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Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (TH2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box–binding protein-1 (XBP1) in the induction of the TH2 cell response through its role in generating TIM4+ DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2–XBP1–TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant TH2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for TH2 cell responses by inducing the development of TIM4+ DCs, which depends on the IL-2–XBP1–SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of TH2 cell–dependent inflammation or allergic diseases. Editor's summary: T helper 2 (TH2) cells mediate allergic responses, and their development depends on dendritic cells (DCs) expressing the receptor TIM4. Yang et al. found that the transcription factor XBP1 induced expression of the gene encoding TIM4 in DCs. Production of the cytokine IL-2 in the airways of allergen-exposed mice induced expression of XBP1 and then TIM4 in DCs through a pathway involving the GEF Sos1 and the GTPase Ras. Targeting this pathway in DCs reduced the severity of experimentally induced allergic airway responses in mice, suggesting that these factors could be therapeutic targets for treating TH2 cell–dependent inflammatory or allergic diseases. —John F. Foley [ABSTRACT FROM AUTHOR]

The mechanism of generation of regulatory T cells (Treg) remains incompletely understood. Recent studies show that CD83 has immune regulatory functions. This study aims to investigate the role of epithelial cell‐derived CD83 in the restoration of immune tolerance in the airway mucosa by inducing the Treg differentiation. In this study, CD83 and ovalbumin (OVA)‐carrying exosomes were generated from airway epithelial cells. An airway allergy mouse model was developed to test the role of CD83/OVA‐carrying exosomes in the suppression of airway allergy by inducing Treg generation. We observed that mouse airway epithelial cells expressed CD83 that could be up‐regulated by CD40 ligand. The CD83 deficiency in epithelial cells retarded the Treg generation in the airway mucosa. CD83 up‐regulated transforming growth factor‐β‐inducible early gene 1 expression in CD4+ T cells to promote Foxp3 expression. Exposure of primed CD4+ T cells to CD83/OVA‐carrying exosomes promoted antigen‐specific Treg generation. Administration of CD83/OVA‐carrying exosomes inhibited experimental airway allergic response. In summary, airway epithelial cells express CD83 that is required in the Treg differentiation in the airway mucosa. Administration of CD83/OVA‐carrying exosomes can inhibit airway allergy that has the translation potential in the treatment of airway allergic disorders. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a disease that frequently relapses and affects more than 0.1% general population; the underlying mechanism is poorly understood. Published data show that polymorphonuclear neutrophils (PMN) contribute to the pathogenesis of UC. This study aims to identify antigen (Ag)‐specific PMNs and investigate their role in UC relapse. In this study, the correlation between PMN activities and UC relapse was assessed in a group of UC patients. A UC mouse model was developed to expand the findings of UC patient study. The results showed that a positive correlation was detected between the high PMN activities and the food Ag‐specific IgG amounts in colon biopsies of UC patients. UC patient‐derived Ag‐specific PMNs could be activated upon exposure to food specific Ag. The Ag/FcγRI complexes were detected on the surface of PMNs in UC patients. Re‐exposure of sensitized PMNs to specific Ag triggered PMN activation and induced UC‐like inflammation in the mouse colon. We conclude that FcγRI plays a critical role in UC relapse. Inhibition of FcγRI can efficiently inhibits experimental UC. [ABSTRACT FROM AUTHOR]

Background: The eosinophil (Eo) activation is a crucial factor evoking allergic rhinitis (AR) attacks; factors; the mechanism of triggering Eo activation remains to be further investigated. The interaction of antigen (Ag) and antibody plays a critical role in evoking allergy attacks. This study aims to elucidate the role of FcγRI, the high affinity receptor of IgG, in the Ag-mediated Eo activation. Methods: Nasal lavage fluids (NLF) were collected from AR patients and healthy control (HC) subjects. Eos were isolated by flow cytometry cell sorting and analyzed by pertinent immunological approaches. Results: Eos composed more than 60% of the cellular components in AR NLF. Exposure to specific Ags (sAgs) in the culture triggered Eos to release inflammatory mediators. High levels of FcγRI were detected on the surface of AR NLF Eos. Exposure to lipopolysaccharide markedly increased the FcγRI expression in naive Eos, which could be bound by Ag-specific IgG (sIgG) to form complexes on the surface of Eos; this made Eos at the sensitized status. Eos bore with the sIgG/FcγRI complexes could be activated upon exposure to sIgG in the culture; these Eos can be designated as Ag-specific Eos. Passive transfer of Ag-specific Eos resulted in profound AR response in mice upon sAg challenge. Depletion of FcγRI on Eos efficiently abolished AR response in mice. Conclusions: AR Eos express high levels FcγRI, that can be bound by sIgG to make Eos sensitized. Re-exposure to specific Ags can activate the sensitized Eos. [ABSTRACT FROM AUTHOR]

