Acyclic nucleoside phosphonates (ANPs) are potent broad-spectrum antivirals, also effective against immunodeficiency viruses and hepatitis viruses. Effects of several ANPs on in vitro cytokine gene expression and nitric oxide (NO) production by murine peritoneal macrophages were investigated. Included in the study were 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; Adefovir), 9-(R)-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; Tenofovir], 9-(S)-[2-(phosphonomethoxy)propyl]adenine; (S)-PMPA), 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP), 9-(R)-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), and 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG). Some of them, i.e. (R)-PMPA, (S)-PMPA, and PMEG, stimulate secretion of TNF-alpha and IL-10 in a concentration-dependent manner, and enhance the IFN-gamma-induced secretion of TNF-alpha. Although unable to activate production of nitric oxide (NO) on their own, these compounds substantially augment NO formation induced by IFN-gamma. Analysis of the expression of inducible NO synthase mRNA indicates that the NO-enhancing effect of ANPs is mediated posttranscriptionally. In contrast to IFN-gamma, production of NO triggered by lipopolysaccharide (LPS) alone, or synergistically by LPS+IFN-gamma, remains unaltered by ANPs. The immunomodulatory effects have been differentially expressed in distinct genotypes of inbred strains of mice, including the low NO-responders Balb/c and high NO-responders C3H/HeN. Although less effectively, PMEG and (R)-PMPA also increase production of TNF-alpha and NO by the IFN-gamma- but not LPS-co-stimulated macrophages from C3H/HeJ mice, which are otherwise hypo-responsive to major immune stimuli provided by IFN-gamma and LPS. It can be concluded that the expression of immunomodulatory properties of ANPs depends on the immune state of cells and its activation by distinct priming signals.
- MeSH
- adjuvancia imunologická farmakologie MeSH
- aktivace makrofágů účinky léků MeSH
- antivirové látky farmakologie MeSH
- cytokiny metabolismus MeSH
- lipopolysacharidy imunologie farmakologie MeSH
- makrofágy účinky léků imunologie MeSH
- myši inbrední BALB C MeSH
- myši inbrední C3H MeSH
- myši MeSH
- nukleosidy farmakologie MeSH
- organofosfonáty farmakologie MeSH
- oxid dusnatý metabolismus MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- synthasa oxidu dusnatého, typ II MeSH
- synthasa oxidu dusnatého biosyntéza MeSH
- TNF-alfa metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adjuvancia imunologická MeSH
- antivirové látky MeSH
- cytokiny MeSH
- lipopolysacharidy MeSH
- Nos2 protein, mouse MeSH Prohlížeč
- nukleosidy MeSH
- organofosfonáty MeSH
- oxid dusnatý MeSH
- synthasa oxidu dusnatého, typ II MeSH
- synthasa oxidu dusnatého MeSH
- TNF-alfa MeSH
Dialyzed leukocyte extract (DLE) (Immodin SEVAC, Czech Republic) was shown to enhance the recovery of the pools of hemopoietic stem cells (CFUs) and of granulocyte-macrophage hemopoietic progenitor cells (GM-CFC) in the bone marrow in vivo, as well as to increase the numbers of leukocytes and thrombocytes in the peripheral blood of mice exposed to a sublethal dose of gamma-rays, with an ensuing increase in the numbers of mice surviving the lethal radiation dose. In experiments performed in vitro, DLE or sera of mice administered with DLE were added to cultures of intact mouse bone marrow cells containing suboptimal concentrations of hemopoietic stimulatory cytokines, namely recombinant mouse interleukin-3 (rmIL-3) or recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF); under these experimental conditions, both DLE and sera of mice administered DLE were found to increase the counts of GM-CFC colonies in the cultures. It can be hypothesized on the basis of the findings obtained in vitro that the described co-stimulating activity (CoSA) of DLE may play a role also under in vivo conditions; the enhancement of the recovery of hemopoiesis suppressed by ionizing radiation may be due to a co-operation of the stimulatory effects of DLE with the action of cytokines endogenously produced in irradiated tissues.
