Jiang-Qi Liu

TSP1-producing B cells show immune regulatory property and suppress allergy-related mucosal inflammation

Specific immunotherapy (SIT) is the only specific remedy for the treatment of allergic diseases currently. B cells are important immune cells in the immunity. The role of B cells in immune regulatory activities has not been fully understood yet. This study aims to elucidate the role of the thrombospondin (TSP)1-producing B cells in the immune regulatory role of SIT. The results showed that after SIT, the frequency of CD35+ B cells was increased in the intestine of mice with food allergy. The CD35+ B cells expressed TSP1 after exposure to specific antigens. Co-culture with the TSP1-producing CD35+ B cells decreased the levels of CD80/CD86 in dendritic cells; the cells convert naïve CD4+ T cells to regulatory T cells to inhibit allergic inflammation in the intestine.

Insulin-like growth factor-1 endues monocytes with immune suppressive ability to inhibit inflammation in the intestine

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.

Thrombospondin-1 (TSP1)-producing B Cells Restore Antigen (Ag)-specific Immune Tolerance in an Allergic Environment

Background: The generation of tolerogenic dendritic cells (TolDCs) in an allergic environment is refractory. Results: Administration of IL-13 antagonists increases TolDCs in an allergic environment. Conclusion: Blocking IL-13 in an allergic environment facilitates the generation of TolDCs. Significance: Using IL-13 antagonists has the potential to enhance the therapeutic effect of the allergic diseases. Restoration of the antigen (Ag)-specific immune tolerance in an allergic environment is refractory. B cells are involved in immune regulation. Whether B cells facilitate the generation of Ag-specific immune tolerance in an allergic environment requires further investigation. This paper aims to elucidate the mechanism by which B cells restore the Ag-specific immune tolerance in an allergic environment. In this study, a B cell-deficient mouse model was created by injecting an anti-CD20 antibody. The frequency of tolerogenic dendritic cell (TolDC) was assessed by flow cytometry. The levels of cytokines were determined by enzyme-linked immunosorbent assay. The expression of thrombospondin-1 (TSP1) was assessed by quantitative real-time RT-PCR, Western blotting, and methylation-specific PCR. The results showed that B cells were required in the generation of the TGF-β-producing TolDCs in mice. B cell-derived TSP1 converted the latent TGF-β to the active TGF-β in DCs, which generated TGF-β-producing TolDCs. Exposure to IL-13 inhibited the expression of TSP1 in B cells by enhancing the TSP1 gene DNA methylation. Treating food allergy mice with Ag-specific immunotherapy and IL-13 antagonists restored the generation of TolDCs and enhanced the effect of specific immunotherapy. In conclusion, B cells play a critical role in the restoration of specific immune tolerance in an allergic environment. Blocking IL-13 in an allergic environment facilitated the generation of TolDCs and enhanced the therapeutic effect of immunotherapy.

Trek1 contributes to maintaining nasal epithelial barrier integrity

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. Electronic supplementary material The online version of this article (doi:10.1038/srep09191) contains supplementary material, which is available to authorized users.

Regulation of TWIK-related potassium channel-1 (Trek1) restitutes intestinal epithelial barrier function

The disruption of epithelial barrier integrity is an important factor in the pathogenesis of various immune disorders. However, the restitution of the compromised barrier functions is difficult. This study investigates the regulation of TWIK-related potassium channel-1 (Trek1) in the restitution of intestinal epithelial barrier functions. The human colon epithelial cell line T84 was cultured in monolayers and used to observe epithelial barrier functions in vitro. An intestinal allergy mouse model was created. Cytokine levels were determined by enzyme-linked immunosorbent assay and western blotting. The results showed that Trek1 deficiency induced T84 monolayer barrier disruption. Allergic responses markedly suppressed the expression of Trek1 in the intestinal epithelia via activating the mitogen-activated protein kinase pathways and increasing the expression of histone deacetylase-1. The inhibition of histone deacetylase-1 by sodium butyrate or the administration of a butyrate-producing probiotic (Clostridium butyricum) restored the intestinal epithelial barrier functions and markedly enhanced the effect of antigen-specific immunotherapy. The data suggest that Trek1 is required for the maintenance of intestinal epithelial barrier integrity. Allergic responses induce an insufficiency of Trek1 expression in the intestinal epithelia. Trek1 expression facilitates the restoration of intestinal epithelial barrier functions in an allergic environment.

