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关键词： IBD mouse models   arthritis   ileitis   transcriptomics   tumor necrosis factor  

摘要： BACKGROUND:Tumor necrosis factor (TNF) is a pleiotropic cytokine that plays a critical role in the pathogenesis of immune-mediated diseases including inflammatory bowel disease (IBD). The stability of its mRNA transcript, determined in part by destabilizing sequences in its AAUU repeats (ARE) gene region, is an important regulator of its tissue and systemic levels. A deletion in the ARE region of the gene resulted in IBD and arthritis in mice and pigs, supporting a critical role for the cytokine in human IBD and several human arthritides. A mutation in the same area of the mouse genome by Genentech scientists (T.Y., M.K.) resulted in a similar but not identical phenotype. METHODS:Here, we compare histopathological, cellular, and molecular features of the strains and propose reasons for their distinct phenotypes. First, while homozygous TNFΔARE mice develop severe arthritis and die after weaning, homozygous Genentech TNFΔARE (ΔG/ΔG) mice have normal lifespans, and males are often fertile. RESULTS:We found that while the ileitic phenotype had peaked at 12 weeks of age in all mice, colitis progressed mostly after 20 weeks of age in heterozygous mice. Their variably penetrant arthritic phenotype progressed mostly after 20 weeks, also in heterozygous mice from both strains. There was expansion of central memory T and B cells in lymphoid organs of TNF-overproducing strains and their transcriptional profile shared well-known pathogenetic pathways with human IBD. Finally, we found differences in the mutated sequences within the ARE regions of the TNF gene and in their microbiota composition and genetic background. These differences likely explain their phenotypic differences. CONCLUSIONS:In summary, we describe a different strain of TNF-overproducing mice with an overlapping, yet not identical phenotype, which may have differential applications than the original strain.

摘要： Patients with renal graft failure can develop human leukocyte antigen (HLA) sensitization when returning to dialysis. There is no consensus on which factors could be associated with an increased risk of this kind of sensitization after graft loss. To try to identify some of these factors, a retrospective observational study was performed in our center. Demographic and transplant-related data were collected: HLA mismatches, changes in calculated panel reactive antibody percentage over time, the immunosuppression withdrawal schedule during the first year on hemodialysis (HD), among others. Patients who developed anti-HLA antibodies after 1 year on HD had a greater number of total HLA mismatches (4.15 ± 1.3 vs 3.3 ± 1.1; P = .001), HLA-DR (1.35 ± 0.7 vs 0.7 ± 0.6; P = .001) and HLA-A mismatches (1.70 ± 0.5 vs 1.27 ± 0.7; P = .004) than patients who never developed anti-HLA antibodies. When we only analyzed patients who develop ≥98% calculated panel reactive antibody versus those who persist without anti-HLA antibodies, these differences were more evident (5.2 ± 1.1 MM vs 3.3 ± 1.1 MM; P < .001). The timing of discontinuation of immunosuppression did not influence sensitization. Thus, we have observed that HLA mismatches influence HLA sensitization after graft failure at least during the first year on HD. This study supports the importance of prioritizing HLA matching in patients who may require >1 graft over the years and being aware of the potential importance of HLA mismatches on sensitization on HD.

关键词： Chronic rhinosinusitis   Interleukin-17A   Nasal polyps   Regulatory T cell  

摘要： During nasal polyp (NP) development, activated T cells differentiate into T helper (Th) 1, Th2, and Th17 cells. Additionally, regulatory T cells (Tregs) that have an immune suppressive function are involved in the pathophysiology of chronic rhinosinusitis (CRS) with NP (CRSwNP). Tregs can act as effector cells that produce inflammatory cytokines, such as interleukin (IL)-17A. We sought to identify the cellular expression of IL-17A and Treg markers in sinonasal tissue from CRSwNP patients and to investigate whether Tregs are involved in IL-17A secretion. The uncinate process (UP) and NP tissues were harvested from patients with CRSwNP, CRS without NP (CRSsNP), and normal controls. Expression of IL-17A and Foxp3 in each group was observed with immunohistochemistry and immunofluorescence. Expression of IL-17A in Treg was evaluated by flow cytometry of single cells isolated from sinonasal tissues. UP tissue from controls (n = 17), UP from CRSsNP (n = 24), and UP (n = 19) and NP (n = 29) from CRSwNP were obtained. The percentage of Foxp3+ cells was higher in CRS tissues compared with normal controls. IL-17A+ cells were most increased in NP tissues from CRSwNP patients. Expression of IL-17A in some Foxp3+ cells was observed in double immunofluorescence. Foxp3+ cells, IL-17A+ cells, and Foxp3+IL-17A+ cells were increased in the UP and NP tissues from CRSwNP patients. CD45RA−Foxp3+ cells were increased in CRSwNP, and IL-17A+ cells were observed most frequently in CD4+CD45RA−Foxp3+ cells from NP tissues. These findings show that CD4+CD45RA−Foxp3+ Tregs are involved in NP pathogenesis by producing IL-17A.

