Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated macrophage-conditioned medium (M-CM) induces megakaryocytic differentiation of HIMeg-1 cells. The megakaryocytic differentiation activity (MDA) is proteinaceous since it is susceptible to treatments by proteinases, heat, and reducing agents. MDA is not thrombopoietin (TPO) since (1) TPO alone or in conjunction with several other recombinant cytokines fails to induce any degree of HIMeg-1 cell differentiation; and (2) a neutralizing antibody against TPO or an antibody against the extracellular domain of c-mpl is unable to abolish M-CM-induced CD41 expression on HIMeg-1 cells. Reverse transcriptase-mediated polymerase chain reaction shows that HIMeg-1 cells express c-mpl but not TPO. Additional neutralizing antibody studies suggest that MDA is not one of the cytokines known to induce some degree of megakaryopoiesis in vitro or in vivo including interleukin 3 (IL-3), IL-6, IL-11, granulocyte-macrophage colony-stimulating factor, erythropoietin, or stem cell factor. On the other hand, MDA appears to be a combination of interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha), since neutralizing antibodies against these two cytokines completely abolish MDA-induced CD41 expression. In addition, either recombinant human IFN-gamma or TNF-alpha alone is capable of inducing CD41 and CD42 expression on HIMeg-1 cells. In combination, IFN-gamma and TNF-alpha induce a maximal level of CD41 and CD42 expression which is also accompanied by an increase in cell size and DNA ploidy level. Thus, our studies indicate that IFN-gamma/TNF-alpha is capable of inducing megakaryocytic differentiation of the HIMeg-1 cell line and that HIMeg-1 is a good system for studying the molecular mechanism mediating megakaryocytic differentiation.
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PMID:Megakaryocytic differentiation of HIMeg-1 cells induced by interferon gamma and tumour necrosis factor alpha but not by thrombopoietin. 987 25

Nasopharyngeal carcinoma (NPC) is an epithelial cancer that is causally associated with Epstein-Barr virus (EBV) infection. NPC tumor biopsies are characterized histopathologically by an abundant infiltration of nonmalignant lymphocytes. We analyzed the expression of various cytokines in NPC tissues to investigate the interaction of the infiltrating lymphocytes and tumor cells. Analysis using reverse transcriptase-PCR revealed the expression of a panel of cytokines in the NPC biopsies: interleukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IFN-gamma, tumor necrosis factor-alpha, transforming growth factor-beta, and IL-1 receptor types I and II. Elevated expression of IL-1alpha and IL-1beta was observed in primary tumors and NPC metastases compared to control tissues. Interestingly, this increased expression correlated with the EBV-encoded viral IL-10 transcript. To determine which cells were responsible for producing IL-1, we determined the cellular constituents of NPC biopsies by immunoflow cytometric analysis. On the basis of data from these analyses, the three major specific cell populations, epithelial cells, CD4+ T cells, and CD8+ T cells, were selected from five NPC tumors using specific, antibody-coated paramagnetic beads. Reverse transcriptase-PCR of RNA from these fractionated cells showed that transcripts of IL-1alpha and IL-1beta were present not only in the malignant epithelial cells but also in CD4+ T cells infiltrating the tumor, a finding confirmed by immunohistochemical staining. We hypothesize that the unusual synthesis of IL-1alpha and IL-1beta by EBV-positive epithelial cells as well as by CD4+ T cells might contribute to lymphocyte infiltration and/or tumor growth during NPC development.
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PMID:Profile of cytokine expression in nasopharyngeal carcinomas: a distinct expression of interleukin 1 in tumor and CD4+ T cells. 1019 35

