BACKGROUND: Oximes are used in addition to atropine to treat organophosphate poisoning. However, the efficiency of oximes is still a matter of debate. In vitro experiments suggested than new oximes are more potent than the commercial oximes. However, the antidotal activity of new oximes has not been assessed in vivo. METHODS: The aim of this work was to assess the safety and efficiency of new oximes compared to pralidoxime in a rat model of diethyl paraoxon-induced non-lethal respiratory toxicity. RESULTS: Safety study of oximes showed no adverse effects on ventilation in rats. KO-33, KO-48, KO-74 oximes did not exhibit significant antidotal effect in vivo. In contrast, KO-27 and BI-6 showed evidence of antidotal activity by normalization of respiratory frequency and respiratory times. KO-27 became inefficient only during the last 30 min of the study. In contrast, pralidoxime demonstrated to be inefficient at 30 min post injection. Inversely, the antidotal activity of BI-6 occurred lately, within the last 90 min post injection. CONCLUSION: This study showed respiratory safety of new oximes. Regarding, the efficiency, KO-27 revealed to be a rapid acting antidote toward diethylparaoxon-induced respiratory toxicity, meanwhile BI-6 was a late-acting antidote. Simultaneous administration of these two oximes might result in a complete and prolonged antidotal efficiency.

• Klíčová slova
• BI-6, KO-27, diethyl-paraoxon, oximes, plethysmography, pralidoxime, rats, ventilatory effects,
• MeSH
• antidota farmakologie   MeSH
• bezpečnost MeSH
• cholinesterasové inhibitory toxicita   MeSH
• dýchání účinky léků   MeSH
• krysa rodu Rattus MeSH
• otrava organofosfáty farmakoterapie   etiologie   MeSH
• oximy farmakologie   MeSH
• paraoxon toxicita   MeSH
• potkani Sprague-Dawley MeSH
• větrání metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidota MeSH
• cholinesterasové inhibitory MeSH
• oximy MeSH
• paraoxon MeSH

We investigated the role of beta3-adrenoceptors (AR) in cold stress (1 or 7 days in cold) in animals lacking main cardioinhibitive receptors-M2 muscarinic receptors (M(2)KO). There was no change in receptor number in the right ventricles. In the left ventricles, there was decrease in binding to all cardiostimulative receptors (beta1-, and beta2-AR) and increase in cardiodepressive receptors (beta3-AR) in unstressed KO in comparison to WT. The cold stress in WT animals resulted in decrease in binding to beta1- and beta2-AR (to 37%/35% after 1 day in cold and to 27%/28% after 7 days in cold) while beta3-AR were increased (to 216% of control) when 7 days cold was applied. MR were reduced to 46% and 58%, respectively. Gene expression of M2 MR in WT was not changed due to stress, while M3 was changed. The reaction of beta1- and beta2-AR (binding) to cold was similar in KO and WT animals, and beta3-AR in stressed KO animals did not change. Adenylyl cyclase activity was affected by beta3-agonist CL316243 in cold stressed WT animals but CL316243 had almost no effects on adenylyl cyclase activity in stressed KO. Nitric oxide activity (NOS) was not affected by BRL37344 (beta3-agonist) both in WT and KO animals. Similarly, the stress had no effects on NOS activity in WT animals and in KO animals. We conclude that the function of M2 MR is substituted by beta3-AR and that these effects are mediated via adenylyl cyclase rather than NOS.

• MeSH
• adenylátcyklasy metabolismus   MeSH
• beta-3-adrenergní receptory metabolismus   MeSH
• fyziologická adaptace * genetika   MeSH
• fyziologický stres * genetika   MeSH
• katecholaminy biosyntéza   MeSH
• myši MeSH
• nízká teplota * MeSH
• receptor muskarinový M2 nedostatek   genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• srdce patofyziologie   MeSH
• srdeční komory enzymologie   patologie   patofyziologie   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenylátcyklasy MeSH
• beta-3-adrenergní receptory MeSH
• katecholaminy MeSH
• receptor muskarinový M2 MeSH
• synthasa oxidu dusnatého MeSH

