CD8+ T cells are essential for adaptive immunity against infection and tumors. Their ability to proliferate after stimulation is crucial to their functionality. Dendritic cells (DCs) are professional antigen-presenting cells that induce their proliferation. Here, we show that thapsigargin-induced LAD2 mast cell (MC) line-released products can impair the ability of monocyte-derived DCs to induce CD8+ T-cell proliferation and the generation of Th1 cytokine-producing T cells. We found that culture medium conditioned with LAD2 MCs previously stimulated with thapsigargin (thapsLAD2) induces maturation of DCs as determined by the maturation markers CD80, CD83, CD86, and HLA-DR. However, thapsLAD2-matured DCs produced no detectable TNFα or IL-12 during the maturation. In addition, although their surface expression of PD-L1 was comparable with the immature or TLR7/8-agonist (R848)-matured DCs, their TIM-3 expression was significantly higher than in immature DCs and even much higher than in R848-matured DCs. In addition, contrary to R848-matured DCs, the thapsLAD2-matured DCs only tended to induce enhanced proliferation of CD4+ T cells than immature DCs. For CD8+ T cells, this tendency was not even detected because thapsLAD2-matured and immature DCs comparably induced their proliferation, which contrasted with the significantly enhanced proliferation induced by R848-matured DCs. Furthermore, these differences were comparably recapitulated in the ability of the tested DCs to induce IFNγ- and IFNγ/TNFα-producing T cells. These findings show a novel mechanism of MC-mediated regulation of adaptive immune responses.

• MeSH
• aktivace lymfocytů * účinky léků   imunologie   MeSH
• buněčná diferenciace * účinky léků   MeSH
• buněčné linie MeSH
• buněčný receptor 2 viru hepatitidy A metabolismus   MeSH
• CD8-pozitivní T-lymfocyty * imunologie   účinky léků   MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky * imunologie   účinky léků   metabolismus   MeSH
• imidazoly farmakologie   MeSH
• lidé MeSH
• mastocyty * imunologie   účinky léků   metabolismus   MeSH
• monocyty imunologie   účinky léků   metabolismus   MeSH
• proliferace buněk * účinky léků   MeSH
• thapsigargin * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The preparation of dendritic cells (DCs) for adoptive cellular immunotherapy (ACI) requires the maturation of ex vivo-produced immature(i) DCs. This maturation ensures that the antigen presentation triggers an immune response towards the antigen-expressing cells. Although there is a large number of maturation agents capable of inducing strong DC maturation, there is still only a very limited number of these agents approved for use in the production of DCs for ACI. In seeking novel DC maturation agents, we used differentially activated human mast cell (MC) line LAD2 as a cellular adjuvant to elicit or modulate the maturation of ex vivo-produced monocyte-derived iDCs. We found that co-culture of iDCs with differentially activated LAD2 MCs in serum-containing media significantly modulated polyinosinic:polycytidylic acid (poly I:C)-elicited DC maturation as determined through the surface expression of the maturation markers CD80, CD83, CD86, and human leukocyte antigen(HLA)-DR. Once iDCs were generated in serum-free conditions, they became refractory to the maturation with poly I:C, and the LAD2 MC modulatory potential was minimized. However, the maturation-refractory phenotype of the serum-free generated iDCs was largely overcome by co-culture with thapsigargin-stimulated LAD2 MCs. Our data suggest that differentially stimulated mast cells could be novel and highly potent cellular adjuvants for the maturation of DCs for ACI.

• MeSH
• adjuvancia imunologická farmakologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné kultury metody   MeSH
• dendritické buňky cytologie   účinky léků   imunologie   MeSH
• imunoterapie adoptivní * MeSH
• kokultivační techniky MeSH
• lidé MeSH
• mastocyty cytologie   účinky léků   imunologie   MeSH
• monocyty cytologie   účinky léků   imunologie   MeSH
• prezentace antigenu účinky léků   imunologie   MeSH
• thapsigargin farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