关键词： Mollugin   ZFP91   IL-1(3   Ubiquitination   Inflammasome  

摘要： Background: Rubia cordifolia L. has been formally included in the Chinese Pharmacopoeia and utilized for centuries as a traditional Chinese medicine. Mollugin, a quinone compound, is a major active compound extracted from Rubia cordifolia L. Mollugin was reported has multiple pharmacological activity, including antiinflammatory, anti-tumor effects. However, the anti-inflammatory mechanism is not yet clear. In this study, we explored the anti-inflammatory activity and potential mechanism of mollugin in vitro and in vivo. Materials and methods: We explored the mechanisms that mollugin suppressed IL-1(3 expression through ZFP91 using various assays, including western blot, immunofluorescence, immunoprecipitation, MTT, RT-PCR, and ELISA assays in vitro. In vivo, oral administration of DSS induced colitis in mice and intraperitoneal injection of alum induced peritonitis in mice. Results: First, the results demonstrated that mollugin dramatically suppressed IL-1(3 secretion through reducing ZFP91 in macrophages. Crucially, we proved that mollugin inhibited K63-linked Pro-IL-1(3 ubiquitination through ZFP91 and limitated Pro-IL-1(3 cleavage efficacy. In addition, ZFP91-mediated Caspase-8 inflammasome component expression was inhibited by mollugin. Furthermore, mollugin inhibited the assembly of the Caspase-8 inflammasome complex by downregulating ZFP91. In vivo studies further revealed that mollugin improved DSSinduced colitis and alum-induced peritonitis in mice by reducing ZFP91. Notely, mollugin significantly altered the abundance of gut flora in DSS-induced colitis mice, which in turn ameliorated the colitis. Conclusion: We present a novel finding that mollugin inhibition of ZFP91 is a crucial regulatory step, preventing undue inflammatory responses and thereby maintaining immune homeostasis. The current study offers new insight into the development of anti-inflammatory therapeutics targeting ZFP91.

关键词： Antigen Presentation   Autophagy   Hypoxia   Immune Response   MHC I Expression  

摘要： Hypoxia is a common feature of solid tumors that has previously been linked to resistance to radiotherapy and chemotherapy, and more recently to immunotherapy. In particular, hypoxic tumors exclude T cells and inhibit their activity, suggesting that tumor cells acquire a mechanism to evade T-cell recognition and killing. Our analysis of hypoxic tumors indicates that hypoxia downregulates the expression of MHC class I and its bound peptides (i.e., the immunopeptidome). Hypoxia decreases MHC-I expression in an oxygen-dependent manner, via activation of autophagy through the PERK arm of the unfolded protein response. Using an immunopeptidomics-based LC-MS approach, we find a significant reduction of presented antigens under hypoxia. Inhibition of autophagy under hypoxia enhances antigen presentation. In experimental tumors, reducing mitochondrial metabolism through a respiratory complex-I inhibitor increases tumor oxygenation, as well as MHC-I levels and the immunopeptidome. These data explain the molecular basis of tumor immune evasion in hypoxic conditions, and have implications for future therapeutic interventions targeting hypoxia-induced alterations in antigen presentation.

关键词： IL-6   Ischemic stroke   MACO   Muscle atrophy  

摘要： Muscle atrophy in pathological or diseased muscles arises from an imbalance between protein synthesis and degradation. Elevated levels of interleukin-6 (IL-6) are a hallmark of ischemic stroke and have been associated with muscle atrophy in certain pathological contexts. However, the mechanisms by which IL-6 induces muscle atrophy in the context of stroke remain unclear. To investigate these effects, we used a rat model of middle cerebral artery occlusion (MCAO) and an in vitro model with the C2C12 cell line to uncover potential molecular mechanisms underlying IL-6-induced muscle atrophy. Our findings revealed elevated protein and serum levels of IL-6, along with increased markers of muscle atrophy, in MCAO rats compared to sham controls. We also observed overactivation of protein ubiquitination pathways and downregulation of muscle regeneration markers in MCAO rats. Further analysis indicated that IL-6 contributes to increased muscle protein ubiquitination. Inhibition of IL-6 signaling led to a significant reduction in infarct size and improved neurological deficit scores. Targeting the IL-6/IL-6R signaling pathway presents a promising therapeutic approach to mitigate muscle atrophy in individuals affected by ischemic stroke.