- MeSH
- buněčné dělení účinky záření MeSH
- faktory stimulující kolonie farmakologie MeSH
- hematopoetické kmenové buňky fyziologie účinky záření MeSH
- hematopoéza účinky záření MeSH
- leukocyty fyziologie MeSH
- myši inbrední C57BL MeSH
- myši inbrední CBA MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- faktory stimulující kolonie MeSH
A possible interaction of immunomodulator muramyl dipeptide (MDP) with 5-HT(7) (5-hydroxytryptamine) receptors was investigated. The activation of 5-HT(7) receptors relaxes the guinea-pig distal ileum. The whole ileum segments were, therefore, cut and placed into the bath. The preparations were precontracted by substance P and potently relaxed by adding incremental concentrations of 5-carboxamidotryptamine (5-CT) (0.01-3.2 microM), less potently by 5-hydroxytryptamine (5-HT) (1-100 microM). The preparations most sensitive to 5-CT were also relaxed by MDP (1-100 microM). Noncumulative concentration-response curves (CRCs) for 5-HT or 5-CT were established in the absence or presence of 5-HT antagonist metergoline (320 nM). Metergoline inhibited the relaxations and shifted the CRCs to the right. In the preparations most sensitive to the effects of both 5-CT and metergoline, the latter substance also inhibited the effect of the highest concentration (100 microM) in CRCs for MDP. In another type of experiments, CRCs for 5-HT or 5-CT were constructed in the presence of low concentrations of MDP (5-500 nM). The relaxations evoked by either drug remained unchanged. These results suggest that low concentrations of MDP do not interact with activation of 5-HT(7) receptors. In higher concentrations MDP acts on this receptor type as a very weak partial agonist.
- MeSH
- acetylmuramyl-alanyl-isoglutamin farmakologie MeSH
- adjuvancia imunologická farmakologie MeSH
- ileum účinky léků fyziologie MeSH
- metergolin farmakologie MeSH
- morčata MeSH
- receptory serotoninové účinky léků MeSH
- serotonin analogy a deriváty farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- morčata MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 5-carboxamidotryptamine MeSH Prohlížeč
- acetylmuramyl-alanyl-isoglutamin MeSH
- adjuvancia imunologická MeSH
- metergolin MeSH
- receptory serotoninové MeSH
- serotonin 7 receptor MeSH Prohlížeč
- serotonin MeSH
Human bronchial epithelial cells are involved in airway immune mechanisms through secretion of cytokines and through cell-cell contacts with immunocompetent cells. The aim of our study was to assess the ability of interferon (IFN) alpha and gamma alone and in combination to modulate human bronchial epithelial cell (HBECs) release of the inflammatory cytokines IL-8 and IL-6 and fibronectin and to induce the surface expression of HLA-DR and ICAM-1 molecules involved in immune interactions with other cells. HBECs spontaneously secreted a limited amount of IL-8, which was significantly increased by IFN gamma. IFN alpha inhibited IFN gamma stimulated IL-8 secretion in a concentration-dependent manner. Further, IFN gamma induced IL-6 and fibronectin secretion, and this was also inhibited by IFN alpha. The expression of HLA-DR antigens was significantly increased by IFN gamma and partially inhibited by co-stimulation with IFN alpha. In contrast, IFN gamma also induced ICAM-1 expression by HBECs but co-stimulation with IFN alpha had no significant effect on the expression of this surface antigen. IFN alpha modulation of HBEC functions does not seem to be restricted to IFN gamma stimulation since either stimulatory or inhibitory effects of INF alpha on IL-8 production have been found in pilot experiments using IL-1 beta, TNF alpha, and TGF beta as stimuli. In summary, IFN-gamma induces a number of responses in HBECs including increased secretion of IL-6, IL-8 and fibronectin and increased expression of HLA-DR and ICAM-1. IFN alpha can inhibit all these except expression of ICAM-1 which is unaffected. IFN alpha can also interact with other inflammatory cytokines, but whether the effects are inhibitory or augmentive depends on the cytokines.
- MeSH
- bronchy cytologie účinky léků imunologie MeSH
- cytokiny biosyntéza MeSH
- epitelové buňky účinky léků imunologie MeSH
- fenotyp MeSH
- fibronektiny biosyntéza MeSH
- HLA-DR antigeny biosyntéza MeSH
- interferon alfa farmakologie MeSH
- interferon gama farmakologie MeSH
- interleukin-6 biosyntéza MeSH
- interleukin-8 biosyntéza MeSH
- kultivované buňky MeSH
- lidé MeSH
- mezibuněčná adhezivní molekula-1 biosyntéza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Názvy látek
- cytokiny MeSH
- fibronektiny MeSH
- HLA-DR antigeny MeSH
- interferon alfa MeSH
- interferon gama MeSH
- interleukin-6 MeSH
- interleukin-8 MeSH
- mezibuněčná adhezivní molekula-1 MeSH
It has been demonstrated that the synthetic immunostimulatory compound, adamantylamide dipeptide (AdDP) produces hematopoiesis-stimulating effects in mice exposed to sublethal doses of ionizing radiation and increases survival in experimental animals irradiated with a lethal dose. These findings might suggest contingent extension of clinical indications for the administration of AdDP for the conditions of hematopoietic suppression, especially in oncology.