• What is already known about this topic? • Eosinophils play a critical role in allergic airway disease pathogenesis. • What does this article add to our knowledge? • Bcl2L12 plays an important role in expanding eosinophil lifespan and facilitating eosinophils to produce eotaxin. • How does this study impact current management guidelines? • To inhibit Bcl2L12 in eosinophils has the translational potential in the treatment of allergic airway diseases. The pathogenesis of airway allergic disorders (AAD) needs to be further investigated. Eosinophils (Eos) are the canonical effector cells in AAD attacks. Bcl2 like protein-12 (Bcl2L12) is an apoptosis inhibitor and an immune regulator. Eos have the defects of apoptosis. This study aims to investigate the role of Bcl2L12 in the AAD pathogenesis by regulating Eo activities. Human nasal lavage fluids (NLF) and mouse bronchoalveolar lavage fluids (BALF) was collected. Eos in NLF and BALF were analyzed by flow cytometry. A murine AAD model was developed with ovalbumin as a specific antigen. We found that Eos isolated from NLF or BALF of AAD subjects expressed high levels of Bcl2L12 and showed defects of apoptosis. The Bcl2L12 expression in Eos was positively correlated with the AAD response. High lipopolysaccharide levels were detected in the AAD airways, that promoted the Bcl2L12 expression in Eos. Bcl2L12 mediated the LPS-induced autocrine eotaxin 1 expression in Eos through activating the MAPK p38/STAT6/NF-κB signal pathway. Depletion of Bcl2L12 in Eos suppressed experimental AAD in mice. AAD Eos express high levels of Bcl2L12, the latter is associated with AAD response by regulating the autocrine eotaxin 1 in Eos. Depletion of Bcl2L12 in Eos attenuates experimental AAD, suggesting that to suppress the Bcl2L12 Eos has the translational potential in the treatment of AAD. [ABSTRACT FROM AUTHOR]

Background: The eosinophilic inflammation plays a critical role in myocarditis (Mcd); its underlying mechanism remains to be further elucidated. This study aims to investigate the role of Bcl2-like protein 12 (Bcl2L12) in inducing the defects of apoptosis in eosinophils (Eos) of the heart tissues. Methods: Human explant heart samples were collected. Eosinophilia and myocarditis (Mcd)-like inflammation were induced in the mouse heart by immunizing with murine cardiac α-myosin heavy chain (MyHCα) peptides. Results: Markedly more Eos were observed in heart tissues from patients with Mcd than those from patients with dilated cardiomyopathy. Eos isolated from Mcd hearts showed the signs of apoptosis defects. The Eo counts in the Mcd heart tissues were positively correlated with the Bcl2L12 expression in Eos isolated from the heart tissues. Exposure to interleukin 5 in the culture induced the expression of Bcl2L12 in Eos. Bcl2L12 bound c-Myc, the transcription factor of Fas ligand (FasL), to prevent c-Myc from binding to the FasL promoter, to restrict the FasL gene transcription in Eos. Inhibition of Bcl2L12 prevented the induction of eosinophilia and Mcd-like inflammation in the mouse heart. Conclusions: The Bcl2L12 expression contributes to apoptosis defects in Eos of the Mcd heart. Blocking Bcl2L12 prevents the eosinophilia induction and alleviates Mcd-like inflammation in mice. [ABSTRACT FROM AUTHOR]

The therapies for food allergy (FA) need to be improved. The generation of inducible regulatory T cells (Tregs) can support immune tolerance in the body. This study aims to suppress experimental FA by inducing Tregs through the employment of modified exosomes (mExosomes). In this study, mExosomes were prepared by incubating dendritic cells with interleukin (IL)‐2 and ovalbumin (OVA, used as a specific antigen) in the culture. Exosomes were purified from culture supernatant and used as the mExosomes. A murine FA model was developed to test the effects of mExosomes on the generation of Tregs in the mouse intestinal tissues and inhibiting FA. The results showed that mExosomes, which carried IL‐2 and a complex of OVA peptide–major histocompatibility complex class II on the surface of exosomes, bound to OVA‐specific CD4+ T cells and induced CD4+ T cells to differentiate into Tregs. In the FA mouse intestinal tissues, we found low IL‐2 levels that were positively correlated with the number of Tregs. Depletion of IL‐2 in mice prevented the generation of Tregs. The levels of peroxisome proliferator‐activated receptor‐γ were increased in the FA intestinal tissues with inhibited IL‐2 production. Administration of mExosomes induced Tregs in the intestinal tissues and efficiently suppressed FA in mice. We conclude that the mExosomes can suppress FA in mice through inducing Tregs. The data suggest that the mExosomes have translational potential in the treatment of FA and other allergic disorders. [ABSTRACT FROM AUTHOR]