We investigated the role of IL-6 in myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE) using IL-6-deficient mice and found that IL-6-deficient mice were resistant to active induction of EAE, but that the treatment of those mice with IL-6 during the preclinical phase caused typical EAE. We also found that both wild-type and IL-6-deficient mice were resistant to passive transfer of EAE by lymphocytes from IL-6-deficient mice, but that passive transfer of lymphocytes from wild-type mice induced typical EAE in IL-6-deficient mice. Histological abnormalities of the central nervous system (CNS) in those IL-6-deficient mice with EAE were similar to those in wild-type mice with EAE. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed no difference in the production of inflammatory cytokines such as IL-1beta, IL-2, TNF-alpha, and IFN-gamma in the CNS of IL-6-deficient mice with EAE as compared to the CNS of wild-type mice with EAE. These results indicated that IL-6 might be an important factor in the induction phase, but might have little influence on the effector phase of EAE. We further estimated the production of cytokines in MOG-stimulated lymph node (LN) cells by enzyme-linked immunosorbent assay. Increased IL-4 and IL-10 production and reduced IL-2 and IFN-gamma production were observed in LN cells from IL-6-deficient mice as compared to LN cells from wild-type mice. These results suggested that a shift of T cell responses from Thl to Th2 might explain the resistance of IL-6-deficient mice to EAE. Taken together, IL-6 may play a crucial role in the induction phase of EAE by modulating Th1/Th2 balance.
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PMID:IL-6 plays a crucial role in the induction phase of myelin oligodendrocyte glucoprotein 35-55 induced experimental autoimmune encephalomyelitis. 1058 Aug 1

Earlier, we reported an association between low in vitro and in vivo IL-1 and IL-6 production, decreased IL-1beta and IL-10 mRNA expression and B cell chronic lymphocytic leukemia (B-CLL) disease progression. We have now further investigated cytokine mRNA transcription in B-CLL cells and cytokine serum levels in B-CLL patients. Reverse transcriptase polymerase chain reaction (RT-PCR) amplification of tumor necrosis factor (TNFalpha), IFNgamma, IL-6 and BCGF was equally often seen in non-progressive and progressive patients. However, 4 out of 23 non-progressive cases expressed mRNA for IL-12 while no IL-12 expression was seen in 15 progressive patients. No IL-12 was found in sera or supernatants from in vitro stimulated B-CLL cells, whereas TNFalpha and IL-10 were detected in sera from 51 and 31 of 65 B-CLL patients, respectively. TNFalpha values were significantly high in sera from patients in stages III and IV with disease progression. TNFalpha and IL-10 were also detected in culture supernatants from in vitro stimulated B-CLL cells, whereas IFNgamma was undetectable in these cultures and rarely positive in serum. Although further investigations are required, our data and that from previous reports indicate that B-CLL-derived cytokines are involved in B-CLL disease progression.
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PMID:Cytokine expression in B-CLL in relation to disease progression and in vitro activation. 1061 92

TNF-alpha is a pleotropic proinflammatory cytokine that has been implicated as a contributing factor in a number of disease processes, primarily through its ability to induce the expression of inflammatory and cytotoxic mediators. TNF-alpha is also involved in cell growth accompanying the healing process in multiple organ systems and influences liver repair following hepatotoxic damage or regeneration following partial hepatectomy. In this respect, TNF-alpha is a known mitogen for hepatocytes. In this paper we describe a novel role for TNF-alpha in the modulation of expression of TGF-alpha, the latter being a complete hepatocyte mitogen. TNF-alpha directly up-regulates TGF-alpha mRNA by up to 7-fold in isolated mouse hepatocytes, whereas neutralization of TNF-alpha significantly decreased liver mRNA and protein expression of TGF-alpha following chemical-induced hepatotoxicity. That TNF-alpha directly stimulated TGF-alpha was suggested by the inability of either anti-IL-6 Abs or cycloheximide to inhibit TNF-alpha-induced TGF-alpha expression in hepatocytes. However, in the presence of anti-TGF-alpha neutralizing Abs, the mitogenic activity of TNF-alpha is abrogated. Using cells transfected with the TGF-alpha promoter, and an RNA polymerase inhibitor, it was shown that TNF-alpha modulates TGF-alpha expression through both pre- and posttranscriptional events. Taken together, these data suggest that TNF-alpha participates in liver repair and regeneration, in part, by directly inducing the expression of TGF-alpha.
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PMID:TNF-alpha regulates transforming growth factor-alpha expression in regenerating murine liver and isolated hepatocytes. 1062 34