SCOPE: The docosahexaenoic acid ester of hydroxy linoleic acid (13-DHAHLA) is a bioactive lipid with anti-inflammatory properties from the family of fatty acid esters of hydroxy fatty acids (FAHFA). METHODS AND RESULTS: To explore the biosynthesis of 13-DHAHLA from dietary oils, C57BL/6N mice are gavaged for 8 days with various corn oil/marine oil mixtures containing the same amount of DHA. Plasma levels of omega-3 FAHFAs are influenced by the lipid composition of the mixtures but do not reflect the changes in bioavailability of polyunsaturated fatty acids in plasma. Triacylglycerol-bound DHA and linoleic acid serve as more effective precursors for 13-DHAHLA synthesis than DHA bound in phospholipids or wax esters. Both 13(S)- and 13(R)-DHAHLA inhibit antigen and PGE2 -induced chemotaxis and degranulation of mast cells to a comparable extent and 13(S)-DHAHLA is identified as the predominant isomer in mouse adipose tissue. CONCLUSION: Here, the optimal nutritional source of DHA is identified, which supports production of anti-inflammatory FAHFAs, as triacylglycerol-based marine oil and also reveals a possible role of triacylglycerols in the synthesis of FAHFA lipokines.

• MeSH
• antiflogistika nesteroidní krev   farmakokinetika   MeSH
• biologická dostupnost MeSH
• chemotaxe účinky léků   MeSH
• kyseliny dokosahexaenové farmakokinetika   MeSH
• kyseliny linolové chemie   MeSH
• kyseliny mastné omega-3 farmakokinetika   farmakologie   MeSH
• mastocyty účinky léků   MeSH
• myši inbrední C57BL MeSH
• oleje chemie   farmakokinetika   MeSH
• stereoizomerie MeSH
• triglyceridy chemie   MeSH
• vodní organismy MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Our aim was to compare the protective efficacy of two different formulations of methylprednisolone in T-2 toxin-induced cardiomyopathy. Methylprednisolone (soluble form, Lemod-solu® and/or depot form, Lemod-depo®, a total single dose of 40 mg/kg im) was given immediately after T-2 toxin (1 LD50 0.23 mg/kg sc). The myocardial tissue samples were examinated by using histopathology, semiquantitative and imaging analyses on day 1, 7, 14, 21, 28 and 60 of the study. Therapeutic application of Lemod-solu® significantly decreased the intensity of myocardial degeneration and haemorrhages, distribution of glycogen granules in the endo- and perimysium, a total number of mast cells and the degree of their degranulation was in correlation with the reversible heart structural lesions (p <  0.01 vs. T-2 toxin). These changes were completely abolished by the therapeutic use of Lemod-solu® plus Lemod-depo® (p <  0.001 vs. T-2 toxin). Our results show that a significant cardioprotective efficacy of methylprednisolone is mediated by its anti-inflammatory activity.

• MeSH
• antiflogistika aplikace a dávkování   terapeutické užití   MeSH
• glykogen metabolismus   MeSH
• kardiomyopatie chemicky indukované   farmakoterapie   MeSH
• léky s prodlouženým účinkem MeSH
• mastocyty účinky léků   metabolismus   patologie   MeSH
• methylprednisolon aplikace a dávkování   terapeutické užití   MeSH
• myokard metabolismus   patologie   MeSH
• potkani Wistar MeSH
• T-2 toxin toxicita   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• adrenalin terapeutické užití   MeSH
• antialergika MeSH
• antihistaminika aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• Aspirin aplikace a dávkování   terapeutické užití   MeSH
• bisfosfonáty terapeutické užití   MeSH
• imunologické faktory MeSH
• individualizovaná medicína MeSH
• inhibitory enzymů MeSH
• inhibitory kostní resorpce MeSH
• interferon alfa terapeutické užití   MeSH
• lidé MeSH
• mastocytóza * diagnóza   farmakoterapie   patologie   MeSH
• mastocyty patologie   účinky léků   MeSH
• omalizumab terapeutické užití   MeSH
• staurosporin analogy a deriváty   terapeutické užití   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Omalizumab je humanizovaná monoklonální anti-IgE protilátka. Váže se na cirkulující IgE, po navázání na IgE vzniká biologicky inertní molekula, která brání další reakci mezi IgE a receptorem pro FcεR1 na mastocytech a bazofilech. Omalizumab ovlivňuje aktivitu mastocytů, které se při této terapii stávají stabilnější. Zvyšuje se práh pro jejich degranulaci, v důsledku které dochází k uvolnění vazoaktivních mediátorů. Omalizumab byl primárně indikován pro terapii pacientů s astmatem, tato indikace byla rozšířena o chronickou spontánní kopřivku. Účinnost a bezpečnost omalizumabu byla prokázána ve 3 randomizovaných, placebem kontrolovaných studiích u pacientů chronickou spontánní kopřivkou.

