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Browsing by Subject "Inflammatory cytokines"
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Item Cleaning up the environment in juvenile myelomonocytic leukemia(AME Publishing Company., 2017-02) Deng, Lisa; Chan, Rebecca J.; Medical and Molecular Genetics, School of MedicineItem Editorial: A new frontier in translational research on autoinflammatory diseases - various aspects of innate immunity on human diseases(Frontiers Media, 2023-01-31) Mukai, Tomoyuki; Ida, Hiroaki; Ueki, Yasuyoshi; Nishikomori, Ryuta; Biomedical Sciences and Comprehensive Care, School of DentistryItem Effector T Helper Cell Subsets in Inflammatory Bowel Diseases(Frontiers Media, 2018-06-01) Imam, Tanbeena; Park, Sungtae; Kaplan, Mark H.; Olson, Matthew R.; Pediatrics, School of MedicineThe gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4+ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4+ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4+ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.Item HUMAN ADIPOSE-DERIVED STEM CELLS ATTENUATE CIGARETTE SMOKE INDUCED BONE MARROW HYPOPLASIA VIA SECRETION OF ANTI-INFLAMMATORY CYTOKINE TSG-6(Office of the Vice Chancellor for Research, 2012-04-13) Xie, Jie; Petrache, Irina; Broxmeyer, Hal E.; March, Keith L.; Feng, Dongni; Cook, Todd G.; Schweitzer, Kelly; Johnstone, Brian H.Introduction We have previously observed bone marrow (BM) hypo-plasia in a murine model of chronic smoking, which was ameliorated by mu-rine adipose-derived stromal cells (ASC). This study was designed to test the hypothesis that ASC exert their marrow protective effects through key paracrine factors. Methods Mice (NSG or C57BL/6) were exposed to ciga-rette smoke (CS) for 1 day to 6 months. Human ASC or ASC conditioned media were administered through intravenous (i.v.) or intraperitoneal (i.p.) injections. Secretion of TSG-6 from ASC in response to TNF alpha and IL-1 beta were measured by ELISA. Expression of TSG-6 in ASC was knocked down by siRNA. BM hematopoietic progenitors were quantified by colony forming-unit assays. Possible engrafted human ASC in mouse BM were ex-amined by anti-human nuclei staining. Results The myelossupressive effect of cigarette smoking occurred acutely (1 day: 65.6% of nonsmoking control, NSC, p<0.01) and worsened with prolonged exposure (3 days: 34.3% NSC, p<0.01). Such damage could be ameliorated with either ASC (111.0% NSC, p>0.05) or ASC conditioned media (105.7% NSC, p>0.05). Inflammatory cytokines (TNF alpha and IL-1 beta) elevated in smokers (Kuschner et al, 1996; de Maat et al, 2002) demonstrated strong cross-species stimulatory effects on secretions of an anti-inflammatory cytokine, TSG-6 from ASC (TNF alpha: 8.7 +/- 1.3 fold, IL-1 beta: 8.2 +/- 1.1 fold). Knocking down TSG-6 (>90%) abolished the marrow-protective effect of ASC. No human cells were detected in recipient mouse bone marrow. Conclusions The pro-tective effects of ASC against smoking-induced myelosuppression are medi-ated by trophic factors rather than cell engraftment or differentiation. TSG-6 appears to play a significant role in the modulatory pathway: smoke--inflammatory cytokine release--TSG6 secretion from ASC--bone marrow protection.Item Inflammatory cytokines and mechanical injury induce post-traumatic osteoarthritis-like changes in a human cartilage-bone-synovium microphysiological system(BMC, 2022-08-18) Dwivedi, Garima; Flaman, Lisa; Alaybeyoglu, Begum; Struglics, André; Frank, Eliot H.; Chubinskya, Susan; Trippel, Stephen B.; Rosen, Vicki; Cirit, Murat; Grodzinsky, Alan J.; Orthopaedic Surgery, School of MedicineBackground: Traumatic knee injuries in humans trigger an immediate increase in synovial fluid levels of inflammatory cytokines that accompany impact damage to joint tissues. We developed a human in vitro cartilage-bone-synovium (CBS) coculture model to study the role of mechanical injury and inflammation in the initiation of post-traumatic osteoarthritis (PTOA)-like disease. Methods: Osteochondral plugs (cartilage-bone, CB) along with joint capsule synovium explants (S) were harvested from 25 cadaveric distal femurs from 16 human donors (Collin's grade 0-2, 23-83years). Two-week monocultures (cartilage (C), bone (B), synovium (S)) and cocultures (CB, CBS) were established. A PTOA-like disease group was initiated via coculture of synovium explants with mechanically impacted osteochondral plugs (CBS+INJ, peak stress 5MPa) with non-impacted CB as controls. Disease-like progression was assessed through analyses of changes in cell viability, inflammatory cytokines released to media (10-plex ELISA), tissue matrix degradation, and metabolomics profile. Results: Immediate increases in concentrations of a panel of inflammatory cytokines occurred in CBS+INJ and CBS cocultures and cultures