Background: Skewed T helper (Th)2 response plays a crucial role in the pathogenesis of allergic diseases. The therapeutic efficacy for allergic diseases is unsatisfactory currently. This study aims to regulate the skewed Th2 response with CARsomes. Methods: The CARsome consisted of an epitope of Dermatophagoides farina‐1 (Derf1), a segment of the anti‐DEC205 antibody, the scFv, and an open reading frame of perforin. This fusion protein binds to DEC205 molecule on the surface of exosomes derived from dendritic cells (DC). The effects of CARsome on inducing antigen (Ag)‐specific Th2 cell apoptosis were assessed both in vivo and in vitro. Results: Exposure to CARsomes in the culture induced Ag‐specific Th2 cell apoptosis. Injection of CARsomes through the vein puncture also induced Ag‐specific Th2 cell apoptosis in the lungs of sensitized mice. CARsomes could induce Ag‐specific regulatory T cells. Administration of CARsomes efficiently inhibited experimental allergic airway inflammation. Conclusions: The CARsomes can inhibit allergic airway inflammation by inducing Ag‐specific Th2 cell apoptosis and induce Ag‐specific regulatory T cells. The data suggest that CARsomes have the translational potential to be used to treat allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Background and aims: Radiotherapy is one of the major remedies for the treatment of cancer, including nasopharyngeal carcinoma (NPC). Radioresistance occurs very often in target cells that is a large drawback in cancer treated with radiotherapy. Livin involves the over-growth of cancer cells. This study aims to investigate the role of livin in the radioresistance formation in NPC cells. Methods: NPC cell lines were exposed to small doses of irradiation to establish a cell model of radioresistance, in which the role of livin in the development of radioresistance was evaluated. Results: The expression of livin was observed in NPC cells, which was significantly increased after exposing to small doses of irradiation. A negative correlation was detected between livin and Fas expression in NPC cells. Livin formed a complex with heat shock factor-1 (HSF1, the transcription factor of Fas) in NPC cells after irradiation, which sped up ubiquitination of HSF1. Livin was involved in suppressing Fas expression in NPC cells with radioresistance. Exposure to livin inhibitors prevented radioresistance development and overcame the established radioresistance in NPC cells. Conclusions: Livin expression in NPC cells plays a critical role in the development of radioresistance. Depletion of livin increases the sensitiveness of NPC cells to irradiation. Target therapy against livin may have the translational potential for the treatment of NPC. [ABSTRACT FROM AUTHOR]

Background: The on‐purpose‐modulated dendritic cells (DCs) have shown charming effects on restoring immune regulatory functions in subjects with immune diseases. Objective: This study aims to construct DCs carrying chimerical antigen (Ag) peptides (CAP‐DCs) to induce interleukin (IL)‐17+ inducible Tregs (iTregs) to alleviate food allergy (FA) in a murine model. Methods: In this study, we constructed CAP‐DCs. The CAP is a fusion protein, consisting of a segment of recombinant scFv of anti‐DEC205 antibody and an ovalbumin (OVA) epitope (IC). A murine OVA‐FA model was developed to test the effects of CAP‐DCs on suppressing the allergic response in the intestine. Results: The CAP‐DCs are characterized as that a complex of scFv‐IC is presented on the surface of the cells, moderately express CD80 and CD86 as well as IL‐6, IL‐23, transforming growth factor (TGF)‐β and CCR9. After being passively transferred with CAP‐DCs or injection of scFv‐IC, Ag‐specific IL‐17+ Foxp3+ iTregs were induced in the intestinal lamina propria of FA mice. The iTregs showed immune suppressive effects on Ag‐specific Th2 response. FA mice were adoptively transferred with the CAP‐DCs or scFv‐IC injection, which resulted in a significant decrease in the number of Ag‐specific Th2 cells and suppression of FA response in an Ag‐specific manner. Conclusions and Clinical Relevance: CAP‐DCs can ameliorate FA response by inducing Ag‐specific IL‐17+ Foxp3+ iTregs and suppressing Ag‐specific Th2 response. To generate CAP‐DCs has the translational potential in the treatment of FA. [ABSTRACT FROM AUTHOR]

