IL-6–dependent spontaneous proliferation is required for the induction of colitogenic IL-17–producing CD8+ T cells

We propose a novel role for interleukin (IL) 6 in inducing rapid spontaneous proliferation (SP) of naive CD8+ T cells, which is a crucial step in the differentiation of colitogenic CD8+ T cells. Homeostasis of T cells is regulated by two distinct modes of cell proliferation: major histocompatibility complex/antigen–driven rapid SP and IL-7/IL-15–dependent slow homeostatic proliferation. Using our novel model of CD8+ T cell–dependent colitis, we found that SP of naive CD8+ T cells is essential for inducing pathogenic cytokine-producing effector T cells. The rapid SP was predominantly induced in mesenteric lymph nodes (LNs) but not in peripheral LNs under the influence of intestinal flora and IL-6. Indeed, this SP was markedly inhibited by treatment with anti–IL-6 receptor monoclonal antibody (IL-6R mAb) or antibiotic-induced flora depletion, but not by anti–IL-7R mAb and/or in IL-15–deficient conditions. Concomitantly with the inhibition of SP, anti–IL-6R mAb significantly inhibited the induction of CD8+ T cell–dependent autoimmune colitis. Notably, the transfer of naive CD8+ T cells derived from IL-17−/− mice did not induce autoimmune colitis. Thus, we conclude that IL-6 signaling is crucial for SP under lymphopenic conditions, which subsequently caused severe IL-17–producing CD8+ T cell–mediated autoimmune colitis. We suggest that anti–IL-6R mAb may become a promising strategy for the therapy of colitis

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells

Background: Neurotransmitters, including substance P (SP) and neurokinin A (NKA), are widely distributed in both the central and peripheral nervous system and their receptors, neurokinin-1 receptor (NK1R) and neurokinin-2 receptor (NK2R), are expressed on immune cells. However, the role of the NKA-NK2R axis in immune responses relative to the SP-NK1R signaling cascade has not been elucidated. Objective: We sought to examine the effect of neuropeptide signaling through NK1Rand NK2R on antigen presentation by dendritic cells (DCs) and the subsequent activation of effector Th cells. Methods: Expression levels of NK1R, NK2R, HLA-class II and costimulatory molecules of human MoDCs and cytokine production by birch pollen antigen-specific CD4+ T cells cocultured with MoDCs in the presence of NK1R and NK2R antagonists were evaluated by quantitative RT-PCR, flow cytometry or ELISA. NK1R and NK2R expression in the lung of patients with asthma and hypersensitivity pneumonitis was evaluated by immunohistochemistry. Results: Human MoDCs significantly upregulated NK2R and NK1R expression in response to poly I:C stimulation in a STAT1-dependent manner. Both NK2R and NK1R were expressed on alveolar macrophages and lung DCs from patients with asthma and pneumonitis hypersensitivity. Surface expression levels of HLA-class II and costimulatory molecules on DCs were modulated by NK1R or NK2R antagonists. Activation of birch pollen-derived antigen-specific CD4+ T cells and their production of cytokines including IL-4 and IFN-γ as well as IL-12 production by MoDCs, were suppressed by blocking NK1R or NK2R after in vitro antigen stimulation. Conclusions: NK1R- and NK2R-mediated neuropeptide signaling promotes both innate and acquired immune responses through activation of human DCs

Fermiology of a topological line-nodal compound CaSb2 and its implication to superconductivity: angle-resolved photoemission study

We performed angle-resolved photoemission spectroscopy with micro-focused beam on a topological line-nodal compound CaSb2 which undergoes a superconducting transition at the onset Tc~1.8 K, to clarify the Fermi-surface topology relevant to the occurrence of superconductivity. We found that a three-dimensional hole pocket at the G point is commonly seen for two types of single-crystalline samples fabricated by different growth conditions. On the other hand, the carrier-doping level estimated from the position of the chemical potential was found to be sensitive to the sample fabrication condition. The cylindrical electron pocket at the Y(C) point predicted by the calculations is absent in one of the two samples, despite the fact that both samples commonly show superconductivity with similar Ts's. This suggests a key role of the three-dimensional hole pocket to the occurrence of superconductivity, and further points to an intriguing possibility to control the topological nature of superconductivity by carrier tuning in CaSb2.Comment: 7 pages, 3 figure

1α,25(OH)2D3 downregulates gene expression levels of muscle ubiquitin ligases MAFbx and MuRF1 in human myotubes

Clinical trials involving in patients with osteoporosis have reported that activated vitamin D3 (1α,25(OH)2D3, calcitriol) can prevent falling by acting on the skeletal muscles. However, pharmacological mechanisms of 1α,25(OH)2D3 with respect to skeletal muscle hypertrophy or atrophy are still poorly understood. Therefore, we examined changes in the expression of several related genes in human myotubes to test whether 1α,25(OH)2D3 influences hypertrophy and atrophy of skeletal muscle. Myotubes treated with 1α,25(OH)2D3 increased interleukin-6 (IL-6) expression and inhibited expression of tumor necrosis factor alpha (TNF-α), whereas the expression of insulin-like growth factor-1 (IGF-1) that is involved in muscle hypertrophy was not affected. However, 1α,25(OH)2D3 treatment significantly inhibited the expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1), ubiquitin ligases involved in muscle atrophy. The analysis of pathways using microarray data suggested that 1α,25(OH)2D3 upregulates AKT-1 by inhibiting the expression of protein phosphatase 2 (PP2A), a phosphatase acting on AKT-1, in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, thereby inhibiting the expression of ubiquitin ligases. Thus, this study showed that 1α,25(OH)2D3 might have an inhibitory effect on the expression of MAFbx and MuRF1 in skeletal muscle and a suppressive effect on muscle degradation in patients with osteoporosis

