Compelling evidence supports the health benefits of physical exercise on the immune system, possibly through the molecules secreted by the skeletal muscles known as myokines. Herein, we assessed the impact of exercise interventions on plasma Heat shock protein 90 (Hsp90) levels in 27 patients with idiopathic inflammatory myopathies (IIM) compared with 23 IIM patients treated with standard-of-care immunosuppressive therapy only, and in 18 healthy subjects undergoing strenuous eccentric exercise, and their associations with the traditional serum markers of muscle damage and inflammation. In contrast to IIM patients treated with pharmacotherapy only, in whom we demonstrated a significant decrease in Hsp90 over 24 weeks, the 24-week exercise program resulted in a stabilization of Hsp90 levels. These changes in Hsp90 levels were associated with changes in several inflammatory cytokines/chemokines involved in the pathogenesis of IIM or muscle regeneration in general. Strenuous eccentric exercise in healthy volunteers induced a brief increase in Hsp90 levels with a subsequent return to baseline levels at 14 days after the exercise, with less pronounced correlations to systemic inflammation. In this study, we identified Hsp90 as a potential myokine and mediator for exercise-induced immune response and as a potential biomarker predicting improvement after physiotherapy in muscle endurance in IIM.
- MeSH
- biologické markery krev metabolismus MeSH
- chemokiny krev metabolismus MeSH
- cytokiny krev metabolismus MeSH
- imunosupresiva terapeutické užití MeSH
- kosterní svaly * metabolismus MeSH
- lidé MeSH
- myozitida * krev farmakoterapie metabolismus terapie MeSH
- proteiny tepelného šoku HSP90 * krev metabolismus MeSH
- terapie cvičením * MeSH
- zánět * krev farmakoterapie metabolismus terapie MeSH
- zdraví dobrovolníci pro lékařské studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
PURPOSE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is the most common drug-resistant epilepsy. Despite major advances in epilepsy research, the epileptogenesis of the MTLE-HS is not well understood. The altered neuroimmune response is one of the pathomechanisms linked to progressive epileptogenesis in MTLE-HS, and understanding its role may help design future cures for pharmaco-resistant MTLE-HS. Here, the neuroimmune function was evaluated by the assessment of cytokine-chemokine profiles in brain samples from the hippocampus of patients with MTLE-HS. METHODS: Brain samples from patients with MTLE-HS collected during epileptosurgical resection (n = 21) were compared to those obtained from autopsy controls (n = 13). The typing of HS was performed according to ILAE consensus classification, and patients were additionally sorted into subgroups based on the severity of neuronal depletion (Wyler grading system). Differences between patients with MTLE-HS with and without a history of febrile seizures were also assessed. RNA was isolated from native samples, and real-time gene expression analysis of cytokine-chemokine profiles, i.e., levels of IL-1β, IL-6, IL-10, IL-18, CCL2, CCL3, CCL4, and STAT3, was carried out by qRT-PCR methodology. RESULTS: Upregulation of IL-1β (p = 0.001), IL-18 (p = 0.0018), CCL2 (p = 0,0377), CCL3 (p < 0.001), and CCL4 (p < 0.001) in MTLE-HS patients was detected when compared to the post-mortem hippocampal samples collected from autopsy controls. The STAT3 expression was higher in more severe neuronal loss and glial scaring determined by different Wyler grades in HS patients. Furthermore, cytokine-chemokine profiles were not different in MTLE-HS patients with or without febrile seizures. CONCLUSION: The upregulation of specific cytokines and chemokines in MTLE-HS provides evidence that the neuroinflammatory process contributes to MTLE epileptogenesis. History of febrile seizures did not alter the immune profiles. Specific immune mediators and related immune pathways represent potential therapeutic targets for seizure control and pharmacoresistancy prevention in MTLE associated with hippocampal sclerosis.