Survivin is an anti-apoptosis protein that may be associated with the development of eosinophilia; the latter is associated with the pathogenesis of many immune disorders. Here we report that less apoptotic eosinophils (Eos) were induced in those isolated from mice suffering from food allergy (FA) than those from naive mice after treating with cisplatin in vitro. Exposure to cisplatin induced more Fas ligand (FasL) expression in Eos isolated from naive mice than in those of FA mouse. Survivin was detected in the intestinal tissue extracts in much higher amounts in the FA group than in the naive group. Immunohistochemistry showed that epithelial cells were the major source of survivin in the intestine. Exposure to IL-4 or IL-13 up-regulated the expression of survivin in intestinal epithelial cells. Survivin interfered with the expression of FasL in Eos. Inhibition of survivin attenuated the eosinophilia-related inflammation in the intestine. In conclusion, intestinal epithelial cell-produced survivin induced defects in apoptosis in Eos to contribute to eosinophilia in the intestine. Inhibition of survivin can suppress the eosinophilia-related intestinal inflammation. The data suggest that survivin may be a novel target for the treatment of FA. [ABSTRACT FROM AUTHOR]

T helper (Th)2 polarization plays an important role in the pathogenesis of allergic diseases; the underlying mechanism remains to be further investigated. B cell lymphoma protein‐2 like protein‐12 (Bcl2L12) has the anti‐apoptotic function. This study aims to elucidate the contribution of Bcl2L12 to Th2 polarization in patients with allergic rhinitis (AR). In this study, human CD4+ T cells were isolated from blood samples collected from AR patients and healthy control (HC) subjects. The immune response profiles of CD4+ T cells were analyzed by immunologic approaches. The results showed that AR CD4+ T cells (CD4+ T cells collected from AR patients) showed defects of apoptosis. The expression of FasL in AR CD4+ T cells was lower than that of HC CD4+ T cells. Serum IL‐5 levels were negatively correlated with the expression of FasL in AR CD4+ T cells. Exposure of CD4+ T cells to IL‐5 in the culture suppressed the expression of FasL and increased the expression of Bcl2L12. IL‐5 increased the levels of Bcl2L12 in CD4+ T cells, the latter bound to the FasL promoter to prevent FasL gene transcription. Inhibition of Bcl2L12 restored the apoptosis machinery in AR CD4+ T cells. In conclusion, overexpression of Bcl2L12 in CD4+ T cells compromises the apoptosis machinery; the latter can be restored by inhibition of Bcl2L12. BcL2L12 in CD4+ T cells may be a novel target for the treatment of AR and other allergic disorders. CD4+ T cells express Bcl2L12, which restricts FasL expression and induces apoptotic defects in CD4+ T cells. [ABSTRACT FROM AUTHOR]

The article offers a study of 3‐methyl‐4‐nitrophenol (MNP), one of the components of diesel‐exhaust particles which l facilitates development of intestinal allergy Topics include exposure of mice fed with MNP and OVA daily showing that exposure to MNP increased absorption of FITC‐ dextran and induced intestinal epithelial barrier dysfunction and facilitated the development of intestinal allergy and suggests that environmental pollution may contribute to the development of allergic disease.

Interleukin (IL)-10-expressing B cells play a critical role in the immune homeostasis in the body; its regulation has not been fully understood. Micro-RNA (miR)-17-92 cluster has strong regulation in the immunity. This study tests a hypothesis that miR-17-92 cluster suppresses IL-10 expression in B cells. In this study, peripheral B cells were collected from patients with allergic rhinitis (AR). The B cells were treated with specific allergens, dust mite extracts, in the culture. The expressions of miR-17-92 cluster and IL-10 in the culture were assessed by real-time quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. The results showed that the levels of miR-19a, but not the rest of the 5 members (miR-17, miR-18a, miR-19b, miR-20a, and miR-92a), were significantly higher in peripheral B cells from AR patients as than in B cells from healthy participants. Exposure of B cells from AR patients to specific allergen, dust mite extracts, significantly increased the levels if miR-19a and suppressed the expression of IL-10 in B cells. The levels of histone deacetylase 11 and acetylated H3K9 were higher, and the RNA polymerase II and c-Maf (the IL-10 transcription factor) were lower, at the IL-10 promoter locus. In conclusion, miR-19a mediates the allergen-specific immune response-decreased IL-10 expression in B cells. [ABSTRACT FROM AUTHOR]