Omalizumab is a humanized monoclonal anti-IgE antibody. It binds to the circulating IgE to form a biologically inert molecule that inhibits further interaction between IgE and FcεR1 receptor on mast cells and basophils. Omalizumab affects the activity of mast cells that become more stable with this treatment. Their degranulation threshold increases, resulting in the release of vasoactive mediators. Omalizumab was primarily indicated for the treatment of patients with asthma; this indication has been extended to include chronic spontaneous urticaria. The safety and efficacy of omalizumab has been demonstrated in three randomized, placebo-controlled studies in patients with chronic spontaneous urticaria.

• Klíčová slova
• chronická spontánní kopřivka, autoreaktivita,
• MeSH
• autoimunita MeSH
• autoimunitní nemoci komplikace   MeSH
• chronická nemoc MeSH
• imunoglobulin E imunologie   MeSH
• lidé MeSH
• mastocyty imunologie   účinky léků   MeSH
• omalizumab * farmakologie   škodlivé účinky   terapeutické užití   MeSH
• urtikarie * etiologie   farmakoterapie   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Mast cells play crucial roles in both innate and adaptive arms of the immune system. Along with basophils, mast cells are essential effector cells for allergic inflammation that causes asthma, allergic rhinitis, food allergy and atopic dermatitis. Mast cells are usually increased in inflammatory sites of allergy and, upon activation, release various chemical, lipid, peptide and protein mediators of allergic reactions. Since antigen/immunoglobulin E (IgE)-mediated activation of these cells is a central event to trigger allergic reactions, innumerable studies have been conducted on how these cells are activated through cross-linking of the high-affinity IgE receptor (FcεRI). Development of mature mast cells from their progenitor cells is under the influence of several growth factors, of which the stem cell factor (SCF) seems to be the most important. Therefore, how SCF induces mast cell development and activation via its receptor, KIT, has been studied extensively, including a cross-talk between KIT and FcεRI signaling pathways. Although our understanding of the signaling mechanisms of the FcεRI and KIT pathways is far from complete, pharmaceutical applications of the knowledge about these pathways are underway. This review will focus on recent progresses in FcεRI and KIT signaling and chemotaxis.

• MeSH
• chemotaxe * účinky léků   MeSH
• lidé MeSH
• mastocyty cytologie   účinky léků   MeSH
• signální transdukce * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH

Ethanol has multiple effects on biochemical events in a variety of cell types, including the high-affinity immunoglobulin E receptor (FcεRI) signaling in antigen-activated mast cells. However, the underlying molecular mechanism remains unknown. To get better understanding of the effect of ethanol on FcεRI-mediated signaling we examined the effect of short-term treatment with non-toxic concentrations of ethanol on FcεRI signaling events in mouse bone marrow-derived mast cells. We found that 15 min exposure to ethanol inhibited antigen-induced degranulation, calcium mobilization, expression of proinflammatory cytokine genes (tumor necrosis factor-α, interleukin-6, and interleukin-13), and formation of reactive oxygen species in a dose-dependent manner. Removal of cellular cholesterol with methyl-β-cyclodextrin had a similar effect and potentiated some of the inhibitory effects of ethanol. In contrast, exposure of the cells to cholesterol-saturated methyl-β-cyclodextrin abolished in part the inhibitory effect of ethanol on calcium response and production of reactive oxygen species, supporting lipid-centric theories of ethanol action on the earliest stages of mast cell signaling. Further studies showed that exposure to ethanol and/or removal of cholesterol inhibited early FcεRI activation events, including tyrosine phosphorylation of the FcεRI β and γ subunits, SYK kinases, LAT adaptor protein, phospholipase Cγ, STAT5, and AKT and internalization of aggregated FcεRI. Interestingly, ethanol alone, and particularly in combination with methyl-β-cyclodextrin, enhanced phosphorylation of negative regulatory tyrosine 507 of LYN kinase. Finally, we found that ethanol reduced passive cutaneous anaphylactic reaction in mice, suggesting that ethanol also inhibits FcεRI signaling under in vivo conditions. The combined data indicate that ethanol interferes with early antigen-induced signaling events in mast cells by suppressing the function of FcεRI-cholesterol signalosomes at the plasma membrane.

