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At least 361 records · Page 20Linked to original sources
PubMed2003

Opioid-induced immunosuppression: is it centrally mediated or peripherally mediated?

Opioid compounds are commonly used pain medications. However, their administration is associated with a number of side-effects. Among them, opioid-induced immunosuppression is a significant medical problem, which is evidenced by a strong association between the use of opioids and exacerbated infections, including AIDS. Research data have demonstrated the effects of opioids to be suppressive on phagocytic, natural killer (NK), B and T cells. However, these immunosuppressive effects may be mediated by mechanisms different from those for antinociceptive actions. This article reviews possible central and peripheral mechanisms of opioid-induced immunosuppression. To the extent that peripherally mediated immunosuppressive effects play a significant role in opioid-induced immunosuppression, novel peripheral opioid antagonists may have a therapeutic role in attenuating opioid-induced immunosuppression without affecting analgesia.

Analgesics, Opioid↗
PubMed2004

Coactivator ASC-2 mediates heat shock factor 1-mediated transactivation dependent on heat shock.

Upon exposure to elevated temperatures, mammalian cells increase the expression of the heat shock proteins (HSP) through activation of the heat shock factor 1 (HSF1). Since most transcription factors require coactivators for efficient transcriptional activity, we tried to identify the coactivator(s) that interacts with and modulates the activities of HSF1. In vitro glutathione S-transferase (GST) pull-down assay revealed that HSF1 strongly interacts with activating signal cointegrator (ASC)-2 and weakly with cyclic adenosine monophosphate responsive element binding protein (CBP). We also show that cotransfection of ASC-2, but not CBP, potentiates HSF1-mediated transactivation based on its cognate element (heat shock element, HSE) linked to luciferase reporter. The molecular interaction of HSF1 and ASC-2 was stimulated by heat shock in cells and the overexpression of HSF1-interacting domain of ASC-2 inhibited the specific induced protein association and HSF1-mediated transactivation. Taking these results together, we suggest that ASC-2 in a novel coactivator for HSF1 and heat shock stress may contribute the strong active transcription complex through sequential recruitment of HSF1 and ASC-2.

Binding Sites↗
PubMed1997

Urokinase-mediated transactivation of the plasminogen activator inhibitor type 2 (PAI-2) gene promoter in HT-1080 cells utilises AP-1 binding sites and potentiates phorbol ester-mediated induction of endogenous PAI-2 mRNA.

Urokinase-type plasminogen activator (u-PA) bound to its receptor, u-PAR, initiates signal transduction pathways able to induce expression of the activator protein-1 (AP-1) family member c-fos [1]. Since transcription factors bound to AP-1 recognition sequences within the PAI-2 gene promoter play a role in basal and phorbol ester-mediated induction of PAI-2 gene expression, we hypothesised that u-PA/u-PAR-mediated modulation of AP-1 activity would in turn influence constitutive and inducible PAI-2 gene expression. Treatment of HT-1080 or U-937 cells with high molecular weight u-PA (HMW u-PA) resulted in induction of nuclear proteins binding to a functional AP-1 element in the proximal PAI-2 promoter. This increase in AP-1 activity correlated with a transactivation of the PAI-2 gene promoter in transiently transfected HT-1080 cells. We also demonstrate the u-PA treatment potentiated phorbol ester (PMA)-mediated induction of PAI-2 mRNA, indicating that u-PA binding produces a bone fide response in vivo.

Base Sequence↗
PubMed1996

Effects of dietary vitamin C and E supplementation on the copper mediated oxidation of HDL and on HDL mediated cholesterol efflux.

Copper mediated oxidative modification of high density lipoprotein (HDL) diminishes its capacity to promote cholesterol efflux from cells in culture. In the present study, HDL was isolated from eight subjects before and after a 10 day administration of the antioxidant vitamins C and E. After incubation HDL (1.25 mg protein/ml) with 10 microM copper for 0-4 h or with 0-20 microM copper for 4 h, thiobarbituric acid reactive substances (TBARS) production was significantly decreased following vitamin administration suggesting that the vitamins decreased the susceptibility of HDL to oxidation. However, two other assays of lipoprotein oxidation, trinitrobenzene sulfonic acid reactivity and conjugated diene formation, did not show a consistent effect of vitamin administration. To study cholesterol efflux, J774 macrophages were labeled with 3H cholesterol (0.1 microCi/ml, 50 micrograms/ml) and incubated with HDL or oxidized HDL (100 micrograms protein/ml) for 24 h. HDL isolated before vitamins and oxidized in vitro was 39% less effective in mediating efflux compared to unmodified HDL, while HDL isolated after vitamins and oxidized was 22% less effective (before vs. after vitamins, P < 0.015). HDL oxidation determined by measuring TBARS production correlated with decreased cholesterol efflux (r = 0.37, P < 0.050). These data suggest that oxidation of HDL interferes with its role in reverse cholesterol transport and that antioxidant vitamins have a protective effect.