Platelet concentrates and especially their further product platelet lysate, are widely used as a replacement for cell culturing. Platelets contain a broad spectrum of growth factors and bioactive molecules that affect cellular fate. However, the cellular response to individual components of the human platelet concentrate is still unclear. The aim of this study was to observe cellular behavior according to the individual components of platelet concentrates. The bioactive molecule content was determined. The cells were supplemented with a medium containing 8% (v/v) of platelet proteins in plasma, pure platelet proteins in deionized water, and pure plasma. The results showed a higher concentration of fibrinogen, albumin, insulin growth factor I (IGF-1), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF), in the groups containing plasma. On the other hand, chemokine RANTES and platelet-derived growth factor bb (PDGF-bb), were higher in the groups containing platelet proteins. The groups containing both plasma and plasma proteins showed the most pronounced proliferation and viability of mesenchymal stem cells and fibroblasts. The platelet proteins alone were not sufficient to provide optimal cell growth and viability. A synergic effect of platelet proteins and plasma was observed. The data indicated the importance of plasma in platelet lysate for cell growth.
- MeSH
- albuminy MeSH
- becaplermin metabolismus MeSH
- buněčné kultury metody MeSH
- chemokiny metabolismus MeSH
- fibrinogen metabolismus MeSH
- fibroblastový růstový faktor 7 MeSH
- fibroblasty metabolismus MeSH
- hepatocytární růstový faktor MeSH
- insulinu podobný růstový faktor I MeSH
- krevní plazma chemie MeSH
- kultivační média chemie MeSH
- lidé MeSH
- mezenchymální kmenové buňky metabolismus MeSH
- plazma bohatá na destičky metabolismus MeSH
- proliferace buněk účinky léků MeSH
- protoonkogenní proteiny c-sis metabolismus MeSH
- trombocyty chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Introduction: Total joint replacement is one of the most common, safe, and efficacious operations in all of surgery. However, one major long-standing and unresolved issue is the adverse biological reaction to byproducts of wear from the bearing surfaces and modular articulations. These inflammatory reactions are mediated by the innate and adaptive immune systems.Areas covered: We review the etiology and pathophysiology of implant debris-associated inflammation, the clinical presentation and detailed work-up of these cases, and the principles and outcomes of non-operative and operative management. Furthermore, we suggest future strategies for prevention and novel treatments of implant-related adverse biological reactions.Expert opinion: The generation of byproducts from joint replacements is inevitable, due to repetitive loading of the implants. A clear understanding of the relevant biological principles, clinical presentations, investigative measures and treatments for implant-associated inflammatory reactions and periprosthetic osteolysis will help identify and treat patients with this issue earlier and more effectively. Although progressive implant-associated osteolysis is currently a condition that is treated surgically, with further research, it is hoped that non-operative biological interventions could prolong the lifetime of joint replacements that are otherwise functional and still salvageable.
The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14+Sirpα+ population of monocyte-derived dendritic cells (CD14+moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14+moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25+Foxp3+ Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14+moDC, the generation of Tregs, and thereby the establishment of central tolerance.
- MeSH
- analýza jednotlivých buněk MeSH
- antigeny CD14 metabolismus MeSH
- autoantigeny imunologie MeSH
- autotolerance MeSH
- chemokiny imunologie metabolismus MeSH
- dendritické buňky imunologie MeSH
- epitelové buňky imunologie metabolismus MeSH
- kolitida imunologie MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- převzatá imunita MeSH
- prezentace antigenu MeSH
- průtoková cytometrie MeSH
- receptory imunologické metabolismus MeSH
- regulační T-lymfocyty imunologie transplantace MeSH
- sekvenční analýza RNA MeSH
- separace buněk MeSH
- signální transdukce imunologie MeSH
- thymus cytologie imunologie MeSH
- toll-like receptory metabolismus MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Calcineurin (CN) inhibitors are effective clinical immunosuppressants but leave patients vulnerable to potentially fatal fungal infections. This study tested the hypothesis that CN inhibition interferes with antifungal immune defenses mediated by monocytes. We showed that NFAT is expressed by human monocytes, and is activated by exposure to fungal ligands. We confirmed that NFAT translocation potently activated target gene transcription using a human monocytic reporter cell line. Inhibition of CN-NFAT by cyclosporine A significantly reduced monocyte production of TNF-α, IL-10, and MCP-1 proteins in response to pattern recognition receptor ligands as well as to Aspergillus fumigatus conidia. Moreover, we revealed that human monocytes express the antifungal protein pentraxin-3 under control of NFAT. In conclusion, clinical CN inhibitors have the potential to interfere with the novel NFAT-dependent pentraxin-3 pathway as well as antifungal cytokine production in human monocytes, thereby impeding monocyte-mediated defenses against fungal infection in immune-suppressed patients.
