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pi3k AND autoimmune

Jing Zhang, Ya-Qin Tan, Ming-Hui Wei, Xiao-Jing Ye, Guan-Ying Chen, Rui Lu, Ge-Fei Du, Gang Zhou
Oral lichen planus (OLP) is a T-cell-mediated autoimmune mucocutaneous disease affected by the interactions among the keratinocytes, CD4(+) T cells and CD8(+) T cells. B7-H1 induced by Toll-like receptors (TLRs), can suppress T cell immune reaction, thereby resulting in immune tolerance. However, the role of TLRs-mediated B7-H1 on keratinocytes in the immune response of OLP is still unknown. The present study showed that TLR4 could induce time-coursed B7-H1 expression on oral keratinocytes, and blocking NF-κB or PI3K/mTOR pathway down-regulated B7-H1 transcriptional expression...
October 20, 2016: Experimental Dermatology
Preeti Vyas, Divya Vohora
Recent findings have publicized phosphoinositide-3-kinases (PI3Ks) as novel therapeutic targets, which are also purported to be involved in the complex pathophysiology of inflammatory and various other diseases. They are recognized to participate in the inflammatory cellular responses by modulating the growth, development and proliferation of various immune cells and hence, affect the release of various cytokines and other inflammatory mediators involved in these manifestations. The review presents a brief synopsis of the PI3K/AKT/mTOR signalling pathway along with the current and future prospects of targeting PI3Ks for various diseases, like malignant, autoimmune, inflammatory, cardiovascular, neurological disorders etc...
October 13, 2016: Current Drug Targets
Yuan Qu, Jing Wu, Jia-Xin Deng, Yu-Ping Zhang, Wan-Yi Liang, Zhen-Lan Jiang, Qing-Hong Yu, Juan Li
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and destruction of the joints as well as an increased risk of cardiovascular disease. RA synovial fibroblasts (RASFs) are involved in the progression of RA and release pro-inflammatory cytokines. On the other hand, microRNAs (miRs) may help control the inflammatory response of immune and non-immune cells. Therefore, our study used lentiviral expression vectors to test the effects of miR-126 overexpression on RASF proliferation and apoptosis...
October 6, 2016: Oncotarget
Shivaprasad H Venkatesha, Kamal D Moudgil
Celastrol, a triterpenoid derived from traditional Chinese medicinal plants, has anti-inflammatory, antioxidant, and anticancer activities. Celastrol has shown preventive/therapeutic effects in experimental models of several chronic diseases. These include, chronic inflammatory and autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and psoriasis), neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis), atherosclerosis, obesity, Type 2 diabetes, and cancer...
2016: Advances in Experimental Medicine and Biology
Weirong Chen, Xiaoxiao Wan, Tobechukwu K Ukah, Mindy M Miller, Subhasis Barik, Alexis N Cattin-Roy, Habib Zaghouani
To contain autoimmunity, pathogenic T cells must be eliminated or diverted from reaching the target organ. Recently, we defined a novel form of T cell tolerance whereby treatment with Ag downregulates expression of the chemokine receptor CXCR3 and prevents diabetogenic Th1 cells from reaching the pancreas, leading to suppression of type 1 diabetes (T1D). This report defines the signaling events underlying Ag-induced chemokine receptor-mediated tolerance. Specifically, we show that the mammalian target of rapamycin complex 1 (mTORC1) is a major target for induction of CXCR3 downregulation and crippling of Th1 cells...