Adult↗
PubMed2003

Development and evaluation of a flow-cytometric assay of specific cell-mediated immune response in activated whole blood for the detection of cell-mediated immunity against varicella-zoster virus.

A new assay for the detection of specific cell-mediated immune (CMI) responses is described. Whole blood, diluted 1/10 in medium, was cultured in the presence or the absence of specific antigens. Results were assessed by flow cytometric analysis with or without immunophenotyping to detect proliferating lymphoblasts among cultured cells. Interferon-gamma, IL-10, and IL-5 in culture supernatants are measured by ELISAs. The assay was evaluated using samples from 37 VZV-antibody-positive children with a history of chickenpox and samples from 15 seronegative children without a history of chickenpox; it displayed a sensitivity of 95% and a specificity of 100% for the detection of varicella-zoster virus (VZV)-specific CMI. The intraassay and interassay variations of the new test were lower than with the conventional assay for CMI, detecting thymidine incorporation in peripheral blood mononuclear cells (PBMCs). Cytokines were detected in only 70% of cultures from VZV-antibody-positive subjects. The cytokine response was restricted to IFN-gamma in most cases. The Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood (FASCIA) is a precise and accurate yet simple and convenient test that can be readily employed for the examination of single samples as well as for large-scale studies.

Adolescent↗
PubMed2000

Zinc has no effect on IL-3-mediated apoptosis of BAF-3 cells but enhances CD95-mediated apoptosis of jurkat cells.

The feasibility of using a zinc-inducible gene expression system for the study of apoptosis-controlling genes in BAF-3 murine B cells and Jurkat human T cells was evaluated. Initially, cell sensitivity to a range of zinc concentrations was examined. It was found that zinc concentrations above 60 microM were toxic to BAF-3 cells and those above 50 microM were toxic to Jurkat cells. Secondly, the zinc concentration required to achieve maximal gene expression was examined. BAF-3 cells transiently transfected with the pMTCB6+/luciferase vector were exposed to zinc concentrations ranging from 0-120 microM, whilst stably transfected Jurkat cells were exposed to 0-70 microM zinc. At zinc concentrations nontoxic to each cell type, the maximum induction achieved was 20-fold (at 60 microM) in BAF-3 cells, and 7.5-fold (at 50 microM) in Jurkat cells. Thirdly, the effect of zinc on apoptosis was examined. It was shown that exposure to nontoxic zinc concentrations had no effect on IL-3 withdrawal-mediated apoptosis of BAF-3 cells. However, in the case of Jurkat cells, pre-exposure to zinc augmented CD95-mediated apoptosis. These results illustrate the importance of characterizing individual cell lines when using zinc-inducible gene expression systems.

Animals↗
PubMed1997

T-cell-mediated epineurial vasculitis and humoral-mediated microangiopathy in cryoglobulinemic neuropathy.

We used immunohistochemistry to assess the role of humoral and cellular factors in endoneurial microangiopathy and epineurial vasculitis in 15 nerve biopsies of patients with axonal neuropathy and monoclonal or mixed cryoglobulinemia (CG). Deposition of immunoglobulins and cytolytic complement was detected in endoneurial capillaries of patients with mixed CG. Epineurial inflammatory infiltrates containing beta2-integrin-positive lymphocytes and monocytes surrounded arterioles expressing cell adhesion molecules, thus suggesting a cell-mediated pathogenesis of the epineurial vasculitis. On the other hand, the absence of immune complex deposition and polymorphonuclear elements suggests a minor role for the humoral mechanisms in the formation of the vasculitic lesions. This study indicates that both cell-mediated mechanisms and immune complexes/cryoglobulins are involved, although at different levels, in the pathogenesis of CG neuropathy.