- MeSH
- adjuvancia imunologická farmakologie MeSH
- amantadin analogy a deriváty farmakologie MeSH
- dipeptidy farmakologie MeSH
- hematopoetické kmenové buňky účinky léků účinky záření MeSH
- hematopoéza účinky léků MeSH
- myši inbrední C57BL MeSH
- myši inbrední CBA MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adamantylamide-alanyl-isoglutamine MeSH Prohlížeč
- adjuvancia imunologická MeSH
- amantadin MeSH
- dipeptidy MeSH
Immunomodulator muramyl dipeptide (MDP) exerts also pronounced neuropharmacological activities which are probably mediated by an interaction with 5-HT receptors. Some of these effects are considered as undesirable by its clinical use. More precise information concerning MDP effects on 5-HT receptors with respect to their many subtypes could result from studies using isolated organs in vitro. Earlier conducted studies of this type provided data that are concisely overviewed and reinterpreted here from the view of current 5-HT receptor classification. Since new 5-HT receptor types have emerged recently, new studies are under way. The results might contribute to the development of novel immunomodulatory drugs devoid of adverse effects.
- MeSH
- acetylmuramyl-alanyl-isoglutamin farmakologie MeSH
- adjuvancia imunologická farmakologie MeSH
- lidé MeSH
- receptory serotoninové klasifikace účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- acetylmuramyl-alanyl-isoglutamin MeSH
- adjuvancia imunologická MeSH
- receptory serotoninové MeSH
The effects of protein-kinase-inhibitors (PKIs) on protein kinase C (PKCs) i.e., staurosporin, calphostin C, H-7, H-8, H-9, on phosphatidyl inositol 3-proteinkinase (PI3-K) i.e., wortmannin, and on protein tyrosine kinase (PTKs) i.e., genistein, herbimycin A, sanguinarin, lavendustin A and B were tested on the induction phase of the primary Ab-response in vitro. The inhibitory action of PKIs was the highest with herbimycin A, sanguinarin, H-9 and wortmannin. Although wortmannin inhibits the function of T-lymphocytes (Taub et al., 1997, Shi et al., 1997), we believe that this communication is the first report of PKIs immunosuppressive action on the inductive steps of Ab-formation.
- MeSH
- inhibitory enzymů farmakologie MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- inhibitory proteinkinas * MeSH
- kultivované buňky MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- proteinkinasa C antagonisté a inhibitory MeSH
- slezina účinky léků imunologie MeSH
- tvorba protilátek účinky léků MeSH
- tyrosinkinasy antagonisté a inhibitory MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- inhibitory enzymů MeSH
- inhibitory fosfoinositid-3-kinasy MeSH
- inhibitory proteinkinas * MeSH
- proteinkinasa C MeSH
- tyrosinkinasy MeSH
A number of immunomodulating agents of different origin have been shown to reduce liver injury of various etiologies. Immunostimulants like levamisole, BCG, a protein polysaccharide from myceria Coriolus vesicolor PS-K, a streptoccocal preparation OK-432 and immunomodulators like N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and its analogs. Selective T-cell suppressors like the polypeptide cyclosporine A (CsA) and the macrolide FK 506 (tacrolimus) have also been claimed to possess hepatoprotrophic or hepatoprotective properties at low doses. The aim of this review article is to highlight the interplay between the administration of immunomodulating agents and the amelioration of hepatic injuries. Hepatic effects of exogenous immunomodulators are discussed with special focus on the most widely used immunosuppressive agents, CsA and tacrolimus. An important question exists as to whether these potential hepatoprotective effects are related mechanistically to the immune system or are working at different levels. Due to the differences in effects and modes of actions of various immunoactive substances presented herein, a common mechanism for their cytoprotective effects cannot be formulated at this stage. Levamisole and cyanidanol may protect cells against necrosis by acting as free radical scavengers. MDP and its analogs reduce carbon tetrachloride-elevated (CCl4) lipid peroxides and their protective effects are primarily on hepatic cytoplasmic membranes where lipid peroxidation and calcium homeostasis interact. MDP reduced CCl4-elevated calcium in both intact hepatocytes and in the post microsomal supernatant suggest that the influx of extracellular calcium across plasma membrane is affected. Elevations of intracellular calcium above a threshold are involved in: the stimulation of Ca2+-sensitive enzymes such as phospholipase A2, endonucleases and proteases, the conversion of xanthine dehydrogenase to xanthine oxidase and the formation of free radicals, all of which disturb biomembranes. MDP and its analogs, in a specific dose range, may act to maintain intracellular calcium within physiological ranges. Highly complex cellular signalling systems, including calcium, are involved in the explanation of the mechanism of the immunosuppressive effect of CsA and tacrolimus. The hepatoprotective effects of these selective immunosuppressive agents, however, are independent of the inhibition of T-cell activation. The cyclophilin and tacrolimus binding proteins of the mitochondria are the receptors for these compounds and play a key role in the regulation of mitochondrial permeability transition pores. CsA or tacrolimus inhibition of mitochondrial permeability transition pores does not require interaction with calcineurin, indicating a dissociation between immunosuppression and mitochondrial protection. The involvement of intracellular or intramitochondrial proteins in the modulation of mitochondrial permeability transition pores with the creation of a partially impermeable state for Ca2+ movement in drug-treated mitochondria and the dissociation of this effect from immunomodulatory actions potentially offers new and promising approaches for the development of new pharmacologicals targeted at therapeutic intervention. Clinical trials of these drugs as hepatoprotective agents are limited. Use of CsA in patients with primary biliary cirrhosis and autoimmune chronic hepatitis and in cirrhotic animal models produced by chronic administration of CCl4 have yielded encouraging results. It seems that this class of compounds may be of substantial benefit in liver protection against many pathological conditions where disturbance in mitochondrial function and in Ca2+ homeostasis appear to be prerequisites for cell injury.