关键词： Zerumbone   anti-inflammatory effect   antioxidant enzyme   periodontal ligament cells   signal transduction  

摘要： OBJECTIVES:Periodontal disease is a chronic inflammatory disease caused by periodontopathogenic bacteria, and its progression leads to periodontal tissue destruction and tooth loss. Zerumbone is a bioactive substance found in ginger () and is known to have bioactive effects such as anticancer effects, but there have been no attempts to use it for periodontitis treatment. In addition, there have been no reports examining its effects on periodontal tissue component cells. In this experiment, we aimed to determine whether zerumbone affects the production of inflammatory mediators induced by tumor necrosis factor (TNF)-α in human periodontal ligament cells (HPDLCs), including its effects on signaling pathways. METHODS:HPDLCs were stimulated by TNF-α (10 ng/ml) with or without zerumbone (6.25, 12.5, or 25 µM). Cytokine production in supernatant was determined using ELISA. Activation of signal transduction pathways and intracellular protein expression were investigated using the western blot analysis. RESULTS:Zerumbone significantly suppressed TNF-α-induced production of CC chemokine ligand 2 (CCL2), CCL20, CXC chemokine ligand 10 (CXCL10), and interleukin-6 (IL-6) in HPDLCs. In addition, zerumbone decreased intercellular adhesion molecule-1 (ICAM-1) and cyclooxygenase-2 (COX-2) expression in TNF-α-stimulated HPDLCs. Furthermore, zerumbone suppressed activation of nuclear factor (NF)-κB and signal transducer and activator of transcription 3 (STAT3) pathways in TNF-α-treated HPDLCs. Finally, zerumbone enhanced the production of heme oxygenase-1 (HO-1), an antioxidant enzyme, in HPDLCs. CONCLUSION:These results suggest that zerumbone suppressed the production of several inflammatory mediators by inhibiting the NF-κB and STAT3 pathways in HPDLCs.

关键词： IL-17A   Synovial inflammation   Osteoarthritis   Endoplasmic reticulum stress  

摘要： The primary clinical manifestations of osteoarthritis (OA) are joint pain and restricted movement capabilities. Synovial inflammation, serving as an initiator of OA progression, intensifies cartilage damage via the generation of various deleterious agents, including pro-inflammatory cytokines and nociceptive mediators. Despite extensive research on modulating synovial inflammation to retard OA progression, the underlying pathophysiological mechanisms of synovial inflammation in OA remain elusive. Interleukin-17A (IL-17A), a pro-inflammatory cytokine released by activated T lymphocytes, is a therapeutic target for numerous inflammatory and autoimmune pathologies. This study investigates the role and mechanism of IL-17A in OA synovial inflammation using both in vivo and in vitro models and examines the impact of the endoplasmic reticulum stress (ERS) inhibitor, 4Phenylbutyric Acid (4-PBA). Our findings indicate that IL-17A may be implicated in synovial inflammation through ERS and suggest a potential therapeutic direction for mitigating synovial inflammation in OA.

关键词： Endometriosis   IL-18   Infertility   Polycystic ovary syndrome   Recurrent spontaneous abortion  

摘要： Interleukin (IL)-18 is one of the members of IL-1 family cytokines, it was originally named as interferon gamma (IFN-γ) inducing factor. IL-18 is a pleiotropic immune regulator and has a bidirectional regulatory effect on immunity. It exerts a potent pro-inflammatory effect by inducing the expression of IFN-γ, also has an important anti-inflammatory role. In recent years, IL-18 has received widespread attention and become a research hotspot. Previous studies have described the roles of IL-18 in the pathogenesis of many diseases. However, the biologic activities of IL-18 and its role in the reproductive endocrine and reproductive immune related diseases are still not well understood, such as endometriosis (EMS), recurrent spontaneous abortion (RSA), polycystic ovary syndrome (PCOS), and infertility, which are closely related to inflammation and immunity. Here, we reviewed the research progress of IL-18 in these diseases in the past few years. This article provides an overview of the latest knowledge about the roles of IL-18 in these diseases, with a view to providing new possibilities for the diagnosis and treatment of reproductive endocrine and reproductive immune related disorders.