Aged↗
PubMed1999

Lethal hepatic apoptosis mediated by tumor necrosis factor receptor, unlike Fas-mediated apoptosis, requires hepatocyte sensitization in mice.

BACKGROUND/AIMS: Tumor necrosis factor a (TNF-alpha) and Fas ligand are apoptotic cell-death mediators that act by binding to their responsive receptors. The aims of this study were to assess the differences between liver cell deaths induced by TNF-alpha and anti-Fas antibody, and to investigate the mechanism by which GalN sensitizes the hepatocyte to injury by TNF-alpha. METHODS: TNF-alpha or anti-Fas antibody was injected into BALB/c mice sensitized or unsensitized by D-galactosamine (GalN). Liver injury was assessed biochemically and histologically. The expressions of TNF receptor (TNFR)1 and TNFR2 mRNA in the liver were determined by Northern blot analysis. Nuclear factor-kappaB (NF-kappaB) DNA binding activity was determined by gel shift assay. RESULTS: In GalN-sensitized mice, hepatocyte apoptosis and liver failure were observed after TNF-alpha injection, but neither occurred in unsensitized mice. Microscopically, GalN preceding TNF-alpha caused massive hemorrhagic liver damage with fragmented hepatocyte nuclei resembling effects of anti-Fas antibody, but GalN largely failed to sensitize to injury by this antibody. TNFR1 mRNA expression in the liver was upregulated within 3 h after GalN administration, and anti-TNFR1 antibody protected GalN-sensitized mice from hepatotoxic effects of TNF-alpha. GalN treatment failed to affect TNF-alpha-induced NF-kappaB activation. CONCLUSIONS: Unlike Fas-related apoptosis, TNFR-mediated apoptosis requires hepatocyte sensitization involving TNFR1 upregulation.

Animals↗
PubMed1997

Vesnarinone inhibits immune-mediated but not Fas (CD95) agonist-mediated hepatic injury.

Previous studies have shown that the administration of concanavalin A (ConA) into mice induces immune-mediated liver injury, which can be largely abrogated by neutralizing tumor necrosis factor(TNF)alpha. Vesnarinone is an experimental drug which is known to inhibit TNF alpha release. Here we demonstrate that vesnarinone inhibits ConA-induced hepatic injury. In a dose-dependent manner, vesnarinone inhibits in several mouse strains the increase of serum aminotransferase concentrations. additional experiments show that vesnarinone inhibits ConA-mediated accumulation of DNA fragmentation in the liver. Furthermore, the drug significantly reduces the levels of circulating TNF alpha and interleukin-6 (IL-6). Vesnarinone does not modulate TNF alpha and IL-6 action on hepatic cells, as shown by its failure to reduce the cytokine specific-stimulation of acute phase plasma proteins in the rat hepatoma H-35 cell line. Neither vesnarinone nor anti-TNF alpha protect against direct liver injury induced by a sublethal dose of agonist anti-Fas (CD95) antibody. Taken together, these results suggest that vesnarinone blocks hepatic injury, in part by inhibiting the release of TNF alpha in vivo.

Acute-Phase Reaction↗
PubMed1998

Locus coeruleus-mediated inhibition of chemosensory responses in the rat nucleus tractus solitarius is mediated by alpha2-adrenoreceptors.

It is known that electrical and L-glutamate stimulation of the locus coeruleus (LC) reduce the multiunit activity evoked in the nucleus of the tractus solitarius (NTS) by cyanoboro-hydride. In the present study, rats anaesthetised with urethane were microinjected with noradrenergic antagonists into the NTS, to test whether the inhibitory effects of LC stimulation on cyanide-evoked discharge in the NTS were mediated by noradrenaline. Microinjection of yohimbine into the NTS (0.2, 0.6, 1.8, 5.4 nmol) induced dose-dependent reduction of the inhibitory effect of LC stimulation on NTS neurones, while prazosin produced no effect. The results indicate that LC-induced inhibition of the cyanide-evoked discharge in the NTS is mediated by endogenous noradrenaline release acting on alpha2-adrenoreceptors.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

Caudal midline medulla mediates behaviourally-coupled but not baroreceptor-mediated vasodepression.