- MeSH
- adjuvancia imunologická terapeutické užití MeSH
- játra zranění MeSH
- lidé MeSH
- nemoci jater farmakoterapie etiologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- adjuvancia imunologická MeSH
Immunostimulatory properties of gram-positive Bacillus firmus were investigated under in vitro conditions using murine peritoneal macrophages. B. firmus stimulated in a concentration and time dependent manner the secretion of tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10), but it had no influence upon interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) production. It also substantially augmented production of nitric oxide (NO) induced by exogenous IFN-gamma. Inhibitory experiments using neutralizing antibodies against TNF-alpha and/or IL-10 have demonstrated that these cytokines are responsible for triggering the underlying mechanism(s) leading to enhanced NO production. The cytokine-stimulatory and NO-costimulatory properties could participate in the antiinfectious and anticancer effects of B. firmus, detected previously in the in vivo experiments.
- MeSH
- aktivace makrofágů * MeSH
- Bacillus imunologie MeSH
- interferon gama analýza farmakologie MeSH
- interleukin-10 antagonisté a inhibitory imunologie metabolismus MeSH
- interleukin-2 analýza MeSH
- lipopolysacharidy farmakologie MeSH
- monoklonální protilátky imunologie farmakologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- Nocardia imunologie MeSH
- oxid dusnatý biosyntéza MeSH
- peritoneální makrofágy metabolismus MeSH
- rekombinantní proteiny MeSH
- synthasa oxidu dusnatého metabolismus MeSH
- TNF-alfa antagonisté a inhibitory imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- interferon gama MeSH
- interleukin-10 MeSH
- interleukin-2 MeSH
- lipopolysacharidy MeSH
- monoklonální protilátky MeSH
- oxid dusnatý MeSH
- rekombinantní proteiny MeSH
- synthasa oxidu dusnatého MeSH
- TNF-alfa MeSH
The literature data assembled in this article document the variation of immunobiological effects of nitric oxide (NO). A number of factors are obviously responsible for the diversity, ranging from inactivity, alleviation, but not rarely to exacerbation of certain pathogenetic processes. A better understanding of NO interactions with the immune system can only be reached if more complex experimental designs to study the effects of reactive nitrogen species are adopted in the future. They should integrate major participating variables and take into account pharmacodynamic/kinetic aspects of NO production in triggering the ultimate effects. If manipulation of NO in the organism by means of recently developed NO inhibitors and NO donors is to become a rational tool of immunopharmacological strategies, detailed knowledge of their pharmacologies and toxicologies is urgently needed in order to differentiate between the effects of NO and other side effects. Hopefully, this approach could improve the predictability of the clinical outcomes of NO manipulation.
- MeSH
- apoptóza MeSH
- arginin metabolismus MeSH
- autoimunitní nemoci metabolismus MeSH
- cytokiny fyziologie MeSH
- cytotoxicita imunologická účinky léků MeSH
- donory oxidu dusnatého farmakologie MeSH
- druhová specificita MeSH
- encefalomyelitida autoimunitní experimentální metabolismus MeSH
- endotoxemie metabolismus MeSH
- idiopatické střevní záněty metabolismus MeSH
- imunitní systém účinky léků fyziologie MeSH
- infekce metabolismus MeSH
- izoenzymy antagonisté a inhibitory metabolismus MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- MHC antigeny II. třídy biosyntéza imunologie MeSH
- myši MeSH
- nádory krevní zásobení metabolismus prevence a kontrola terapie MeSH
- oxid dusnatý farmakologie fyziologie MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- arginin MeSH
- cytokiny MeSH
- donory oxidu dusnatého MeSH
- izoenzymy MeSH
- MHC antigeny II. třídy MeSH
- oxid dusnatý MeSH
- synthasa oxidu dusnatého MeSH