The causative factors and pathogenesis of food allergy (FA) is not fully understood yet. Cold stress (CS) occurs frequently in human life that influences physiological activities in the body. In this study, we aimed to investigate the chronic CS (CS) effects on promoting the expression of IL-33 in intestinal epithelial cells. CS was carried out by placing mice at 4 °C for 1 h daily for 7 consecutive days. We developed a mouse model used to test the effects of CS on the FA development. We found that, similar to conventional FA mouse model, CS induced the core body temperature to drop markedly in mice, increased intestinal epithelial barrier permeability and facilitated FA development. CS promoted interleukin (IL)-33 expression in intestinal epithelial cells through the adrenocorticotropic hormone (ACTH)/cortisol axis and via inducing the Il33 promoter methylation. CS facilitated the FA development in mice, that could be blocked by depletion of IL-33 expression in intestinal epithelial cells. CS induces IL-33 expression in intestinal epithelial cells to promote Th2 polarization in the intestinal tissues and facilitates FA development. [ABSTRACT FROM AUTHOR]

It is known that the immune tolerance can be naturally established in the intestine, while the mechanism by which the immune tolerance development in the intestine is not fully understood yet. Vasoactive intestinal peptides (VIP) has the immune regulatory functions. This study aims to investigate the role of VIP in the immune tolerance development in the intestine. Intestinal epithelial cell (IEC)-derived exosomes were prepared. The exosomes carried IL-10 and antigen/MHC II complexes. VIP-deficient (VIPd) mice and wild type mice were employed to test the role of VIP in the development of immune tolerance in the intestine. VIPd mice failed to induce type 1 regulatory T cells (Tr1 cells) in the intestine and retarded the establishment of antigen (Ag)-specific immune tolerance. Exposure to VIP in the culture induced IL-10 expression in intestinal epithelial cells (IECs). Exosomes derived from ovalbumin (OVA, used as a specific Ag)/VIP-primed IECs carried IL-10 and OVA/MHC II complexes; these exosomes were designated IL10CARs (IL-10/chimeric antigen receptor-carrying exosomes). IL10CARs could recognize OVA-specific CD4+ T cells and converted OVA-specific CD4± T cells to OVA-specific Tr1 cells. Administration of IL10CARs suppressed experimental food allergy. The data show that IL10CARs are capable of suppressing experimental FA by inducing antigen-specific Tr1 cells, which has the translation potential for FA treatment. [ABSTRACT FROM AUTHOR]

The abnormality of immune regulation plays a critical role in the pathogenesis of cancer; the underlying mechanism has not been fully understood yet. This study aims to investigate the role of cancer specific T helper (Th)2 response in the inhibition of colon cancer (Cca) cell growth. The results showed that with Cca cell (CT26 cell) extracts as an antigen, the Cca-extract specific Th2 response was induced in the Cca-bearing mice. The Cca mass size was significantly reduced, or radically disappeared (5 out of 10; or 50%); the survival rate was markedly improved in mice immunized with Cca-extract, but not in those immunized with another tumor cell (U87 cell) extracts or to bovine serum albumin. The immunization with Cca-extract also induced Cca cell apoptosis and converted the intra-Cca Tregs to T helper (Th) 9 cells. In conclusion, Cca-specific Th2 responses inhibit Cca growth in a mouse model via inducing Cca cell apoptosis and converting intra-Cca Tregs to Th9 cells. [ABSTRACT FROM AUTHOR]

Epithelial barrier integrity is critical to maintain the homeostasis in the body. The regulatory mechanism of the epithelial barrier function has not been fully understood. This study aims to elucidate the role of the TWIK-related potassium channel-1 (Trek1) in the regulation of the epithelial barrier function of the nasal mucosa. In this study, the levels of Trek1 were assessed by real time RT-PCR and Western blotting. The epithelial barrier function of the rat nasal epithelia was evaluated by the Ussing chamber system. The results showed that Trek1 was detected in the human and rat nasal epithelia, which were significantly lower in patients and rats with allergic rhinitis than that in healthy controls. Exposure to the signature T helper 2 cytokine, interleukin (IL)-4, markedly suppressed the expression of Trek1 in the nasal mucosa via up regulating the expression of the histone deacetylase (HDAC)1. The IL-4-induced rat nasal epithelial barrier dysfunction could be blocked by HDAC1 inhibitor (Trichostatin A), or sodium butyrate, or administration of Clostridium Butyricum. We conclude that Trek1 is critical to maintain the nasal epithelial barrier function. [ABSTRACT FROM AUTHOR]

