Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) suppresses many immune responses, both innate and adaptive. Suppression is mediated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. The AhR mediates TCDD toxicity presumably through the alteration of transcriptional events, either by promoting gene expression or potentially by physically interacting with other transcription factors. Another transcription factor, NF-kappaB/Rel, is involved in several signaling pathways in immune cells and is crucial for generating effective immune responses. Dendritic cells (DCs), considered to be the "pacemakers" of the immune system, were recently recognized as targets of TCDD and are also dependent on NF-kappaB/Rel for activation and survival. In these studies, we investigated whether TCDD would alter the activation of NF-kappaB/Rel in DCs. The dendritic cell line DC2.4 was exposed to TCDD before treatment with tumor necrosis factor alpha (TNF-alpha) or anti-CD40, and NF-kappaB/Rel activation was measured by electrophoretic mobility shift assay and immunoblotting. TCDD suppressed the binding of NF-kappaB/Rel to its cognate response element in TNF-alpha- and anti-CD40-treated cells and blocked translocation to the nucleus. The AhR was shown to associate with RelA, after coimmunoprecipitation, and seemed to block its binding to DNA. It is noteworthy that p50 homodimers freely bound to DNA. These results suggest that TCDD may alter the balance between NF-kappaB/Rel heterodimers and transcriptional inhibitory p50 homodimers in DCs, leading to defects in the DCs and suppression of the immune response.
Mol Pharmacol 2002 Sep
PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses tumor necrosis factor-alpha and anti-CD40-induced activation of NF-kappaB/Rel in dendritic cells: p50 homodimer activation is not affected. 1218 50

Antibody evolution in vivo proceeds mainly by stepwise improvements, accomplished by single base pair substitutions. Lately, receptor revision, i.e. exchange of large parts of the V gene for another sequence, has been suggested to provide a complementary route for affinity maturation. By employing a receptor revision like evolution process in vitro using combinatorial libraries and phage display selection, we demonstrate here that maturation of a clone may preferentially proceed through exchange of a large gene segment rather than via minor sequence changes. These modifications of a CD40-specific human antibody fragment outline how receptor revision like events may provide an advantage to a particular clonotype put under selective pressure.
Mol Immunol 2002 Oct
PMID:In vitro molecular evolution of antibody genes mimicking receptor revision. 1222 Aug 92

Our studies show that ischemia-reperfusion (I/R) in the isolated rat lung causes retention of lymphocytes, which is associated with increased microvascular permeability, as determined by quantitative measurement of the microvascular filtration coefficient (K(f,c)). Immunoneutralization of either CD40 or CD40L, cell surface proteins important in lymphocyte-endothelial cell proinflammatory events, results in significantly lower postischemic K(f,c) values. Antagonism of CD40-CD40L signaling also results in attenuation of I/R-elicited macrophage inflammatory protein-2 production. Rat lymphocytes activated ex vivo with phorbol 12-myristate, 13-acetate increased K(f,c) in isolated lungs independently of I/R, and this increase was prevented by pretreating lungs with anti-CD40. In addition to lymphocyte involvement via CD40-CD40L interactions, our studies also show that I/R injury is potentiated by antagonism of IL-10 produced locally within the postischemic lung, whereas exogenous, rat recombinant IL-10 provided protection against I/R-induced microvascular damage. Thus acute lymphocyte involvement in lung I/R injury involves CD40-CD40L signaling mechanisms, and these events may be influenced by local IL-10 generation.
Am J Physiol Lung Cell Mol Physiol 2002 Dec
PMID:Involvement of CD40-CD40L signaling in postischemic lung injury. 1238 54