Allergic diseases belong to one of the most common diseases with steadily increasing incidence even among young children. There is an urgent need to identify a prognostic marker pointing to increased risk of allergy development enabling early preventive measures introduction. It has been shown that administration of selected probiotic strains or mixtures could prevent allergy development. In our study, we have tested the capacity of probiotic strain Escherichia coli O83:K24:H31 (E. coli O83) to promote dendritic cell (DC) maturation and polarisation of immune responses. Increased presence of activation marker CD83 was observed on DC stimulated by E. coli O83 and DC of newborns of allergic mothers have significantly more increased cell surface presence of CD83 in comparison to children of healthy mothers. Increased gene expression and secretion of IL-10 was detected in DC stimulated with E. coli O83 being higher in DC of newborns of healthy mothers in comparison to allergic ones. Generally, increased presence of intracellular cytokines (IL-4, IL-13, IFN-gamma, IL-17A, IL-22, IL-10) was detected in CD4+ T cells cocultured with DC of children of allergic mothers in comparison to healthy ones. E. coli O83 primed DC significantly increased IL-10 and IL-17A in CD4 T cells of newborns of healthy mothers in comparison to the levels detected in CD4 T cells cocultured with control non-stimulated DC. We can conclude E. coli O83 induces dendritic cell maturation and IL-10 production in DC. Newborns of allergic mothers have generally increased reactivity of both DC and CD4 T cells which together with decreased capacity of DC of newborns of allergic mothers to produce IL-10 could support inappropriate immune responses development after allergen encounter.

• Klíčová slova
• Allergy, Cord blood, Cytokine, Dendritic cell, Probiotic,
• MeSH
• aktivace lymfocytů MeSH
• alergie imunologie   MeSH
• buněčná diferenciace MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• dendritické buňky mikrobiologie   fyziologie   MeSH
• dospělí MeSH
• Escherichia coli fyziologie   MeSH
• imunita získaná od matky MeSH
• interleukin 22 MeSH
• interleukin-10 metabolismus   MeSH
• interleukin-17 metabolismus   MeSH
• interleukiny metabolismus   MeSH
• kokultivační techniky MeSH
• kultivované buňky MeSH
• lidé MeSH
• matky MeSH
• novorozenec MeSH
• probiotika MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• interleukin-10 MeSH
• interleukin-17 MeSH
• interleukiny MeSH

The eye has been described as an immunologically privileged site where immunity is purely expressed. It has been demonstrated that administration of antigen into the eye induces only a weak immune response. However, the anterior part of the eye represents an important protective barrier against pathogens and other harmful invaders from the outer environment. Therefore, effective immune mechanisms, which operate locally, need to be present there. Because the cornea has been shown to be a potent producer of various cytokines and other molecules with immunomodulatory properties, we investigated a possible regulatory role for the individual corneal cell types on cytokine production by activated T cells. Mouse spleen cells were stimulated with the T cell mitogen concanavalin A in the presence of either corneal explants or cells of corneal epithelial or endothelial cell lines and the production of T helper 1 (Th1) or Th2 cytokines was determined by enzyme-linked immunosorbent assay (ELISA) or reverse transcription-polymerase chain reaction (RT-PCR). We found that the cornea possesses the ability to inhibit, in a dose-dependent manner, production of the inhibitory and anti-inflammatory cytokines interleukin (IL)-4 and IL-10 by activated T cells. The production of cytokines associated with protective immunity [IL-2, IL-1beta, interferon (IFN)-gamma ] was not inhibited under the same conditions. Corneal explants deprived of epithelial and endothelial cells retained the ability to suppress production of anti-inflammatory cytokines. This suppression was mediated by a factor produced by corneal stromal cells and occurred at the level of cytokine gene expression. We suggest that by this mechanism the cornea can potentiate a local expression of protective immune reactions in the anterior segment of the eye.

• MeSH
• aktivace lymfocytů MeSH
• cytokiny biosyntéza   MeSH
• ELISA metody   MeSH
• interferon gama analýza   genetika   MeSH
• interleukin-1 biosyntéza   MeSH
• interleukin-10 biosyntéza   MeSH
• interleukin-2 biosyntéza   MeSH
• interleukin-4 biosyntéza   genetika   MeSH
• kokultivační techniky MeSH
• konkanavalin A farmakologie   MeSH
• kultivační techniky MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• slezina MeSH
• stroma rohovky imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• interferon gama MeSH
• interleukin-1 MeSH
• interleukin-10 MeSH
• interleukin-2 MeSH
• interleukin-4 MeSH
• konkanavalin A MeSH