• MeSH
• cholesterol metabolismus   MeSH
• cytokiny genetika   metabolismus   MeSH
• ethanol farmakologie   MeSH
• exprese genu účinky léků   MeSH
• fosforylace MeSH
• mastocyty účinky léků   metabolismus   MeSH
• myši MeSH
• receptory IgE metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• vápník metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Asthma bronchiale (AB) je heterogenní onemocnění dýchacích cest, charakterizované zán tem, poklesem plicních funkcí a přestavbou. Zánět je obranná prospěšná reakce imunitního systému na poškození. Vlivy životního prostředí spouštějí epigenetické mechanismy ovlivňující geny, které se tak mohou podílet na rozvoji fenotypu onemocnění. Neadekvátní imunitní odpověď na nepatogenní podněty u astmatika vede k rozvoji chronické zánětlivé odpovědi podílející se na patogenezi AB. Uvolněné mediátory a př ímý kontakt mezi žírnými buňkami a eozinofily potencují rozvoj chronického zánětu. Epitel dýchacích cest u astmatu reaguje abnormální odpovědí na narušení vyvolané vlivy prostř dí aktivující epiteliální-mezenchymální jednotku (EMTU).

Bronchial asthma is a heterogeneous disorder of the conducting airways involving chronic airway inflammation, declining airway function and tissue remodelling. Inflammation is a response of the immune system to injury which is beneficial to the host. An aberrant immu ne response to non-pathogenic stimuli in the asthmatic airway leads to a chronic inflammatory response relevant to the pathogenesis of the dis ease. The soluble and physical interplay between MC–Eos can create favorable conditions for persistence of inflammation. The airway epithelium in asthma is abnormal with increased susceptibility to environmental injury and impaired repair associated with activation of the epithelial -mesenchymal trophic unit (EMTU).

• MeSH
• alveolární makrofágy cytologie   imunologie   účinky léků   MeSH
• biomedicínský výzkum * metody   trendy   MeSH
• bronchiální astma * diagnóza   etiologie   terapie   MeSH
• bronchiální nemoci diagnóza   epidemiologie   etiologie   MeSH
• chronická bronchitida * diagnóza   farmakoterapie   terapie   MeSH
• eozinofily patologie   účinky léků   MeSH
• epigenomika metody   MeSH
• lidé MeSH
• mastocyty cytologie   patologie   účinky léků   MeSH
• proteiny SOCS imunologie   MeSH
• receptor PAR-2 imunologie   MeSH
• respirační sliznice cytologie   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9, suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma symptoms, demonstrating the immunosuppressive potency of tick-derived molecules.

• MeSH
• bronchiální astma genetika   imunologie   patologie   MeSH
• cystatiny imunologie   farmakologie   MeSH
• degranulace buněk imunologie   MeSH
• genetická transkripce MeSH
• imunosupresiva farmakologie   MeSH
• interakce hostitele a parazita imunologie   MeSH
• interferonové regulační faktory nedostatek   genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• interleukin-6 genetika   imunologie   MeSH
• interleukin-9 antagonisté a inhibitory   genetika   imunologie   MeSH
• mastocyty účinky léků   imunologie   patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• přirozená imunita účinky léků   MeSH
• promotorové oblasti (genetika) MeSH
• receptory interleukinu-1 genetika   imunologie   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH