mice. As the results, seabuckthorn juice suppressed the lesions in jejunum tissue, diarrhea and allergic symptoms in shrimp allergy mice. Seabuckthorn juice also reduced serum concentrations of tumor necrosis factor-α (TNF-α) as well as immunoglobulin E (IgE) and stimulated the secretion of interleukin-10 (IL-10) in mice with shrimp allergy. Taken together, our findings suggest that increased IL-10 by seabuckthorn juice inhibits Th2 cytokine production to suppress shrimp allergic symptoms. Furthermore, seabuckthorn juice also regulates shrimp allergy by reducing jejunum lesions, inhibiting levels of TNF-α and IgE.

The immunity-promoting activity of porcine placenta in mice as an immunomodulator for functional foods

This study was to explore the immunity-promoting activity of porcine placenta as a potential raw material for functional foods. Porcine placenta was subjected to the analysis for its bioactive substances, and their immunity-promoting activity was determined in mice supplemented with porcine placenta extract (PPE) and freeze-dried porcine placenta powder at high (PPH) and low (PPL) dosage. Results showed that porcine placenta contained placental peptides and 15 free amino acids, and the amounts of estrogen and progesterone in products developed from porcine placenta were within the limit of national standard. Mice model experiment revealed that compared with the control, the PPH treatment significantly improved the spleen index (P < 0.05) by increasing the phagocytic rate of macrophages from 20 % to 60 % and the conversion rate of T lymphocytes from 8 % to 60 %. The qPCR analysis disclosed that the porcine placenta powder enhanced mice immunity via promoting the expression of Th1 cytokines of interleukin-2 (IL-2) and IFN-γ, especially the former, by almost 8 times in the spleens of male mice, while inhibited Th2 cytokines of IL-4 and IL-10. This investigation has provided a reference for the development of porcine placenta as a raw material applied in functional foods to improve human immunity.

Tanshinone IIA alleviates ovalbumin-induced allergic rhinitis symptoms by inhibiting Th2 cytokine production and mast cell histamine release in mice

Context Studies have shown that tanshinone IIA (TIIA) has an anti-inflammatory effect, but the effect on allergic rhinitis (AR) is unclear. Objective In this study, we explore the effect of TIIA on AR. Materials and methods AR mice model was established by the intraperitoneal (ip) injection of 50 μg ovalbumin (OVA). AR mice in the dose tested groups were treated with TIIA (10 mg/kg/d, ip) or dexamethasone (Dex) (2.5 mg/kg/d, oral). The number of nasal rubbing in mice was counted. Inflammatory, goblet and mast cells in nasal mucosal tissue were detected. The contents of histamine, OVA-immunoglobulin E (IgE), OVA-immunoglobulin G1 (IgG1), tumour necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-5, interferon-γ (IFN-γ) and IL-12 in nasal lavage fluid (NALF) or serum were measured. Human mast cells (HMC-1) were treated with C48/80 to release histamine or TIIA for therapeutic effect, and the cell viability, histamine content and mast cell degranulation were examined. Results OVA promoted the number of nasal rubbings in mice (78 times/10 min, p< 0.001), increased the inflammatory, goblet and mast cells in nasal mucosal tissue, and significantly (p< 0.001) elevated the levels of histamine (120 ng/mL), OVA-IgE (2 pg/mL), OVA-IgG1 (90 ng/mL), TNF-α (2.3 pg/mL), IL-4 (150 pg/mL) and IL-5 (65 pg/mL) in serum or NALF of OVA-induced AR mice. However, both TIIA and Dex inhibited the effect of OVA on AR mice. Besides, TIIA reversed the promotion of histamine release (30%) and mast cell degranulation induced by C48/80. Discussion and conclusions TIIA alleviates OVA-induced AR symptoms in AR mice, and may be applied as a therapeutic drug for patients with Th2-, or mast cell-allergic disorders.

The combination therapy of Everolimus and anti-PD-1 improves the antitumor effect by regulating CD8+ T cells in bladder cancer.