Gene delivery of CD40 Ligand (CD40L) has shown promise in murine models of melanoma and adenocarcinoma; however, its potential for thoracic malignancies such as malignant mesothelioma remains unclear. In this study, we investigated the hypothesis that CD40L gene therapy would be effective in local and distant tumor suppression in mesothelioma using an immunocompetent murine model. Using a recombinant adenovirus encoding murine CD40L (AdCD40L), we demonstrated no suppression of in vitro cell growth for the AC29 (mesothelioma) cell line. However, inoculation of immunocompetent CBA/J mice with AC29 cells treated ex vivo with AdCD40L resulted in significant suppression of tumor formation in vivo when compared with controls (P < 0.001). Intratumoral inoculation of AdCD40L into previously established AC29 tumors yielded similar antitumor results and was associated with increased recruitment of intratumoral CD8+ T cells. Adoptive transfer of CD8+ T cells from AdCD40L-treated tumor bearing mice conferred protection to naive mice given an AC29 tumor challenge. Finally, in mice with two synchronous tumors, treatment of one of the tumors with AdCD40L resulted in a regression of both tumors. These findings demonstrate the development of tumor specific CD8+ T cells by AdCD40L and support the further development of AdCD40L for the treatment of malignant mesothelioma.
Am J Respir Cell Mol Biol 2003 Sep
PMID:Efficacy of CD40 ligand gene therapy in malignant mesothelioma. 1267 4

CD40, a tumor necrosis factor receptor superfamily member, is up-regulated on intraheptatic endothelial cells (IHEC) and epithelial cells during inflammatory liver disease, and there is evidence that the functional outcome of CD40 ligation differs between cell types. Ligation of CD40 on cholangiocytes or hepatocytes results in induction of Fas-mediated apoptosis, whereas ligation of IHEC CD40 leads to enhanced chemokine secretion and adhesion molecule expression. We now report that differential activation of two transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), in primary human hepatocytes or IHEC, is associated with and may explain, in part, the different responses of these cell types to CD40 ligation. CD40 ligation induced a rise in NF-kappaB activity in hepatocytes,which peaked at 2 h and returned to baseline by 24 h; however, IHEC CD40 ligation resulted in a sustained up-regulation of NF-kappaB (>24 h). In hepatocytes, CD40 ligation led to sustained up-regulation of AP-1 activity >24 h associated with increased protein levels of RelA (p65), c-Jun, and c-Fos, whereas no induction of AP-1 activity was observed in IHECs. Analysis of mitogen-activated protein kinase phosphorylation (phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH(2)-terminal kinase 1/2) and expression of inhibitor kappaBalpha were entirely consistent, and thus confirmed the profiles of NF-kappaB and AP-1 signaling and the effects of the selective inhibitors assessed using electrophoretic mobility shift assay or Western immunoblotting. CD40 ligation resulted in induction of apoptosis in hepatocytes after 24 h, but on IHECs, CD40 ligation resulted in proliferation. Inhibition of (CD40-mediated) NF-kappaB activation prevented IHEC proliferation and led to induction of apoptosis. Selective extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase inhibitors reduced levels of apoptosis in (CD40-stimulated) hepatocytes by approximately 50%. We conclude that differential activation of these two transcription factors in response to CD40 ligation is associated with differences in cell fate. Transient activation of NF-kappaB and sustained AP-1 activation is associated with apoptosis in hepatocytes, whereas prolonged NF-kappaB activation and a lack of AP-1 activation in IHECs result in proliferation.
Mol Biol Cell 2003 Apr
PMID:Differential induction of nuclear factor-kappaB and activator protein-1 activity after CD40 ligation is associated with primary human hepatocyte apoptosis or intrahepatic endothelial cell proliferation. 1268 91