There are two types of infection caused by pathogenic microorganisms, intracellular infection and intercellular infection. Infection of pathogenic leptospira is an intercellular infection. The immunological reaction of host to intercellular infection is unique. The potential immunogen of an expressed protein should meet three criteria: it can be degraded (by antigen-present cells in the host); it should have antigenic epitope which can be recognized by specific antibodies and have at least one epitope that can be recognized by an MHC II protein and T cell receptor. In this study we report the cloning of an L. interrogans protein in plasmid rpDJt and the immunogencity of the expressed protein derivative. A genomic library of L. interrogans serovar lai strain 017 was constructed with the plasmid vector pUC18. Recombinant plasmids, designated pDJH2 and pDJ8 were screened from the bank. EcoRI-inserted fragment of 1. 9 kb recombinant DNA of pDJH2 was ligated into T7 RNA polymerase/promoter vectors (pT7-7). Then they were transformed into E. coli JM109 (De3), one of subclones, designated rpDJt was achieved. SDS-PAGE showed that the molecular weights of expression proteins were 68 kd and 23 kd respectively, designated p68 and p23. Purifying and isolating p68 and p23, we separated them from SDS-Polyacrylamide gels by using Side-Strip method. After fragmenting and electroeluting, p68 and p23 were injected into guinea pigs and rabbits. An extremely strong immune response to p68 was obtained since an anti-p68 antibody response could be detected to a dilution 1:524,288 (guinea pigs) and 1:262,144 (rabbits) by ELISA while anti-P23 antibody being 1:1024 (the same to guinea pigs and rabbits). The results of improved MTT and conA 3HTdR transformation methods showed the activities and proliferation of Th-cells were increased in guinea pigs after p68 immunization (IL-6, 83.25 IU/ml, IL-2, 28.75 IU/ml; RPI, 2.04, SI, 65.62%) Thlymphocyte existed in two subclasses, the Th1- and Th2-cells. A major role of Th2-cells is to "help" B-cells differentiate, replicate, and secrete antibody. The properties of these interactions explain why p68 makes good antigen and p23 does not. The antigens responsible for eliciting the production of protective antibodies are not known; however, several outer membrane proteins on L. interrogans are candidates for vaccine. Our results suggest that expresion protein p68 from recombinants (rpDJt) may be a candidate for gene engineered subunit vaccine for Leptospirosis.
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PMID:[Immunogenecity of expressed protein p68 from recombinant plasmid rpDJt in L. interrogans serovar lai]. 1068 17

Rheumatoid arthritis (RA) is accompanied by synovial inflammation, proliferation, and cartilage destruction. The reasons the activation of synovial fibroblasts often persists despite antiinflammatory therapy are not known. One possibility is that the synovial membrane becomes gradually repopulated with immature mesenchymal and bone marrow cells with altered properties. To explore this hypothesis, we have investigated the expression in RA synovial tissues of various embryonic growth factors from the wingless (wnt) and frizzled (fz) families, which have been implicated in cell-fate determination in both bone marrow progenitors and limb-bud mesenchyme. Reverse transcriptase-PCR analysis revealed expression of five wnt (wnt1, 5a, 10b, 11, and 13) and three fz (fz2, 5, and 7) isoforms in RA synovial tissues. Osteoarthritis synovial tissues expressed much less wnt5a and fz5. Northern blotting confirmed the overexpression of wnt5a and fz5 in RA synovial tissues, in comparison to a panel of normal adult tissues. Compared with normal synovial fibroblasts, cultured RA fibroblast-like synoviocytes expressed higher levels of IL-6, IL-8, and IL-15. Transfection of normal fibroblasts with a wnt5a expression vector reproduced this pattern of cytokine expression and stimulated IL-15 secretion. These results suggest that the unusual phenotypic properties of RA fibroblasts may be attributable partly to their replacement with primitive fibroblast-like synoviocytes with characteristics of immature bone marrow and mesenchymal cells. Clear delineation of the signaling pathway(s) initiated by the wnt5a/fz5 ligand-receptor pair in the RA synovium may yield new targets for therapeutic intervention.
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PMID:Expression and function of wingless and frizzled homologs in rheumatoid arthritis. 1068 8