with S alone (IL-1, IL-6, IL-8, and TNF-α among others). CBS+INJ and CBS also showed increased chondrocyte death compared to uninjured CB. The release of sulfated glycosaminoglycans (sGAG) and associated ARGS-aggrecan neoepitope fragments to the medium was significantly increased in CBS and CBS+INJ groups. Distinct metabolomics profiles were observed for C, B, and S monocultures, and metabolites related to inflammatory response in CBS versus CB (e.g., kynurenine, 1-methylnicotinamide, and hypoxanthine) were identified. Conclusion: CBS and CBS+INJ models showed distinct cellular, inflammatory, and matrix-related alterations relevant to PTOA-like initiation/progression. The use of human knee tissues from donors that had no prior history of OA disease suggests the relevance of this model in highlighting the role of injury and inflammation in earliest stages of PTOA progression.Item Reciprocal Inhibition of Adiponectin and Innate Lung Immune Responses to Chitin and Aspergillus fumigatus(Frontiers, 2019-05-10) Amarsaikhan, Nansalmaa; Stolz, Dylan J.; Wilcox, Amber; Sands, Ethan M.; Tsoggerel, Angar; Gravely, Haley; Templeton, Steven P.; Microbiology and Immunology, School of MedicineChitin is a structural biopolymer found in numerous organisms, including pathogenic fungi, and recognized as an immune-stimulating pathogen associated molecular pattern by pattern recognition molecules of the host immune system. However, programming and regulation of lung innate immunity to chitin inhalation in the context of inhalation of fungal pathogens such as Aspergillus fumigatus is complex and our understanding incomplete. Here we report that the systemic metabolism-regulating cytokine adiponectin is decreased in the lungs and serum of mice after chitin inhalation, with a concomitant decrease in surface expression of the adiponectin receptor AdipoR1 on lung leukocytes. Constitutive lung expression of acidic mammalian chitinase resulted in decreased inflammatory cytokine gene expression and neutrophil recruitment, but did not significantly affect lung adiponectin transcription. Exogenous recombinant adiponectin specifically dampened airway chitin-mediated eosinophil recruitment, while adiponectin deficiency resulted in increased airway eosinophils. The presence of adiponectin also resulted in decreased CCL11-mediated migration of bone marrow-derived eosinophils. In contrast to purified chitin, aspiration of viable conidia from the high chitin-expressing A. fumigatus isolate Af5517 resulted in increased neutrophil recruitment and inflammatory cytokine gene expression in adiponectin-deficient mice, while no significant changes were observed in response to the isolate Af293. Our results identify a novel role for the adiponectin pathway in inhibition of lung inflammatory responses to chitin and A. fumigatus inhalation.Item Survival Factor A (SvfA) Contributes to Aspergillus nidulans Pathogenicity(MDPI, 2023-01-21) Lim, Joo-Yeon; Jung, Ye-Eun; Hwang, Hye-Eun; Kim, Cheol-Hee; Basaran-Akgul, Nese; Goli, Sri Harshini; Templeton, Steven P.; Park, Hee-Moon; Microbiology and Immunology, School of MedicineSurvival factor A (SvfA) in Aspergillus nidulans plays multiple roles in growth and developmental processes. It is a candidate for a novel VeA-dependent protein involved in sexual development. VeA is a key developmental regulator in Aspergillus species that can interact with other velvet-family proteins and enter into the nucleus to function as a transcription factor. In yeast and fungi, SvfA-homologous proteins are required for survival under oxidative and cold-stress conditions. To assess the role of SvfA in virulence in A. nidulans, cell wall components, biofilm formation, and protease activity were evaluated in a svfA-gene-deletion or an AfsvfA-overexpressing strain. The svfA-deletion strain showed decreased production of β-1,3-glucan in conidia, a cell wall pathogen-associated molecular pattern, with a decrease in gene expression for chitin synthases and β-1,3-glucan synthase. The ability to form biofilms and produce proteases was reduced in the svfA-deletion strain. We hypothesized that the svfA-deletion strain was less virulent than the wild-type strain; therefore, we performed in vitro phagocytosis assays using alveolar macrophages and analyzed in vivo survival using two vertebrate animal models. While phagocytosis was reduced in mouse alveolar macrophages challenged with conidia from the svfA-deletion strain, the killing rate showed a significant increase with increased extracellular signal-regulated kinase ERK activation. The svfA-deletion conidia infection reduced host mortality in both T-cell-deficient zebrafish and chronic granulomatous disease mouse models. Taken together, these results indicate that SvfA plays a significant role in the pathogenicity of A. nidulans.