Pulmonary dendritic cells (DC) can induce both tolerogenic as well as inflammatory immune responses in the lung. Conversely, little is known about the impact of ongoing airway inflammation on pulmonary DC biology. In noninflammatory conditions, expression of T cell costimulatory molecules on mouse airway DCs is low and only upregulated after homing into draining thoracic lymph nodes. In this study, we reveal that ongoing allergic airway inflammation induces a premature upregulation of the T cell costimulatory molecules CD40, B7-2 and intercellular adhesion molecule 1 on DCs still present in the airways. In contrast, high surface expression of inducible costimulator ligand, involved in respiratory tolerance induction is restricted to DCs from noninflamed lungs. In addition, during inflammation the migratory flux of allergen-transporting airway DCs toward draining thoracic nodes increases both in amplitude as well as in speed. Remarkably, migratory DCs from inflamed airways are short-lived in the draining lymph nodes, a finding that is temporally associated with a marked loss of the antiapoptotic protein Bcl-2 in these cells. This study demonstrates the profound effects of ongoing allergen-driven airway inflammation on the dynamics of pulmonary DC physiology, a knowledge that could be exploited in the development of novel DC-based immunotherapies.
Am J Respir Cell Mol Biol 2003 Sep
PMID:Accelerated airway dendritic cell maturation, trafficking, and elimination in a mouse model of asthma. 1270 44

Graft rejections as well as tolerance are true representation of the specificity, sophistication and redundancy of an elegantly and meticulously designed immune system. Tolerance is in a way similar to the process of self-recognition where lymphoid clones, during development, baring self-reactive receptor are eliminated or rendered in active by "clonal deletion" leading to a state of accommodation and acceptance (anergic). On the other hand, both acute and chronic rejections are manifestation of the purpose of existence of the immune system, which is to defend the host against foreign invaders. Thus, in order to treat (control) graft rejection it is necessary to determine and understand the steps leading to recognition, stimulation, activation, and amplification of the immune system. The first step leading to the initiation of the immune system cascade is recognition. Which can either be direct where donor antigens of the major histocompatibility complex (MHC) expressed on the donor cells (passenger leukocytes) or tissues are recognised by the host immune system. The direct recognition pathway initiates acute graft rejection. Alternatively processed donor MHC peptides presented by the recipient antigen presenting cells (APC) initiate the indirect pathway of immune response, which is as important as the direct recognition especially in chronic rejection. Recognition is followed by the ligation of a series of adhesion molecules starting with an antigen to its specific T-cell receptor (TCR)/cluster of differentiation (CD) complex, expressed on the surface of the T cell. In order for the activation to precede additional costimulatory signals, such as ligation of the CD28/B7, CD4/HLA class II and CD/HLA class I antigens are required. The activation process is accompanied by an increase of cytokines production such as interleukin (IL)-2, IL-12, interferon (INF) and tumour necrosis factor (TNF) by the primed T cell. The complexity and the polymorphic nature of the immune system have necessitated designing agents that inhibit the immune system at different levels. Cyclosporine and Tacrolimus, collectively known as calcineurin inhibitors, seems to act on the IL-2 by inhibiting its production thus leading to a decrease in the proliferation of the activated lymphocyte. Rapamycin, which is similar to Tacrolimus, inhibits graft rejection by blocking IL-2 activation and phosphorylation of 70 S6 kinase thus inhibiting the progression of T-cell from G to S phase. While Cellcept (MMF) reduce the proliferation of T cell by inhibiting purine synthesis and by its action on ionosine monophosphate dehydrogenase. Anti-lymphocyte antibodies (ATG) deplete circulating lymphocytes while selective monoclonal antibodies are directed against IL-2 receptor thus reducing the rate of proliferation of activated T cells. Recently, antibodies to the CD40/CD40 ligand have been shown to induce long-term graft survival with the inhibition of the Th1 cytokines (INF), IL-2 and IL-12 and upregulating the Th2 cytokines IL-4 and IL-10. Lastly graft rejection can be reduced by blockade of the B7/CD28 costimulation pathway with the fusion protein CTLA-4Ig. With the availability of such potent and diverse agents it is now possible to develop multi drug regiments that can depress the immune system at the different steps of the activation cascade, with minimal side effects, thus improving graft and patient survival rates.
Mol Immunol 2003 Jul
PMID:The mosaic of immunosuppressive drugs. 1283 79