Effects of an educational intervention on oral hygiene and self-care among people with mental illness in Japan: a longitudinal study

Abstract Background The oral hygiene of patients with a mental illness is an important concern in psychiatric care, and it is necessary to increase the level of self-care among these patients. In this study, we administered an oral care questionnaire to people with mental illness in Japan and compared their answers before (baseline) and at 1 week and 1, 3 and 6 months after they participated in an educational program. Methods The questionnaire was distributed to 390 patients. It included questions about age, education, income, between-meal snacks, number of teeth, frequency of tooth brushing, and other items. The educational program was developed for the purposes of improving self-care. Results Before the program, the proportion of male patients who had had a mental illness for ≥ 10 years was significantly higher among those patients who did not brush their teeth before bed. In addition, such patients did not have primary care dentists, and a significantly higher proportion of male patients, compared with female patients, did not undergo routine dental checkups more than once per year. The educational program resulted in an improvement in the use of fluoride toothpaste from baseline to 6 months after the intervention (p = 0.001). The daily use of interdental brushes or floss was significantly different 6 months after the intervention. Conclusions Male and long-term inpatients need oral hygiene instructions. Our educational program showed the effects of using oral hygiene tools. Future studies should include a control group to measure the impact of the educational program

Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs.

We have previously described a method for adoptive immunotherapy of cancer based on antigen-specific Th1 cells. However, efficient induction of anti-tumor responses using Th1 cells remains a formidable challenge, especially for MHC class II-negative tumors. In the present study, we sought to develop a novel strategy to eradicate established tumors of the MHC class II-negative, ovalbumin (OVA)-expressing EG-7 cells. Tumor-bearing mice were intradermally treated with OVA-specific Th1 cells, combined with the model tumor antigen (OVA), near the tumor-draining lymph node (DLN). We found that tumor growth was significantly inhibited by this strategy and 50–60% of tumor-bearing mice were completely cured. Tumor eradication was crucially dependent on the generation of OVA/H-2Kb-specific CTLs in the tumor DLNs and tumor site. The injected Th1 cells were mainly distributed in tumor DLNs, where they vigorously proliferated and enhanced the activation of dendritic cells. Strikingly, we also found that the accumulation of CD4+CD25+ regulatory T cells (Tregs) was significantly inhibited in tumor DLNs by Th1 cell adjuvant therapy and this abrogation was associated with IFN secreted by Th1 cells. These results identify Th1 cell adjuvant therapy combined with tumor vaccination as a novel approach to the treatment of human cancer

3-Methylcholanthrene-induced transforming growth factor-β-producing carcinomas, but not sarcomas, are refractory to regulatory T cell-depletion therapy

Regulatory T cell (Treg) is one of the major immunosuppressors in tumor-bearing hosts. Although Treg-depletion therapy has been shown to induce a complete cure in tumor-bearing mice, this is not always successful treatment. Using 3-methylcholanthrene (MCA)-induced primary mouse tumors, we examined the distinct regulation of Treg-mediated immunosuppression between carcinomas and sarcomas. We demonstrated that the numbers of Tregs were greatly increased in SCC-bearing mice compared with sarcoma-bearing mice. This appeared to be because SCC produced higher levels of active TGF-β, which is essential for inducing Tregs, compared with sarcoma. Moreover, SCC, but not sarcomas were refractory to Treg-depletion therapy by anti-CD25 mAb administration. The refractoriness of SCC against Treg-depletion therapy was due to the rapid recovery of Tregs in SCC-bearing mice compared with sarcoma-bearing mice. However, combination treatment of anti-TGF-β mAb with anti-CD25 mAb caused a significant reduction of Treg recovery and induced a complete cure in SCC-bearing mice. Thus, we first demonstrated the refractoriness of mouse carcinoma against Treg-depletion therapy using anti-CD25 mAb administration. We also proposed a novel Treg-blocking combination therapy using anti-CD25 mAb and anti-TGF-β mAb to induce a complete cure of tumor-bearing hosts

Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b+CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of human leukocyte antigen (HLA)-DR, and an attenuated T cell-stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR on CD14+ monocyte-derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL-6-mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL-6-mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL-6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients

IL-11 induces differentiation of myeloid-derived suppressor cells through activation of STAT3 signalling pathway

Myeloid-derived suppressor cells (MDSCs) are immune negative regulators in the tumour microenvironment. Interleukin (IL)-11, a member of IL-6 family cytokines, functions through the unique receptor IL-11 receptor α coupled with the common signal transducer gp130. IL-11-gp130 signalling causes activation of the JAK/STAT3 pathway. IL-11 is highly upregulated in many types of cancers and one of the most important cytokines during tumourigenesis and metastasis. However, the precise effect of IL-11 on differentiation into MDSCs is still unknown. Here, we found that CD11b+CD14+ monocytic MDSCs were generated from peripheral blood mononuclear cells (PBMCs) of healthy donors in the presence of IL-11. IL-11-conditioned PBMCs induced higher expression of immunosuppressive molecules such as arginase-1. A reduction of T-cell proliferation was observed when MDSCs generated in the presence of IL-11 were co-cultured with CD3/CD28-stimulated, autologous T cells of healthy donors. Culture of normal PBMCs with IL-11 led to STAT3 phosphorylation and differentiation into MDSCs via STAT3 activation. We confirmed expressions of both IL-11 and phosphorylated STAT3 in tumour tissues of colorectal cancer patients. These findings suggest that monocytic MDSCs may be induced by IL-11 in the tumour microenvironment. Thus, IL-11-mediated regulation in functional differentiation of MDSCs may serve as a possible target for cancer immunotherapy