This study aimed to investigate the efficacy of Everolimus (EVE) in combination with immune checkpoint inhibitors (ICIs) in bladder cancer treatment and the underlying mechanisms. In vitro, MB49 cells were exposed to gradient concentrations (0nM-100nM) of EVE for 48h, to investigate the cell viability and cell proliferative potential. In vivo, we applied a subcutaneous tumor mouse model of bladder cancer and the mice were treated with EVE monotherapy (different doses) or in combination with anti-programmed cell death protein 1 (PD-1) agents to study the impacts on tumor growth and explore the immune mechanism. The influences of treatments on peripheral immune profiles and tumor immune microenvironment were also discussed. EVE could inhibit the growth of MB49 cells in vitro. Though high-dose EVE monotherapy could induce tumor regression in vivo, it also contributed to immunosuppression. High-dose EVE inhibited the expression of PD-L1 by inhibiting Th1 cytokine secretion, while combined therapy with PD-1 inhibitors showed no extra profit. Low-dose EVE in combination with PD-1 inhibitors could effectively suppress tumor growth by increasing periphery CD8+ T cell frequency and GZMB+ CD8+ T cell frequency in the tumor microenvironment. High-dose EVE monotherapy induced tumor regression, but with immunosuppression to some content. Combination therapy with low-dose EVE and PD-1 inhibitor could effectively inhibit the growth of bladder tumors by enhancing the antitumor immunity of CD8+ T cells in both periphery and tumor microenvironment.

Cholinergic anti-inflammatory pathway ameliorates murine experimental Th2-type colitis by suppressing the migration of plasmacytoid dendritic cells

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.

Evaluation the therapeutic efficacy of different concentration of amphotericin B drug in mice infected with visceral leishmaniosis.

Liposomal amphotericin B (Amph B) has been used effectively to treat leishmaniosis, in spite of its high toxicity appeared in some patients. In our study, Amph B was administered in Leishmania donovani that infected BALB/c male mice using different concentrations to evaluate its efficacy challenge against infection as well as its effect in modulating immunity of the host. We observed that low doses with short duration of Amph B as a therapy regime significantly enhanced the induction of Th1 cytokine (INF-γ), but suppressed Th2 cytokine (IL-10) production. Groups of mice infected with L. donovani and treated with Amph B showed clearly increasing in INF-γ level and reduction in IL-10 level in concentration (3, 4, 5 mg/ml/kg) with best result in 5 mg/ml/kg (accumulation dose 25 mg/ml) than concentrations (6, 7 mg/ml/kg). We hypothesized that Amph B with low doses and short duration regime worked to mediate immunotherapeutic for eliminating the parasite-induced immunosuppression.

Sophora flavescens Alkaloids and Corticosteroid Synergistically Augment IL-10/IL-5 Ratio with Foxp3-Gene-Epigenetic Modification in Asthma PBMCs.

BackgroundIt has been demonstrated that ASHMI (antiasthma-simplified herbal medicine intervention) can improve airway function and reduce inflammation in human asthmatic patients with high safety and tolerability. In addition, ASHMI significantly suppresses Th2 cytokine production and increases Th1 cytokine production in treating asthma.ObjectiveAllergic asthma is associated with dysregulation of cytokines. We focused on IL-5 and IL-10 as signature Th2 and Treg cytokines to characterize ASHMI immunomodulatory components.MethodsThe effects of ASHMI and individual herbal constituents on IL-5 and IL-10 production by PBMCs from asthmatic subjects were determined ex vivo. Sophora flavescens (SF)-F2, containing alkaloid compounds, effects on PBMC IL-10 and IL-5 production in the presence or absence of dexamethasone (Dex), and on DNA methylation levels at the foxp3 gene promoter were determined.ResultsThe ratio of anti-CD3/CD28 stimulated IL-10/IL-5 production by PBMCs from asthmatic subjects was significantly reduced compared to healthy subjects. In PBMCs from asthmatic subjects, ASHMI significantly reduced IL-5 production and increased IL-10 secretion in a dose-dependent manner (p < 0.05–0.01). SF-F2 was most effective in increasing IL-10, whereas SF-F4 (flavonoid compounds) was most effective in suppressing IL-5 production. Dex-treated PBMCs from asthma subjects showed a trend of increasing ratio of IL-10/IL-5 while demonstrating reduced levels in both IL-5 and IL-10 (p < 0.05). Co-culture with Dex and SF-F2 significantly prevented Dex suppression of IL-10, while retained Dex-suppression of IL-5 production, and increased IL-10/IL-5 ratio by Dex. Co-culture with SF-F2 and Dex significantly reduced DNA methylation levels at the foxp3 gene promoter at CpG−126.ConclusionThe SF alkaloid-rich fraction may be responsible for ASHMI induction of IL-10 production by PBMCs and plays a synergistic effect with Dex for augmenting IL-10/IL-5 ratio.