Within the caudal medulla there are two regions whose activation leads to vasodepression and bradycardia, the caudal ventrolateral medulla and a discrete region of the caudal midline medulla. This study investigated, in the halothane anaesthetized rat, the contribution of these two vasodepressor regions to "homeostatic" and "behaviourally-coupled" cardiovascular regulation. In an initial set of experiments the contribution of each of these two regions to the hypotension and bradycardia evoked by acute hypovolaemia (15% haemorrhage) was investigated. It was found that inactivation of the caudal midline medulla significantly attenuated (cobalt chloride) or completely blunted (lignocaine) the hypotension and bradycardia evoked by acute hypovolaemia. In contrast, inactivation of the caudal ventrolateral medulla using cobalt chloride, although attenuating the magnitude of the hypotension and completely blocking the bradycardia, did not delay the onset of the hypotension evoked by acute hypovolaemia. The caudal ventrolateral medulla is known to be critical in homeostatic cardiovascular control through the expression of the "baroreceptor reflex" and the hypotension and bradycardia evoked by activation of cardiopulmonary afferents. In a second series of experiments we found inactivation of the caudal midline medulla played no role in baroreflex-evoked bradycardia (i.v. phenylephrine) or the hypotension and bradycardia evoked by cardiopulmonary afferent activation (i.v. 5-hydroxytryptamine). These data suggest that the caudal midline medulla and caudal ventrolateral medulla play different roles in cardiovascular control. The caudal ventrolateral medulla is involved in mediating cardiovascular changes associated with a variety of stimuli including "homeostatic" and "behaviourally-coupled" cardiovascular changes, whereas the caudal midline medulla is critical for mediating "behaviourally-coupled" changes in arterial pressure and heart rate.

Animals↗
PubMed1998

Fc epsilon RI on dendritic cells: a receptor, which links IgE mediated allergic reaction and T cell mediated cellular response.

Dendritic cells (DC) are bone marrow derived cells with strong antigen presenting capacity and can induce primary immune responses by activating naive T cells. Cells of this lineage are called as professional antigen presenting cells (APC), because of their primary function as APC. Since the demonstration of IgE bound epidermal Langerhans cells (LC) in atopic dermatitis (AD) patients, a role of IgE bearing DC as a regulator of IgE mediated allergic reactions is emphasized. Indeed, IgE molecules on DC are functional. DC can take up, process and present IgE bound antigens to T cells more efficiently by means of their surface IgE receptor, FcepsilonRI. In addition to its role as an antigen focusing molecule, DC FcepsilonRI may have another function to induce co-stimulatory signals to T cells, by which Th2 type T cell activation is preferentially induced. Thus, this receptor could serve as an amplifying factor for T cell mediated allergic reactions.

Animals↗
PubMedDate not supplied

When engineered to produce latent TGF-beta1, antigen specific T cells down regulate Th1 cell-mediated autoimmune and Th2 cell-mediated allergic inflammatory processes.

To determine whether T cells which produce large amounts of latent TGF-beta1 are capable of down-regulating autoimmune and allergic disease, myelin basic protein (MBP)-specific and ovalbumin (OVA)-specific BALB/c cloned Th1 cells were transduced with cDNA for murine TGF-beta1 by coculture with fibroblasts producing a genetically engineered retrovirus. The transduced MBP-specific Th1 cells were found to lose the capacity to provoke EAE in BALB/c mice, and to gain instead the ability to protect against EAE in (SJLxBALB/c) F1 mice immunized with proteolipid protein (PLP). This protective effect was not obtained with OVA-specific TGF-beta1 transduced Th1 cells. The transduced OVA-specific Th1 cells did protect against airway hyperreactivity induced by Th2-cell mediated responses to inhaled OVA. This effect was again antigen specific and it also could not be obtained with untransduced OVA-specific Th1 cells. In both cases these effects of antigen specific TGF-beta1 transduced T cells were nullified by administration of neutralizing anti-TGF-beta mAb. Thus, the antigen specificity of the cloned T cells allows the site-specific local delivery of therapeutic active TGF-beta1 to both Th1 and Th2 cell-mediated inflammatory infiltrates.

Animals↗
PubMed2001

Distinguishing BIS-mediated and BAS-mediated disinhibition mechanisms: a comparison of disinhibition models of Gray (1981, 1987) and of Patterson and Newman (1993).