The pathogenesis of some chronic inflammation such as inflammatory bowel disease is unclear. Insulin-like growth factor-1 (IGF1) has active immune regulatory capability. This study aims to investigate into the mechanism by which IGF1 modulates the monocyte (Mo) properties to inhibit immune inflammation in the intestine. In this study, the production of IGF1 by intestinal epithelial cells was evaluated by real time RT-PCR and Western blotting. Mos were analyzed by flow cytometry. A mouse colitis model was created with trinitrobenzene sulfonic acid. The results showed that mouse IECs produced IGF1, which could be up regulated by exposure to CpG-ODN (CpG-oligodeoxynueleotides) in the culture. Culture the CpG-ODN-primed IEC cells and Mos or exposure of Mos to IGF1 in the culture induced the Mos to express IL-10. The IGF1-primed Mos showed the immune suppressive effect on inhibiting the immune inflammation in the mouse colon. In conclusion, the IGF1-primed Mos are capable of suppressing immune inflammation in the intestine. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Dietary obesity is usually characterized by leptin resistance and abnormal lipid metabolism. Lithocarpus polystachyus Rehd.(Sweet Tea) leaf is a kind of Chinese folkloric medicine, and it has been widely used for obesity, diabetes, and hypertension in South China. The present study is aimed at investigating the pharmacological mechanism of the anti-hyperleptinaemia effects of Sweet Tea leaves extract in high fat diet-induced obese rats. Materials and methods: We induced high fat diet obesity for 14weeks to test the corrective effects of three ST doses (75, 150 and 300mg/kg per day) for 8 weeks. At the end of the experiment, body weight, fasting blood glucose and serum lipids, superoxide dismutase (SOD), malondialdehyde (MDA), fasting serum insulin and leptin, C-reactive protein, adiponectin and resistin levels were measured, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was also calculated. mRNA gene expression of PPARγ (peroxisome proliferator-activated receptor γ) and C/EBPα(CCAAT/enhancer-binding protein α) in epididymal adipose tissue of DIO control and experimental groups were evaluated. Results: Sweet Tea leaves extract could significantly decrease the levels of serum lipids, attenuate body weight gain and lower circulatingleptin and insulin levels, ameliorate the state of oxidative stress, raise serum adiponectin, reduce circulating CRP and resistin levels, and depress the expression of PPARγ and C/EBPα in epididymal adipose tissue of obese rats. Conclusion: The present findings suggest that ST can effectively attenuate the leptin resistance at least through anti-hyperlipidemic activity and thus has the therapeutic potential in treating hyperlipidemia and hyperleptinaemia related to dietary obesity. [Copyright &y& Elsevier]

• The frequency of regulatory T cell (Treg) is not reduced in patients with allergic rhinitis (AR). • The immune suppressive function of Treg is impaired in AR patients. • Signal of Toll like receptor is required in maintenance of Treg function. Dysfunction of immune regulatory cells has been recognized in a variety of immune diseases; the underlying mechanism remains to be further investigated. This study aims to investigate the critical role of Toll-like receptor (TLR) signal in the maintenance of function of regulatory T cells (Tregs). In this study, Tregs were isolated from patients with allergic rhinitis (AR) and healthy control (HC) subjects. The role of TLR signal in the maintenance of Treg's function was tested with experiments of cell culture and an AR mouse model. We observed that the immune suppressive function of AR Treg (Tregs isolated from AR patients) was impaired, although the number of peripheral AR Treg was comparable with HC Treg. Expression of transforming growth factor (TGF)-β was lower in AR Tregs than that in HC Tregs that was positively correlated with expression of Mal in Tregs; the latter was lower in AR Tregs as compared to HC Tregs. TGF-β mRNA in Tregs decayed spontaneously in the culture. Activation of Mal counteracted TGF-β decay and maintained the Treg's immune regulatory function. Mal bound Tristetraprolin (TTP) to prevent TTP from inducing TGF-β mRNA decay. Absence of TLR signals resulted in Treg dysfunctional and worsened experimental AR response in a murine model. In conclusion, TLR signal is required in the maintenance of Treg function. Absence of TLR signal may result in Treg dysfunction and immune intolerance. [ABSTRACT FROM AUTHOR]