September 26, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ming Xiang, Tingting Liu, Wanyue Tan, Hongyu Ren, Hua Li, Junjun Liu, Hui Cao, Qi Cheng, Xiulan Liu, Hucheng Zhu, Yali Tuo, Jianping Wang, Yonghui Zhang
: The central purpose of this study was to investigate therapeutic effects of the botanical derivative kinsenoside (KD) in experimental autoimmune hepatitis (AIH). Treatment with KD substantially reduced hepatic histopathological damage, induced by lymphocyte infiltration and pro-inflammatory cytokines, in ConA-induced T cell-mediated hepatitis, and in dendritic cells loaded with hepatocellular carcinoma cells (DC/Hepa1-6) induced murine AIH. Interactions between immune cells after KD treatment in AIH were detected by anti-CD8 antibody blocking, CD8(+) T cells sorting, and vaccinated mice with KD-pretreated DCs in a DC/Hepa1-6 model...
September 17, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Meriem Riani, Sébastien Le Jan, Julie Plée, Anne Durlach, Richard Le Naour, Guy Haegeman, Philippe Bernard, Frank Antonicelli
BACKGROUND: The outcome of bullous pemphigoid (BP), the most frequent autoimmune skin-blistering disease, involves matrix metalloproteinase 9 (MMP-9), IL-17, and IL-23 release from infiltrated inflammatory cells. The chemokine CXCL10 has been associated with several autoimmune diseases, but its participation in BP pathophysiology still needs to be clarified. OBJECTIVE: We sought to assess whether BP outcome was associated with different CXCL10 levels and to evaluate the contribution of CXCL10 to the described cytokine/protease inflammatory loop associated with disease outcome...
September 13, 2016: Journal of Allergy and Clinical Immunology
Hannah H Chen, Norman Händel, Joanne Ngeow, James Muller, Michael Hühn, Huei-Ting Yang, Mario Heindl, Roos-Marijn Berbers, Ahmed N Hegazy, Janina Kionke, Lamis Yehia, Ulrich Sack, Frank Bläser, Anne Rensing-Ehl, Julia Reifenberger, Julia Keith, Simon Travis, Andreas Merkenschlager, Wieland Kiess, Christian Wittekind, Lisa Walker, Stephan Ehl, Stefan Aretz, Michael L Dustin, Charis Eng, Fiona Powrie, Holm H Uhlig
BACKGROUND: Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. OBJECTIVES: Because regulation of the phosphoinositide 3-kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]). METHODS: Patients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3)(+) Treg cell levels, and phenotype...
June 18, 2016: Journal of Allergy and Clinical Immunology
Xu Zhang, Na Li, Han Shao, Yan Meng, Liping Wang, Qian Wu, Ying Yao, Jinbao Li, Jinjun Bian, Yan Zhang, Xiaoming Deng
Inflammatory diseases such as sepsis and autoimmune colitis, characterized by an overwhelming activation of the immune system and the counteracting anti-inflammatory response, remain a major health problem in worldwide. Emerging evidence suggests that methane have a protective effect on many animal models, like ischaemia reperfusion injury and diabetes-associated diseases. Whether methane could modulating inflammatory diseases remains largely unknown. Here we show that methane-rich saline (MS) ip treatment (16 ml/kg) alleviated endotoxin shock, bacteria-induced sepsis and dextran-sulfate-sodium-induced colitis in mice via decreased production of TNF-α and IL-6...
2016: Scientific Reports
Katie A Lloyd, Andrew R Moore, Bryony N Parsons, Adrian O'Hara, Malcolm Boyce, Graham J Dockray, Andrea Varro, D Mark Pritchard
BACKGROUND AND AIMS: Elevated circulating concentrations of the hormone gastrin contribute to the development of gastric adenocarcinoma and types-1 and 2 gastric neuroendocrine tumors (NETs). MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate proteins which in turn influence various biological processes. We hypothesised that gastrin induces the expression of specific gastric miRNAs within CCK2 receptor (CCK2R) expressing cells and that these mediate functionally important actions of gastrin...