The theoretical framework developed by J. A. Gray (1981, 1987a, 1987b) was used to study disinhibitory behavior. Using a point-scoring reaction time procedure, 4 different experiments were conducted to differentiate 2 disinhibitory mechanisms associated with the behavioral activation system (BAS) and the behavioral inhibition system (BIS). Consistent with the work of C. M. Patterson and J. P. Newman (1993), the BAS-mediated mechanism was related to a lack of inhibition in reward-directed behavior after introducing an occasional aversive contingency and to deficits in learning from aversive cues when responding for reward (Experiments 1-3). The BIS-mediated mechanism was related to a higher ability to extinguish aversive associations (Experiment 1), a lower aversive generalization gradient (Experiment 3), and a lower interference with appetitive behavior in the presence of aversive stimuli (Experiment 4).

Adult↗
PubMed2003

Automatic mediation or absence of mediation? Commentary on Crutcher and Ericsson (2000).

R. J. Crutcher and K. A. Ericsson (2000; see record 2000-05419-014) showed that subjects stopped reporting mnemonic mediation in a recall task after sufficient practice. They concluded that subjects continued to use the mediator indefinitely but that its execution eventually became automatic and no longer required access to working memory. Their article thus supports the more general hypothesis that multistep cognition can take place without awareness. In this article the authors evaluate that conclusion on both conceptual and empirical grounds and report results of a new experiment that indicate that a qualitative shift to direct, unmediated recall can occur for at least some tasks.

Attention↗
PubMed1993

Specific repression of TATA-mediated but not initiator-mediated transcription by wild-type p53.

The p53 protein is apparently central to the development of human cancers because both alleles are often found to be mutated in different tumour types. In addition, wild-type p53 can inhibit transformation by viral and cellular oncogenes in vitro, so p53 has been classified as a tumour suppressor. Investigations of the normal function of p53 have indicated that at least one of its functions could involve the activation of gene expression through the binding of specific DNA-regulatory sequences. Also, overexpression of p53 can mediate growth arrest and repress transcription from a variety of promoters. We demonstrate here both in vivo and in vitro that expression of wild-type p53 specifically represses the activity of promoters whose initiation is dependent on the presence of a TATA box. Promoters whose accurate transcription is directed by a pyrimidine-rich initiator element, however, are immune to the effects of p53. Furthermore, we observe that repression is mediated by an interaction of p53 with basal transcription factor(s). Thus, p53 appears to repress the activity of certain promoters through direct communication with TATA box-dependent basal transcription machinery.

3T3 Cells↗
PubMed1999

Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP).

Butyrate exerts potent anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis. However, the molecular mechanisms mediating these effects remain largely unknown. Using the Caco-2 cell line, a well established model of colon cancer cells, our data show that butyrate induced apoptosis (maximum 79%) is mediated via activation of the caspase-cascade. A key event was the proteolytic activation of caspase-3, triggering degradation of poly-(ADP-ribose) polymerase (PARP). Inactivation of caspase-3 with the tetrapeptide zDEVD-FMK completely inhibited the apoptotic response to butyrate. In parallel, butyrate potently up-regulated the expression of the pro-apoptotic protein bak, without changing Caco-2 cell bcl-2 expression. Butyrate-induced Caco-2 cell apoptosis was completely blocked by the addition of cycloheximide, indicating the necessity of protein synthesis. However, when this inhibitor was added at a time point where bak expression was already enhanced (12 - 16 h after butyrate stimulation), it failed to protect Caco-2 cells against apoptosis. Taken together, these data provide evidence that the molecular events involved in butyrate induced colon cancer cell apoptosis include the caspase-cascade and the mitochondrial bcl-pathway.

Apoptosis↗
PubMed2006

Asn- and Asp-mediated interactions between transmembrane helices during translocon-mediated membrane protein assembly.

Inter-helix hydrogen bonding involving asparagine (Asn, N), glutamine (Gln, Q), aspartic acid (Asp, D) or glutamic acid (Glu, E) can drive efficient di- or trimerization of transmembrane helices in detergent micelles and lipid bilayers. Likewise, Asn-Asn and Asp-Asp pairs can promote the formation of helical hairpins during translocon-mediated membrane protein assembly in the endoplasmic reticulum. By in vitro translation of model integral membrane protein constructs in the presence of rough microsomes, we show that Asn- or Asp-mediated interactions with a neighbouring transmembrane helix can enhance the membrane insertion efficiency of a marginally hydrophobic transmembrane segment. Our observations suggest that inter-helix hydrogen bonds can form during Sec61 translocon-assisted insertion and thus could be important for membrane protein assembly.

Amino Acid Sequence↗