Immunosuppressive drugs are widely used to treat undesirable immune reaction, however their clinical use is often limited by harmful side effects. The combined application of immunosuppressive agents with mesenchymal stem cells (MSCs) offers a promising alternative approach that enables the reduction of immunosuppressive agent doses and simultaneously maintains or improves the outcome of therapy. The present study aimed to determinate the effects of immunosuppressants on individual T cell subpopulations and to investigate the efficacy of MSC-based treatment combined with immunosuppressive drugs. We tested the effect of five widely used immunosuppressants with different action mechanisms: cyclosporine A, mycophenolate mofetil, rapamycin, and two glucocorticoids - prednisone and dexamethasone in combination with MSCs on mouse CD4+ and CD8+ lymphocyte viability and activation, Th17 (RORγt+), Th1 (T-bet+), Th2 (GATA-3+) and Treg (Foxp3+) cell proportion and on the production of corresponding key cytokines (IL-17, IFNγ, IL-4 and IL-10). We showed that MSCs modulate the actions of immunosuppressants and in combination with immunosuppressive drugs display distinct effect on cell activation and balance among different T lymphocytes subpopulations and exert a suppressive effect on proinflammatory T cell subsets while promoting the functions of anti-inflammatory Treg lymphocytes. The results indicated that MSC-based therapy could be a powerful strategy to attenuate the negative effects of immunosuppressive drugs on the immune system.

• Klíčová slova
• Immunomodulation, Immunosuppressive drugs, Mesenchymal stem cells, Stem cell therapy, T cells,
• MeSH
• aktivace lymfocytů účinky léků   imunologie   MeSH
• cyklosporin farmakologie   MeSH
• cytokiny metabolismus   MeSH
• dexamethason farmakologie   MeSH
• glukokortikoidy farmakologie   MeSH
• imunosupresiva farmakologie   MeSH
• kokultivační techniky MeSH
• kultivované buňky MeSH
• kyselina mykofenolová farmakologie   MeSH
• mezenchymální kmenové buňky cytologie   imunologie   metabolismus   MeSH
• myši inbrední BALB C MeSH
• prednison farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• průtoková cytometrie MeSH
• sirolimus farmakologie   MeSH
• T-lymfocyty - podskupiny cytologie   účinky léků   imunologie   MeSH
• transplantace mezenchymálních kmenových buněk metody   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyklosporin MeSH
• cytokiny MeSH
• dexamethason MeSH
• glukokortikoidy MeSH
• imunosupresiva MeSH
• kyselina mykofenolová MeSH
• prednison MeSH
• sirolimus MeSH

Mesenchymal stem cells (MSCs) represent a population of cells which have the ability to regulate reactivity of T and B lymphocytes by multiple mechanisms. The immunoregulatory activities of MSCs are strictly influenced by the cytokine environment. Here we show that two functionally distinct cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), significantly potentiate the ability of MSCs to inhibit IL-10 production by activated regulatory B cells (Bregs). However, MSCs in the presence of IL-4 or IFN-γ inhibit the IL-10 production by different mechanisms. Preincubation of MSCs with IFN-γ led to the suppression, but pretreatment with IL-4 of neither MSCs nor B cells resulted in the suppression of IL-10 production. The search for candidate regulatory molecules expressed in cytokine-treated MSCs revealed different patterns of the gene expression. Pretreatment of MSCs with IFN-γ, but not with IL-4, induced expression of indoleamine-2,3-dioxygenase, cyclooxygenase-2 and programmed cell death-ligand 1. To identify the molecule(s) responsible for the suppression of IL-10 production, we used specific inhibitors of the putative regulatory molecules. We found that indomethacine, an inhibitor of cyclooxygenase-2 (Cox-2) activity, completely abrogated the inhibition of IL-10 production in cultures containing MSCs and IFN-γ, but had no effect on the suppression in cell cultures containing MSCs and IL-4. The results show that MSCs can inhibit the response of B cells to one stimulus by different mechanisms in dependence on the cytokine environment and thus support the idea of the complexity of immunoregulatory action of MSCs.

• Klíčová slova
• Cyclooxygenase 2, Cytokine environment, Gene expression, IFN-γ, IL-10, IL-4, Immunoregulation, Mesenchymal stem cells, Regulatory B cells,
• MeSH
• aktivace lymfocytů účinky léků   imunologie   MeSH
• antigeny CD279 genetika   imunologie   metabolismus   MeSH
• buněčné mikroprostředí účinky léků   imunologie   MeSH
• cyklooxygenasa 2 genetika   imunologie   metabolismus   MeSH
• cytokiny imunologie   metabolismus   farmakologie   MeSH
• ELISA MeSH
• exprese genu účinky léků   genetika   imunologie   MeSH
• indolamin-2,3,-dioxygenasa genetika   imunologie   metabolismus   MeSH
• interferon gama farmakologie   MeSH
• interleukin-10 imunologie   metabolismus   MeSH
• interleukin-4 farmakologie   MeSH
• interleukin-6 genetika   imunologie   metabolismus   MeSH
• kokultivační techniky MeSH
• kultivované buňky MeSH
• mezenchymální kmenové buňky účinky léků   imunologie   metabolismus   MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• regulační B-lymfocyty účinky léků   imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD279 MeSH
• cyklooxygenasa 2 MeSH
• cytokiny MeSH
• IL4 protein, human MeSH Prohlížeč
• indolamin-2,3,-dioxygenasa MeSH
• interferon gama MeSH
• interleukin-10 MeSH
• interleukin-4 MeSH
• interleukin-6 MeSH
• PDCD1 protein, human MeSH Prohlížeč