June 14, 2016: Oncotarget
Alexandra Kitz, Marine de Marcken, Anne-Sophie Gautron, Mitja Mitrovic, David A Hafler, Margarita Dominguez-Villar
Foxp3(+) regulatory T cells (Tregs) exhibit plasticity, which dictates their function. Secretion of the inflammatory cytokine IFNγ, together with the acquisition of a T helper 1 (Th1)-like effector phenotype as observed in cancer, infection, and autoimmune diseases, is associated with loss of Treg suppressor function through an unknown mechanism. Here, we describe the signaling events driving the generation of human Th1-Tregs. Using a genome-wide gene expression approach and pathway analysis, we identify the PI3K/AKT/Foxo1/3 signaling cascade as the major pathway involved in IFNγ secretion by human Tregs...
August 2016: EMBO Reports
Emily R Mercadante, Ulrike M Lorenz
Conventional T (Tcon) cells are crucial in shaping the immune response, whether it is protection against a pathogen, a cytotoxic attack on tumor cells, or an unwanted response to self-antigens in the context of autoimmunity. In each of these immune settings, regulatory T cells (Tregs) can potentially exert control over the Tcon cell response, resulting in either suppression or activation of the Tcon cells. Under physiological conditions, Tcon cells are able to transiently overcome Treg-imposed restraints to mount a protective response against an infectious threat, achieving clonal expansion, differentiation, and effector function...
2016: Frontiers in Immunology
Xiang Hu, Chaofeng Han, Jing Jin, Kewei Qin, Hua Zhang, Tianliang Li, Nan Li, Xuetao Cao
Interleukin-10 (IL-10) plays a central role in regulation of intestinal mucosal homeostasis and prevention of inflammatory bowel disease (IBD). We previously reported that CD11b(hi) regulatory dendritic cells (DCs) can produce more IL-10, and CD11b can negatively regulate Toll-like receptors (TLRs)-induced inflammatory responses in macrophages. However whether CD11b and its signaling can control autoimmunity via IL-10 production remains unclear. Here we found that CD11b deficient (Itgam(-/-)) mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, with more tumor necrosis factor α (TNF-α) while less IL-10 production...
2016: Scientific Reports
Youjun Xiao, Maohua Shi, Qian Qiu, Mingcheng Huang, Shan Zeng, Yaoyao Zou, Zhongping Zhan, Liuqin Liang, Xiuyan Yang, Hanshi Xu
Piperlongumine (PLM) is a natural product from the plant Piper longum that inhibits platelet aggregation, atherosclerosis plaque formation, and tumor cell growth. It has potential value in immunomodulation and the management of autoimmune diseases. In this study, we investigated the role of PLM in regulating the differentiation and maturation of dendritic cells (DCs), a critical regulator of immune tolerance, and evaluated its clinical effects in a rheumatoid arthritis mouse model. We found that PLM treatment reduced LPS-induced murine bone marrow-derived DC maturation, characterized by reduced expression of CD80/86, secretion of MCP-1, IL-12p70, IL-6, TNFα, IFN-γ, and IL-23, and reduced alloproliferation of T cells; however, PLM does not affect cell differentiation...
June 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Yejin Kim, Tae Wan Kim, Yun Seong Park, Eui Man Jeong, Dong-Sup Lee, In-Gyu Kim, Hum Chung, Young-Il Hwang, Wang Jae Lee, Hyeong Gon Yu, Jae Seung Kang
IL-22 is a pro- and anti-inflammatory cytokine that is mainly produced by T cells and NK cells. Recent studies have reported the increased number of IL-22 producing T cells in patients with autoimmune noninfectious uveitis; however, the correlation between IL-22 and uveitis remains unclear. In this study, we aimed to determine the specific role of IL-22 and its receptor in the pathogenesis of uveitis. Serum concentration of IL-22 was significantly increased in uveitis patients. IL-22Rα was expressed in the retinal pigment epithelial cell line, ARPE-19...