Deer Velvet and Eleutherococcus senticosus Mixture Regulated Immune Function in C57BL/6N Mice with Immunosuppression Induced by Forced Swimming.

Immunosuppression occurs in response to a variety of external antigens. However, various immune cells and cytokines can activate the immune system. In this study, it was found that fermented deer velvet (FD) and fermented Eleutherococcus senticosus (FE) extract (FDE) mixtures regulated the immunity of animals that underwent induced immunosuppression through forced swimming exercise (FSE). Seven mouse treatment groups were included in the experiment: normal controls, FSE controls, positive controls (FSE+red ginseng 300 mg/kg body weight), FD200 (FSE+FD 200 mg/kg body weight), FE200 (FSE+FE 200 mg/kg body weight), FDE50 (FSE+FDE 50 mg/kg body weight), and FDE200 (FSE+FDE 200 mg/kg body weight). Oral intake of experimental and control substances lasted for 2 weeks. Oral FDE intake increased cell counts for major histocompatibility complex (MHC) I, MHC II, CD4(+) T cells, and CD8(+) T cells compared with controls. Moreover, FDE increased Th1 (interleukin [IL]-2 and interferon gamma) cytokine proliferation, T cell proliferation, IL-12 and IL-15 production, and natural killer cell activity compared with controls. In addition, FDE inhibited Th2 cytokines (IL-4, IL-6, IL-10, and tumor necrosis factor alpha) and nitric oxide production, increased B cell proliferation and leukocyte count, and promoted immunoglobulin A and G serum levels compared with controls. Thus, the finding that FDE increased immune function in an immunosuppression model suggests that FDE has immunomodulatory capacity.

Suppression of Th2 cytokines as a potential mechanism for reduced antibody response following PFOA exposure in female B6C3F1 mice

Perfluorooctanoic acid (PFOA), a member of the Per- and polyfluoroalkyl substances, is a highly persistent “forever” chemicals with increasing concern for its potential health effects. However, the mechanisms of PFOA immunotoxic effects are poorly understood. We assessed the antibody response to a physiological antigen stimulation and associated cytokine response upon PFOA exposure. The significant decrease in the IgM antibody response to the T cell dependent antigen keyhole limpet hemocyanin (KLH) at a dose lower than the previously documented LOAEL was accompanied by a significant reduction of the Th2 serum cytokines IL-5 and IL-13, a non-significant dose-response reduction of IL-4, a significant reduction of the Th1 cytokine IL-12, and a non-significant dose-response increase in IL-2 and IFNγ. PFOA significantly decreased the pro-inflammatory cytokines IL-17α and IL-1α, decreased (non-significantly but dose-response) IL-6, and a significantly increased TNFα. Overall, the modulation of serum Th1/Th2 cytokines could explain the reduction in antibody response, pointing to a potential role for T helper cells in the immunotoxicity of PFOA. Further, the higher than anticipated weight loss and increased liver weight, compared to previous studies using similar doses, highlight the potential importance of the route and duration of exposure, contributing to the total accumulated dose, in assessing the toxicity of PFOA.