Recent studies affirm costimulatory blockade as a beneficial means of preventing allograft rejection. The precise molecular effects of these pathways, however, are not entirely understood. A striking example is in the costimulatory pathways, 4-1BB/4-1BBL, CD40/CD40L, and B7/CD28. Blocking any one of these prolongs graft survival, yet each operates via distinct immunomodulatory signals. To examine the mechanistic relationships among these signals, our approach was a comprehensive investigation of their molecular constituents. Using a model of heterotopic heart transplantation in mice with a costimulatory pathway deficiency, we analyzed the expression profiles of a large panel of immune and inflammatory genes using ribonuclease protection assays coupled with algorithms. We found that while graft survival was prolonged in all groups, each pathway modulates a unique profile of expressed genes. There were 19 genes, for example, with significant changes in expression compared to the control, yet none of these were similarly modulated in all three groups. Our study reveals that despite similar delays of allograft rejection, the molecular basis for this effect is distinct in all three costimulatory pathways. Furthermore, we underscore the existence of numerous molecular mechanisms affecting graft survival. This, in turn, provides crucial implications for clinical treatment post-transplant where inhibitors would be designed to target multiple mechanisms.
J Mol Med (Berl) 2003 Oct
PMID:Analysis of costimulation by 4-1BBL, CD40L, and B7 in graft rejection by gene expression profiles. 1293 98

Endothelial-mesenchymal transdifferentiation (EMT) is believed to play a crucial role in embryonic vascular development and intimal thickening, which contributes to the pathogenesis of atherosclerotic lesions. However, the mechanisms by which it occurs, as well as the signals that control it, have not yet been elucidated. Given the important role played by the CD40-CD40 ligand (CD40L) system during the initiation and progress of atherosclerosis, we investigated whether both CD40 and CD40L were present in the aortic wall during EMT and the advanced stages of chicken embryo development. CD40-CD40L expression was found on endothelial cells (ECs), mesenchymal cells, and smooth muscle cells (SMCs) at all stages examined, and appeared to be distributed across the aortic wall. However, some notable differences between the expression patterns were observed. CD40 had a more restricted distribution compared to CD40L, and did not stain every cell type of the aortic wall. According to immunoblotting and enzyme-linked immunosorbent assay (ELISA) analyses, the CD40L content was highest at day 7 of development. An important and novel finding was the expression of CD40L in areas where ECs transdifferentiate into mesenchymal cells. Specifically, CD40L was associated to the surface of cells that were detaching and migrating from the monolayer of ECs, whereas for CD40 a very diffuse subcellular localization was seen at the monolayer and the detaching and migrating cells. These data suggest a possible role for CD40-CD40L interactions during EMT and the remodeling of the aorta.
Anat Rec A Discov Mol Cell Evol Biol 2003 Oct
PMID:CD40 and CD40L expression in the chicken embryo aorta: possible role in the endothelial-mesenchymal transdifferentiation process. 1297 18

Reactive oxygen species (ROS) have been indicated as important signal mediators for many cell surface receptors. We previously demonstrated that ROS are generated by cross-linking surface receptor CD40 and consequently induce c-Jun N-terminal kinase activation and interleukin-6 secretion in murine B cells. In this study, we investigated further the involvement of ROS in CD40-mediated signaling events in B cells. CD40-mediated proximal events, which include protein serine phosphorylation, protein translocation between membranes and cytosol, as well as receptor complex formation, were inhibited after the pre-incubation of cells with an antioxidant N-acetyl-L-cysteine (NAC). Additionally, B cell responses after long-term ligation of CD40, such as protein expression, nuclear transcription factor kappaB (NFkappaB) activation, and cell proliferation, were also affected when cells were treated with NAC. These data suggest that CD40-induced ROS play critical roles in CD40-mediated B cell regulation.
Mol Cell Biochem 2003 Oct
PMID:Reactive oxygen species play roles on B cell surface receptor CD40-mediated proximal and distal signaling events: effects of an antioxidant, N-acetyl-L-cysteine treatment. 1457 70


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