Tumor-specific Th2 responses inhibit growth of CT26 colon-cancer cells in mice via converting intratumor regulatory T cells to Th9 cells

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.

Inhibition of squamous cancer growth in a mouse model by Staphylococcal enterotoxin B-triggered Th9 cell expansion.

Currently, therapy for squamous cancer (SqC) is unsatisfactory. Staphylococcal enterotoxin B (SEB) has strong immune regulatory activity. This study tests the hypothesis that SEB enforces the effect of immunotherapy on SqC growth in a mouse model. C3H/HeN mice and the SqC cell line squamous cell carcinoma VII were used to create an SqC mouse model. Immune cell assessment was performed by flow cytometry. Real-time RT-PCR and western blotting were used to evaluate target molecule expression. An apoptosis assay was used to assess the suppressive effect of T helper-9 (Th9) cells on the SqC cells. The results showed that immunotherapy consisting of SEB plus SqC antigen significantly inhibited SqC growth in the mice. The frequency of Th9 cells was markedly increased in the SqC tissue and mouse spleens after treatment. SEB markedly increased the levels of signal transducer and activator of transcription 5 phosphorylation and the expression of histone deacetylase-1 (HDAC1) and PU.1 (the transcription factor of the interleukin 9 (IL-9) gene) in CD4+ T cells. Exposure to SqC-specific Th9 cells markedly induced SqC cell apoptosis both in vitro and in vivo. In conclusion, the administration of SEB induces Th9 cells in SqC-bearing mice, and theseTh9 cells inhibit SqC growth.

Histone acetyltransferease p300 modulates TIM4 expression in dendritic cells

TIM4 (T cell immunoglobulin mucin domain molecule-4) plays a critical role in the initiation of skewed T helper (Th) 2 polarization. The factors regulating TIM4 expression are unclear. This study tests a hypothesis that p300 and STAT6 (signal transducer and activator transcription-6) regulates TIM4 expression in dendritic cells (DC). In this study, a food allergy mouse model was developed with ovalbumin (a specific antigen) and cholera toxin (CT; an adjuvant). The chromatin immunoprecipitation assay was performed to evaluate the chromatin changes at TIM4 and STAT6 promoters. The TIM4 expression was evaluated by real time RT-PCR and Western blotting. The results showed that high levels of p300 and TIM4 were detected in the intestinal DCs of mice with intestinal allergy. p300 is involved in the CT-induced TIM4 expression in DCs. p300 interacts with the chromatin at the TIM4 promoter locus in DCs isolated from allergic mice. CT increases p300 expression to regulate STAT6 levels in DCs. STAT6 mediates the CT-induced TIM4 expression in DCs. In conclusion, p300 and STAT6 mediate the microbial product CT-induced TIM4 expression in DCs.

TIM4-TIM1 interaction modulates Th2 pattern inflammation through enhancing SIRT1 expression

Skewed T helper 2 (Th2)-cell polarization plays a critical role in the pathogenesis of allergic inflammations; however, the underlying mechanisms require further elucidation. The aim of the present study was to investigate the mechanisms through which the interaction between T-cell immunoglobulin and mucin domain (TIM)4 and TIM1 regulates the expression of silent information regulator 1 (SIRT1) in Th2 cells, and the role of SIRT1 in Th2-cell polarization during nasal allergic inflammation. The results demonstrated that TIM4 expression by splenic dendritic cells was increased in mice with allergic rhinitis, and the TIM4̸TIM1 interaction promoted CD4+ T cells to express SIRT1 during allergic inflammation via enhancing phosphoinositide 3-kinase/Akt phosphorylation. SIRT1 then facilitated CD4+ T-cell proliferation through downregulating the expression of Fas ligand, caspase-3 and p53 in mice with nasal allergic inflammation. In conclusion, the interaction of TIM4̸TIM1 was found to promote Th2-cell proliferation through enhancing SIRT1 expression in mice with nasal allergic rhinitis.

Dust mite allergen, glutathione S-transferase, induces T cell immunoglobulin mucin domain-4 in dendritic cells to facilitate initiation of airway allergy.

Allergens from dust mites play a critical role in the pathogenesis of airway allergy. The mechanism by which dust mite allergens induce allergic diseases is not fully understood yet.