2016: PloS One
H S Liu, J Zhang, J-L Guo, C Y Lin, Z-W Wang
BACKGROUND: Myocarditis, characterized by myocyte necrosis, fibrosis, and degeneration with mononuclear cell infiltration, always causes heart failure in patients. Phosphoinositide 3-kinase (PI3K) is a pivotal kinase known to regulate inflammatory responses in cardiac diseases. Although previous research has suggested that PI3K was involved in cardiac diseases such as myocardial infarction, it is still unclear whether the inhibition of PI3K is essential for the treatment of myosin-induced myocarditis...
January 2016: Current Research in Translational Medicine
Yun-Jung Lee, Tae Joon Won, Kyeong Eun Hyung, Ye Won Jang, Soo Jeong Kim, Do Ik Lee, So-Young Park, Kwang Woo Hwang
T cells play an important role in adaptive immune responses that destroy pathogens or infected cells. Therefore, regulation of T cell activity is important in various diseases, such as autoimmune diseases, hypersensitivity, and cancer. The conjugation of small ubiquitin-related modifier (SUMO) is a post-translational protein modification that regulates activity, stability, and subcellular translocation of target proteins. In this study, CD8(+) T cells overexpressing SUMO2 showed greater proliferation and cytotoxic activity against tumor cells in the presence of IL-6 than wild-type CD8(+) T cells in vitro...
May 2016: Archives of Pharmacal Research
N A Zwang, R Zhang, S Germana, M Y Fan, W D Hastings, A Cao, L A Turka
Phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated (MEK) signaling are central to the survival and proliferation of many cell types. Multiple lines of investigation in murine models have shown that control of the PI3K pathway is particularly important for regulatory T cell (Treg) stability and function. PI3K and MEK inhibitors are being introduced into the clinic, and we hypothesized that pharmacologic inhibition of PI3K, and possibly MEK, in mixed cultures of human mononuclear cells would preferentially affect CD4(+) and CD8(+) lymphocytes compared with Tregs...
September 2016: American Journal of Transplantation
Zhaoliang Su, Pan Zhang, Ying Yu, Hongxiang Lu, Yanfang Liu, Ping Ni, Xiaolian Su, Dan Wang, Yueqin Liu, Jia Wang, Huiling Shen, Wenlin Xu, Huaxi Xu
Macrophages can be reprogramming, such as the classical activated macrophage, M1 or alternative activated macrophages, M2 phenotype following the milieu danger signals, especially inflammatory factors. Macrophage reprogramming is now considered as a key determinant of disease development and/or regression. Experimental autoimmune myocarditis (EAM) is characterized by monocytes/macrophage infiltration, Th17 cells activation and inflammatory factors producing such as high mobility group box 1 (HMGB1). Whether infiltrated macrophages could be reprogramming in EAM? HMGB1 was associated with macrophage reprogramming? Our results clearly demonstrated that infiltrated macrophage was reprogrammed towards a proinflammatory M1-like phenotype and cardiac protection by monocytes/macrophages depletion or HMGB1 blockade in EAM; in vitro, HMGB1 facilitated macrophage reprogramming towards M1-like phenotype dependent on TLR4-PI3Kγ-Erk1/2 pathway; furthermore, the reprogramming M1-like macrophage promoted Th17 expansion...
2016: Scientific Reports
L Aragoneses-Fenoll, M Montes-Casado, G Ojeda, Y Y Acosta, J Herranz, S Martínez, C Blanco-Aparicio, G Criado, J Pastor, U Dianzani, P Portolés, J M Rojo
Class IA phosphoinositide 3-kinases (PI3Ks) are essential to function of normal and tumor cells, and to modulate immune responses. T lymphocytes express high levels of p110α and p110δ class IA PI3K. Whereas the functioning of PI3K p110δ in immune and autoimmune reactions is well established, the role of p110α is less well understood. Here, a novel dual p110α/δ inhibitor (ETP-46321) and highly specific p110α (A66) or p110δ (IC87114) inhibitors have been compared concerning T cell activation in vitro, as well as the effect on responses to protein antigen and collagen-induced arthritis in vivo...
April 15, 2016: Biochemical Pharmacology
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