Highlights • The expression of Bcl2L12 is higher in CD4 + T cells of patients with food allergy. • The CD4 + T cells with higher Bcl2L12 expression are prone to differentiate into Th2 cells. • Bcl2L12 played a crucial role in the induction of food allergy in mice. Abstract The skewed T helper (Th) 2 response plays a central role in the pathogenesis of allergic diseases, while its initiating factors remain elusive. Recent studies indicate that Bcl2 like protein-12 (Bcl2L12) is associated with the Th2-biased inflammation. This study is designed to test a hypothesis that Bcl2L12 plays a critical role in the initiation of allergic response. In this study, peripheral CD4+ T cells were isolated from food allergy (FA) patients and healthy subjects; A mouse FA model was developed to test the role of Bcl2L12 in induction of allergic response in the intestine. The results showed that expression of Bcl2L12 by CD4+ T cells was higher in FA patients and FA mice and positively correlated with expression of Th2 cytokines. CD4+ T cells from FA patients showed a Bcl2L12-dependent tendency to differentiate into Th2 cells. Bcl2L12 played a crucial role in induction of allergic response in the intestine. Physical contact between Bcl2L12 and GATA3 facilitated GATA3 to bind Il4 promoter to promote expression of IL-4. Adoptive transfer with Bcl2L12-deficient CD4+ T cells to Rag2¯/¯ mice did not reconstitute the efficient CD4+ T cell response as the mice could not be induced FA, while Rag2¯/¯ mice received WT CD4+ T cell transfer were induced FA. In conclusion, Bcl2L12 plays a crucial role in the induction of Th2 polarization and allergic response in the intestine. The Bcl2L12 in CD4+ T cells may be a potential target for the treatment of FA. [ABSTRACT FROM AUTHOR]

Eosinophils (Eos) are the canonical effector cells in allergic rhinitis (AR) and many inflammatory diseases. The mechanism of eosinophilia occurring in the lesion sites is not fully understood yet. Twist1 protein (Twist, in short) is an apoptosis inhibitor that also has immune regulatory functions. This study aims to investigate the role of Twist in the pathogenesis of eosinophilia in AR. In this study, surgically removed human nasal mucosal samples were obtained from patients with chronic sinusitis and nasal polyps with AR (the AR group) or without AR (the nAR group). Eos were isolated from the samples by flow cytometry. We found that abundant Eos were obtained from the surgically removed nasal mucosa tissues of both nAR and AR groups. Significantly higher Ras activation was detected in AR Eos than that in nAR Eos. Ras activation was associated with the apoptosis resistance in AR Eos. The Twist (an apoptosis inhibitor) expression was higher in AR Eos, which was positively correlated with the Ras activation status. The sensitization to IgG induced Twist expression in Eos, in which Ras activated the MAPK-HIF-1α pathway, the latter promoted the Twist gene transcription. Twist bound Rac GTPase activating protein-1 to sustain the Ras activation in Eos. Ras activation sustained the apoptosis resistance in Eos. In conclusion, high Ras activation was detected in the AR nasal mucosal tissue-isolated Eos. IgG-sensitization induced Ras activation and Twist expression in Eos, that conferred Eos the apoptosis resistance. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (T H 2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box-binding protein-1 (XBP1) in the induction of the T H 2 cell response through its role in generating TIM4 + DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2-XBP1-TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant T H 2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for T H 2 cell responses by inducing the development of TIM4 + DCs, which depends on the IL-2-XBP1-SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of T H 2 cell-dependent inflammation or allergic diseases.

Rationale : Mast cells play a crucial role in allergic diseases. Yet, the regulation of mast cell bioactivities is not fully understood. This study aims to elucidate the role of B cell lymphoma 2 like protein 12 (Bcl2L12), one of the anti-apoptosis proteins, in regulating mast cell apoptosis. Methods : A food allergy (FA) mouse model was developed to establish mast cell over population in the intestinal tissue. Either compound 48/80 (C48/80) or specific antigens were used to activate mast cells in the intestinal mucosa. Results : After treating with C48/80, apoptosis was induced in mast cells of the intestine of naive control mice, but not in FA mice. The expression of Fas ligand (FasL) was lower in the mast cells of FA mice. Interleukin (IL)-5 was responsible for the suppression of FasL by upregulating the expression of Bcl2L12 in mast cells. Bcl2L12 prevented c-Myc, the major transcription factor of FasL, from binding the FasL promoter to inhibit the expression of FasL in mast cells. Inhibition of Bcl2L12 restored the apoptosis machinery of mast cells in the FA mouse intestine. Conclusions : The apoptosis machinery in mast cells is impaired in an allergic environment. Inhibition of Bcl2L12 restores the apoptosis machinery in mast cells in the FA mouse intestine., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