- MeSH
- antifungální látky metabolismus MeSH
- Aspergillus fumigatus účinky léků MeSH
- C-reaktivní protein metabolismus MeSH
- chemokiny metabolismus MeSH
- cyklosporin farmakologie MeSH
- inhibitory kalcineurinu farmakologie MeSH
- interleukin-10 metabolismus MeSH
- lidé MeSH
- monocyty účinky léků metabolismus MeSH
- myeloidní buňky účinky léků metabolismus MeSH
- myši MeSH
- sekvence nukleotidů MeSH
- sekvenční homologie aminokyselin MeSH
- sérový amyloidový protein metabolismus MeSH
- signální transdukce účinky léků MeSH
- THP-1 buňky MeSH
- TNF-alfa metabolismus MeSH
- transkripční faktory NFATC metabolismus MeSH
- transport proteinů účinky léků MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The immune microenvironment in inflammatory breast cancer (IBC) is poorly characterised, and molecular and cellular pathways that control accumulation of various immune cells in IBC tissues remain largely unknown. Here, we discovered a novel pathway linking the expression of the tetraspanin protein CD151 in tumour cells with increased accumulation of macrophages in cancerous tissues. It is notable that elevated expression of CD151 and a higher number of tumour-infiltrating macrophages correlated with better patient responses to chemotherapy. Accordingly, CD151-expressing IBC xenografts were characterised by the increased infiltration of macrophages. In vitro migration experiments demonstrated that CD151 stimulates the chemoattractive potential of IBC cells for monocytes via mechanisms involving midkine (a heparin-binding growth factor), integrin α6β1, and production of extracellular vesicles (EVs). Profiling of chemokines secreted by IBC cells demonstrated that CD151 increases production of midkine. Purified midkine specifically stimulated migration of monocytes, but not other immune cells. Further experiments demonstrated that the chemoattractive potential of IBC-derived EVs is blocked by anti-midkine antibodies. These results demonstrate for the first time that changes in the expression of a tetraspanin protein by tumour cells can affect the formation of the immune microenvironment by modulating recruitment of effector cells to cancerous tissues. Therefore, a CD151-midkine pathway can be considered as a novel target for controlled changes of the immune landscape in IBC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- MeSH
- antigeny CD151 imunologie metabolismus MeSH
- chemokiny metabolismus MeSH
- lidé MeSH
- makrofágy metabolismus patologie MeSH
- midkin metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí fyziologie MeSH
- zánětlivé nádory prsu metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Papillon-Lefèvre syndrome (PLS) is characterized by nonfunctional neutrophil serine proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation by normal and NSP-deficient human and mouse granulocytes. Stimulated with solid or soluble NET inducers, normal neutrophils formed aggregates and both released and degraded cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed release. Maximum output of cytokines/chemokines occurred mostly at densities between 2 × 107 and 4 × 107 neutrophils/cm3. Assessment of neutrophil density in vivo showed that these concentrations are surpassed during inflammation. Association with aggregated NETs conferred protection of neutrophil elastase against α1-antitrypsin. In contrast, eosinophils did not influence cytokine/chemokine concentrations. The proteolytic degradation of inflammatory mediators seen in NETs was abrogated in Papillon-Lefèvre syndrome (PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators works as a built-in safeguard for inflammation. The absence of this negative feedback mechanism might be responsible for the nonresolving periodontitis seen in PLS.-Hahn, J., Schauer, C., Czegley, C., Kling, L., Petru, L., Schmid, B., Weidner, D., Reinwald, C., Biermann, M. H. C., Blunder, S., Ernst, J., Lesner, A., Bäuerle, T., Palmisano, R., Christiansen, S., Herrmann, M., Bozec, A., Gruber, R., Schett, G., Hoffmann, M. H. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases.