The immunoregulatory properties of mesenchymal stem cells (MSCs) have been well documented in various models in vitro and in vivo. Furthermore, a population of regulatory B cells (Bregs) that produce relatively high concentrations of IL-10 has been recently described. To study the relationship between MSCs and Bregs, we analyzed the effects of MSCs on IL-10 production by lipopolysaccharide (LPS)-activated mouse B cells. The production of IL-10 by B cells remained preserved in the presence of MSCs and was even significantly enhanced by IFN-γ. However, the production of IL-10 was strongly suppressed in cultures containing MSCs and IFN-γ. Preincubation of MSCs, but not of B cells, with IFN-γ induced the suppression of IL-10 secretion in cultures containing MSCs and B cells. The supernatants from IFN-γ-treated MSCs had no inhibitory effect, and the suppression of IL-10 production was abrogated if the MSCs and B cells were separated in a transwell system. Analysis of the gene expression of IFN-γ- or IFN-γ and LPS-treated MSCs revealed a strong upregulation of genes for indoleamine-2,3-dioxygenase (IDO), cyclooxygenase-2 (Cox-2) and programmed cell death-ligand 1 (PD-L1). While the inhibition of IDO activity or the inclusion of the neutralization monoclonal antibody anti-PD-L1 did not abrogate the suppression, indomethacin, an inhibitor of Cox-2, completely inhibited the MSC-mediated suppression of IL-10 production. Accordingly, the production of IL-10 by B cells was inhibited by exogenous prostaglandin E2. The results thus suggest that IFN-γ-treated MSCs strongly inhibit IL-10 production by activated B cells by a mechanism requiring cell contact and involving the Cox-2 pathway.

• Klíčová slova
• B cells, Cyclooxygenase-2, IL-10 production, Immunosuppression, Mesenchymal stem cells,
• MeSH
• aktivace lymfocytů účinky léků   MeSH
• antigeny CD274 antagonisté a inhibitory   genetika   imunologie   MeSH
• B-lymfocyty cytologie   účinky léků   imunologie   MeSH
• cyklooxygenasa 2 genetika   imunologie   MeSH
• difuzní komory kultivační MeSH
• dinoproston farmakologie   MeSH
• indolamin-2,3,-dioxygenasa genetika   imunologie   MeSH
• indomethacin farmakologie   MeSH
• inhibitory cyklooxygenasy farmakologie   MeSH
• interferon gama farmakologie   MeSH
• interleukin-10 antagonisté a inhibitory   genetika   imunologie   MeSH
• kokultivační techniky MeSH
• kultivační média speciální farmakologie   MeSH
• lipopolysacharidy farmakologie   MeSH
• mezenchymální kmenové buňky cytologie   účinky léků   imunologie   MeSH
• mezibuněčná komunikace imunologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• neutralizující protilátky farmakologie   MeSH
• primární buněčná kultura MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD274 MeSH
• Cd274 protein, mouse MeSH Prohlížeč
• cyklooxygenasa 2 MeSH
• dinoproston MeSH
• IL10 protein, mouse MeSH Prohlížeč
• indolamin-2,3,-dioxygenasa MeSH
• indomethacin MeSH
• inhibitory cyklooxygenasy MeSH
• interferon gama MeSH
• interleukin-10 MeSH
• kultivační média speciální MeSH
• lipopolysacharidy MeSH
• neutralizující protilátky MeSH
• Ptgs2 protein, mouse MeSH Prohlížeč

