Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. 相似文献
Conclusion: The current study confirmed the significant high mobility group box 1 (HMGB1) was promoted in human nasopharyngeal carcinoma (NPC) tissues by Epstein-Barr virus (EBV) infection, in association with the malignant status of NPC, and promoted the proliferation NPC cells RAGE-dependently. Objectives: The present study was to examine the association of HMGB1 over-expression in human NPC with the EBV-positivity and to determine the regulatory role of HMGB1 on the proliferation of NPC cells in vitro. Methods: Real-time PCR and Western blotting were utilized to examine the HMGB1 expression. EBV infection in CNE-2 cells was performed to investigate the HMGB1 promotion by EBV infection. RNA interference technology was utilized for the RAGE knockout. Results: It was demonstrated that HMGB1 was significantly higher in both mRNA and protein levels in the EBV-positive NPC tissues, in marked association with the malignant status of NPC, and with the LMP1 DNA level in EBV-positive NPC samples. In addition, the MTT assay, growth curve, and the colony forming assay confirmed the promotion by HMGB1 to the proliferation of CNE-2 cells, depending on RAGE. 相似文献
Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. 相似文献
RAGE (receptor for advanced glycation end products) is a multiligand receptor on the cell surface. Ligand-RAGE interactions activate several signal transduction pathways that propagate cellular oxidative stress and inflammatory response. RAGE expressed on the CD4+ T cells has been identified as a central transduction receptor which affects the activation, proliferation, migration and differentiation of the cells. In addition, blockade of RAGE suppressed the development of multiple immune-related disorders mediated by CD4+ T cells. These studies highlight the importance of RAGE and its ligands for CD4+ T cells. This article briefly reviews the role of RAGE and its ligands on the proliferation, migration and differentiation of CD4+ T cells and summarizes the related research progress. 相似文献
S100A9 belongs to the S100 family of calcium‐binding proteins and plays a key role in many inflammatory conditions. Recent studies have found that S100A9 was elevated significantly in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients, and might be a biomarker for fibrotic interstitial lung diseases. However, the exact function of S100A9 in pulmonary fibrosis needs further studies. We performed this study to investigate the effect of S100A9 on human embryo lung fibroblast (HLF) proliferation and production of cytokines and collagen, providing new insights into the possible mechanism. S100A9 promoted proliferation of fibroblasts and up‐regulated expression of both proinflammatory cytokines interleukin (IL)‐6, IL‐8, IL‐1β and collagen type III. S100A9 also induced HLF cells to produce α‐smooth muscle actin (α‐SMA) and receptor for advanced glycation end‐product (RAGE). In addition, S100A9 caused a significant increase in extracellular‐regulated kinase (ERK)1/2 mitogen‐activated protein kinase (MAPK) phosphorylation, while the status of p38 and c‐Jun N‐terminal kinase (JNK) phosphorylation remained unchanged. Treatment of cells with S100A9 also enhanced nuclear factor kappa B (NF‐κB) activation. RAGE blocking antibody pretreatment inhibited the S100A9‐induced cell proliferation, cytokine production and pathway phosphorylation. S100A9‐mediated cell activation was suppressed significantly by ERK1/2 MAPK inhibitor and NF‐κB inhibitor. In conclusion, S100A9 promoted HLF cell growth and induced cells to secret proinflammatory cytokines and collagen through RAGE signalling and activation of ERK1/2 MAPK and NF‐κB pathways. 相似文献
The aim of our study was to investigate the protective effects of Paeoniflorin (PF) against injury induced by AGE-modified bovine serum albumin (AGE-BSA) in human umbilical vein endothelial cells (HUVECs), and to examine the underlying mechanisms of these effects. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine cell viability. Protein expression levels were determined by western blotting. For function-blocking experiments, we used small interfering RNA molecules (siRNA) for function-blocking experiments. At 6 h, we found that 100 μg/mL AGE-BSA reduced the viability of HUVECs. However, pretreatment with PF restored cell viability in a dose-dependent manner. AGE-BSA increased the levels of microtubule-associated protein light chain 3-II (LC3-II) and the receptor for advanced glycation end products (RAGE). Expression of p62 protein was also increased, but not at a statistically significant level. Pretreatment with PF further increased levels of LC3-II and RAGE, but reduced the expression of p62. In cells transfected with Atg5 and RAGE siRNA, cell viability and expression of LC3-II decreased in both the AGE-BSA and PF + AGE-BSA treatments. PF can protect HUVECs from AGE-BSA-induced injury by upregulating autophagy and promoting the completion of autophagy flux. RAGE plays an important role in this autophagic protection effect. 相似文献
Objective: To investigate the expression of high mobility group protein B1 (HMGB1) and its receptor, receptor for advanced glycation end-product (RAGE), in renal cancer tissue and surrounding normal tissue and to analyze the relationship between the expression level of the protein and receptor as well as the clinical pathological characteristics and prognosis in renal cancer patients. Methods: A total of 80 renal carcinoma patients who were surgically treated in our hospital from February 2004 to December 2012 were included in this study. Normal paratumoral tissues were collected as a control. All diagnoses were confirmed with a postoperative pathological examination. All patients had complete pathological data. The expression of HMGB1/RAGE proteins in renal cancer tissue and paratumoral tissue was examined using immunohistochemical methods. Results: The positive expression rate of HMGB1 was 71% in renal cancer tissue, which was significantly higher than that in the paratumoral normal tissue (25%). The positive expression rate of RAGE was 72% in renal cancer tissue, which was significantly higher than that in the paratumoral normal tissue (27%). Further analysis did not indicate a correlation between the positive expression of HMGB1 and RAGE proteins and gender, age and tumor size (P > 0.05), whereas the expression patterns were shown to correlate with tumor differentiation, clinical stage and lymph node metastasis (P < 0.05). The expression of HMGB1 exhibited a significant positive correlation with RAGE level (P < 0.05), the expression of HMGB1/RAGE proteins exhibited a negative correlation with the prognosis of patients, and the five-year survival rate of patients with positive expression was significantly lower than that of patients with negative expression (P < 0.05). Conclusion: HMGB1/RAGE exhibited significantly elevated expression in renal cancer tissues that was closely related to the clinical prognosis of patients; thus, the expression levels may become a new target in the treatment of renal carcinoma. 相似文献
Introduction: High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that promotes inflammation when released extracellularly after cellular activation, stress, damage or death. HMGB1 operates as one of the most intriguing molecules in inflammatory disorders via recently elucidated signal and molecular transport mechanisms. Treatments based on antagonists specifically targeting extracellular HMGB1 have generated encouraging results in a wide number of experimental models of infectious and sterile inflammation. Clinical studies are still to come.
Areas covered: We here summarize recent advances regarding pathways for extracellular HMGB1 release, receptor usage, and functional consequences of post-translational modifications. The review also addresses results of preclinical HMGB1-targeted therapy studies in multiple inflammatory conditions and outlines the current status of emerging clinical HMGB1-specific antagonists.
Expert opinion: Blocking excessive amounts of extracellular HMGB1, particularly the disulfide isoform, offers an attractive clinical opportunity to ameliorate systemic inflammatory diseases. Therapeutic interventions to regulate intracellular HMGB1 biology must still await a deeper understanding of intracellular HMGB1 functions. Future work is needed to create more robust assays to evaluate functional bioactivity of HMGB1 antagonists. Forthcoming clinical studies would also greatly benefit from a development of antibody-based assays to quantify HMGB1 redox isoforms, presently assessed by mass spectrometry methods. 相似文献