- MeSH
- chemokiny metabolismus MeSH
- cytokiny metabolismus MeSH
- dospělí MeSH
- extracelulární pasti metabolismus MeSH
- inhibitory proteas metabolismus MeSH
- ionomycin farmakologie MeSH
- kyselina močová farmakologie MeSH
- lidé MeSH
- mediátory zánětu metabolismus MeSH
- mladiství MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- NADPH-oxidasy genetika MeSH
- neutrofily účinky léků metabolismus MeSH
- parodontitida metabolismus MeSH
- proteolýza MeSH
- tetradekanoylforbolacetát farmakologie MeSH
- zánět prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In this study, we compared selected silymarin components, such as quercetin (QE), 2,3-dehydrosilybin (DHS) and silybin (SB), with the anti-inflammatory drug indomethacin (IND) in terms of their wound healing potential. In view of the fact that pathological cutaneous wound healing is associated with persistent inflammation, we studied their anti-inflammatory activity against inflammation induced by bacterial lipopolysaccharide (LPS). We investigated the regulation of crucial pro-inflammatory transcription factors-nuclear factor kappa-B (NF-κB) and activator protein 1 (AP-1)-as well as the expression of downstream inflammatory targets by Western blotting, real-time PCR (RT-PCR), electrophoretic mobility shift assay (EMSA), and/or enzyme-linked immunosorbent assay (ELISA) in vitro using primary normal human dermal fibroblasts (NHDF). We demonstrated the greater ability of DHS to modulate the pro-inflammatory cytokines production via the NF-κB and AP-1 signaling pathways when compared to other tested substances. The prolonged exposure of LPS-challenged human dermal fibroblasts to DHS had both beneficial and detrimental consequences. DHS diminished interleukin-6 (IL-6) and interleukin-8 (IL-8) secretion but induced the significant upregulation of IL-8 mRNA associated with NF-κB and AP-1 activation. The observed conflicting results may compromise the main expected benefit, which is the acceleration of the healing of the wound via a diminished inflammation.
- MeSH
- antiflogistika farmakologie MeSH
- chemokiny metabolismus MeSH
- cytokiny metabolismus MeSH
- dermatitida farmakoterapie genetika metabolismus patologie MeSH
- exprese genu MeSH
- fibroblasty účinky léků metabolismus MeSH
- hojení ran účinky léků MeSH
- lidé MeSH
- lipopolysacharidy imunologie MeSH
- messenger RNA genetika metabolismus MeSH
- NF-kappa B metabolismus MeSH
- proliferace buněk účinky léků MeSH
- silymarin farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcεRIs). Aggregation of FcεRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E2 , sphingosine-1-phosphate, and β-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines.
- MeSH
- alergie imunologie MeSH
- chemokiny metabolismus MeSH
- cytokiny metabolismus MeSH
- degranulace buněk * MeSH
- imunizace MeSH
- imunoglobulin E metabolismus MeSH
- mastocyty imunologie MeSH
- mediátory zánětu metabolismus MeSH
- receptory IgE metabolismus MeSH
- receptory spřažené s G-proteiny metabolismus MeSH
- signální transdukce MeSH
- toll-like receptory metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