BACKGROUND: Insulin resistance is in addition to impaired beta-cell function decisive for the development of type 2 diabetes. It is also known that obesity creates conditions for the development of insulin resistance. The authors tried therefore to influence insulin sensitivity by short-term reducing diets in obese type 2 diabetics. METHODS AND RESULTS: The group of patients comprised 12 obese type 2 diabetics, BMI: 40.3 +/- 8.9 kg/m2, age 50 +/- 8 years. The control group was formed by 12 healthy non-obese subjects. The following parameters of glucose tolerance were assessed: total glucose consumption to maintain euglycaemia (M) during an isoglycaemic hyperinsulinaemic clamp on a Biostator, index of tissue sensitivity to insulin (M/I), metabolic glucose clearance (MCRG), number of insulin receptors on erythrocytes (Ro) and the insulin affinity for receptors (Ko). A reducing diet, 600 kcal/day, was served for 7 days during hospitalization. The body weight of diabetics dropped by 3.2 +/- 1.5 kg, p < 0.001, there was a significant decline of the basal blood sugar level (G(o)) from 11.4 +/- 3.6 to 8.4 +/- 3.0 mmol/l, p < 0.01; 2 there was a significant reduction of the serum insulin level (Io) from 30 +/- 18 to 27 +/- 19 mU/l, p < 0.02, whereby glucose uptake M increased from 24.0 +/- 7.5 to 29.5 +/- 8.9 mumol/kg/min, p < 0.01 and at the same time the metabolic glucose clearance increased from 2.3 +/- 0.9 to 4.0 +/- 2.5 ml/kg/min, p < 0.01, while the index of tissue sensitivity to insulin M/I increased less significantly from 16.3 +/- 7.4 to 18.0 +/- 10.5 mumol/kg/min per mU x 100). There was a decline in the number of insulin receptors on erythrocytes from 245 +/- 66 to 192 +/- 61 pmol/l, p < 0.02, whereby their affinity improved: 12.8 +/- 3.9 as compared with 17.3 +/- 5.4 10(8) l/mol, p < 0.01 but the insulin bond remained unchanged. CONCLUSIONS: A short-term reducing diet leads to improvement of the majority of investigated indicators which is manifested in particular by improved action of insulin, above all at a postreceptor level. Significant reduction of the number of insulin receptors was partly compensated by improved affinity, while the insulin bond did not change in a marked way.

• MeSH
• diabetes mellitus 2. typu metabolismus   MeSH
• diabetes mellitus dietoterapie   metabolismus   MeSH
• glukózový toleranční test MeSH
• inzulin krev   MeSH
• inzulinová rezistence * MeSH
• krevní glukóza analýza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• obezita * MeSH
• redukční dieta * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inzulin MeSH
• krevní glukóza MeSH

Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2'-deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon gamma (IFNgamma), IFNbeta and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNbeta-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.

• MeSH
• bromodeoxyuridin farmakologie   MeSH
• cytokiny genetika   metabolismus   MeSH
• distamyciny farmakologie   MeSH
• HeLa buňky MeSH
• interferony genetika   metabolismus   MeSH
• interleukin-10 genetika   metabolismus   MeSH
• interleukin-6 genetika   metabolismus   MeSH
• interleukin-8 genetika   metabolismus   MeSH
• interleukiny genetika   metabolismus   MeSH
• Janus kinasa 1 genetika   metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• RNA interference MeSH
• signální transdukce účinky léků   MeSH
• stárnutí buněk účinky léků   MeSH
• synergismus léků MeSH
• transkripční faktor STAT1 genetika   metabolismus   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bromodeoxyuridin MeSH
• cytokiny MeSH
• distamyciny MeSH
• interferony MeSH
• interleukin 20 MeSH Prohlížeč
• interleukin-10 MeSH
• interleukin-24 MeSH Prohlížeč
• interleukin-6 MeSH
• interleukin-8 MeSH
• interleukiny MeSH
• Janus kinasa 1 MeSH
• stallimycin MeSH Prohlížeč
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH

The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.

• Klíčová slova
• CCL27, CCR10, drug resistance, myeloma, stroma cells,
• MeSH
• apoptóza účinky léků   MeSH
• bortezomib farmakologie   MeSH
• chemokin CCL27 metabolismus   MeSH
• chemorezistence * MeSH
• inhibitory proteasomu farmakologie   MeSH
• interakce mezi receptory a ligandy účinky léků   MeSH
• interleukin-10 genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   enzymologie   genetika   patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• pohyb buněk účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• receptory CCR10 genetika   metabolismus   MeSH
• receptory interleukinu-10 genetika   metabolismus   MeSH
• RNA interference MeSH
• senioři MeSH
• signální transdukce účinky léků   MeSH
• transfekce MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bortezomib MeSH
• CCL27 protein, human MeSH Prohlížeč
• CCR10 protein, human MeSH Prohlížeč
• chemokin CCL27 MeSH
• IL10 protein, human MeSH Prohlížeč
• inhibitory proteasomu MeSH
• interleukin-10 MeSH
• proteasomový endopeptidasový komplex MeSH
• receptory CCR10 MeSH
• receptory interleukinu-10 MeSH