T helper (Th)2 polarization plays an important role in the pathogenesis of allergic diseases; the underlying mechanism remains to be further investigated. B cell lymphoma protein-2 like protein-12 (Bcl2L12) has the anti-apoptotic function. This study aims to elucidate the contribution of Bcl2L12 to Th2 polarization in patients with allergic rhinitis (AR). In this study, human CD4 + T cells were isolated from blood samples collected from AR patients and healthy control (HC) subjects. The immune response profiles of CD4 + T cells were analyzed by immunologic approaches. The results showed that AR CD4 + T cells (CD4 + T cells collected from AR patients) showed defects of apoptosis. The expression of FasL in AR CD4 + T cells was lower than that of HC CD4 + T cells. Serum IL-5 levels were negatively correlated with the expression of FasL in AR CD4 + T cells. Exposure of CD4 + T cells to IL-5 in the culture suppressed the expression of FasL and increased the expression of Bcl2L12. IL-5 increased the levels of Bcl2L12 in CD4 + T cells, the latter bound to the FasL promoter to prevent FasL gene transcription. Inhibition of Bcl2L12 restored the apoptosis machinery in AR CD4 + T cells. In conclusion, overexpression of Bcl2L12 in CD4 + T cells compromises the apoptosis machinery; the latter can be restored by inhibition of Bcl2L12. BcL2L12 in CD4 + T cells may be a novel target for the treatment of AR and other allergic disorders., (©2019 Society for Leukocyte Biology.)

The Th2-biased inflammation and immune deregulation play a critical role in the pathogenesis of ulcerative colitis (UC). Recent studies indicate that the Bcl2-like protein 12 (Bcl2L12) is associated with immune deregulation of UC. This study aims to investigate the role of Bcl2L12 in the induction of aberrant Th2-biased inflammation. In this study, peripheral blood samples were collected from patients with inflammatory bowel disease. The Th2 cell activities were analyzed by flow cytometry, real-time quantitative RT-PCR, and Western blotting. Mice with Bcl2L12-knockout CD4 + T cells were used in the experiments. The results showed that the expression of Bcl2L12 was detected in peripheral CD4 + T cells, which was significantly higher in UC patients than in healthy subjects. A positive correlation between the expression of Bcl2L12 and Th2 cytokines was detected in CD4 + T cells from UC patients. Naive CD4 + T cells with Bcl2L12 overexpression were prone to differentiate into Th2 cells. Mice with Bcl2L12 deficiency failed to induce the Th2-biased inflammation in the intestine. Bcl2L12 bound GATA3 to form a complex to enhance the binding between GATA3 and the Il4 promoter to enhance the expression of IL-4 in CD4 + T cells. CD4 + T cells with Bcl2L12 overexpression were resistant to apoptosis. In conclusion, the Bcl2L12 is a critical factor in the induction of aberrant Th2 polarization by upregulating Th2 responses and downregulating Th2 cell apoptosis. Bcl2L12 may be a novel therapeutic target in the management of the disorders with Th2-biased inflammation., (Copyright © 2018 by The American Association of Immunologists, Inc.)

The pathogenesis of food allergy (FA) is to be further investigated. Regulatory B cells (B10 cell) play a critical in the maintenance of the homeostasis in the intestine. Deregulation of B10 cell is associated with immune inflammation. Micro RNA (miR) 155 is involved in affecting immune cell function. This study tests a hypothesis that miR-155 affects the B10 cell function to facilitate the initiation of FA. In this study, BALB/c mice were sensitized to ovalbumin (OVA) to induce FA-like inflammation in the intestine. B cells were isolated from the intestine by magnetic cell sorting. The expression of miR-155 and IL-10 in B cells was assessed by real time RT-PCR. The results showed that mice sensitized to OVA showed FA-like inflammation and lower frequency of B10 cell in the intestine. B cells isolated from the intestine of FA mice showed higher levels of miR-155 and lower levels of IL-10. Although all the three T helper (Th)2 cytokines, including interleukin (IL)-4, IL-5 and IL-13, were higher in the serum, only IL-13 was positively correlated with the levels of miR-155 in the intestinal B cells. Exposure to IL-13 in the culture markedly increased the expression of miR-155 and suppressed the expression of IL-10 in B cells. Blocking miR-155 abolished the IL-13-induced IL-10 suppression in B cells and inhibited FA response in mice. In conclusion, miR-155 plays a critical role in the initiation of FA in mice. Blocking miR-155 has therapeutic potential in the treatment of FA., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.