Increasing evidence suggests that paraneoplastic syndrome may be mediated by tumor-related cytokine release, although the specific factors involved remain to be clearly defined. The cancer cells used in the present study were obtained from a 67-year-old man with metastatic renal cell carcinoma in the subcutaneous space who demonstrated marked leukocytosis (37,800/mm3). The primary tumor of the kidney was pathologically diagnosed as renal cell carcinoma consistent with the sarcomatoid type. On microscopic observation, the cultured cells exhibited an epithelial appearance with vacuole formation in their cytoplasm. Ultrastructural observations revealed relatively marked microvilli and a tight junction. Significant amounts of GM-CSF, G-CSF, IL-6, and IL-8 concentrations in the culture media were identified by an enzyme-linked immunosorbent assay. Reverse transcriptase polymerase chain reaction (RT-PCR) significantly exhibited marker protein m-RNA expression in cancer cells. In addition, GM-CSF receptor and IL-6 receptor mRNA expression was also demonstrated by RT-PCR. The administration of both IL-6 and GM-CSF induced cell-proliferation activities estimated by both [3H]-thymidine and bromodeoxyuridine labeling. Anti-IL-6 antibody and anti-GM-CSF antibody neutralized the enhanced proliferative activities generated by these cytokines. Our findings indicate that the established renal cancer cell line can be demonstrated by both the production of multiple cytokines and by their promotion of autocrine growth. These cells are thus considered to be useful as an effective model for multipotent differentiated renal cell carcinoma, as well as for studying the mechanisms of action of autocrine growth.
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PMID:Autocrine growth promotion by multiple hematopoietic growth factors in the established renal cell carcinoma line KU-19-20. 1099 81

Although 3':5' cyclic adenosine monophosphate (cAMP) is known to modulate cytokine production in a number of cell types, little information exists regarding cAMP-mediated effects on this synthetic function of human airway smooth-muscle (HASM) cells. We examined the effect of increasing intracellular cAMP concentration ([cAMP](i)) on tumor necrosis factor (TNF)-alpha-induced regulated on activation, normal T cells expressed and secreted (RANTES) and interleukin (IL)-6 secretion from cultured HASM cells. Pretreatment of HASM with prostaglandin (PG) E(2), forskolin, or dibutyryl cAMP inhibited TNF-alpha-induced RANTES secretion but increased TNF-alpha-induced IL-6 secretion. Moreover, stimulation with PGE(2), forskolin, or dibutyryl cAMP alone increased basal IL-6 secretion in a concentration-dependent manner. SB 207499, a specific phosphodiesterase type 4 inhibitor, augmented the inhibitory effects of PGE(2) and forskolin on TNF-alpha-induced RANTES. Collectively, these data demonstrate that increasing [cAMP](i) in HASM effectively increases IL-6 secretion but reduces RANTES secretion promoted by TNF-alpha. Reverse transcriptase/polymerase chain reaction and ribonuclease protection assays suggested that these opposite effects of increased [cAMP](i) on TNF-alpha- induced IL-6 and RANTES secretion may occur at the transcriptional level. Accordingly, we examined the effects of TNF- alpha and cAMP on the regulation of nuclear factor (NF)-kappaB, a transcription factor known to modulate cytokine synthesis in numerous cell types. Stimulation of HASM cells with TNF-alpha increased NF-kappaB DNA-binding activity. However, increased [cAMP](i) in HASM neither activated NF-kappaB nor altered TNF-alpha- induced NF-kappaB DNA-binding activity. These results were confirmed using a NF-kappaB-luciferase reporter assay. Together, our data suggest that TNF-alpha-induced IL-6 and RANTES secretion may be associated with NF-kappaB activation, and that inhibition of TNF-alpha-stimulated RANTES secretion and augmentation of IL-6 secretion by increased [cAMP](i) in HASM cells occurs via an NF-kappaB-independent mechanism.
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PMID:Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells. Modulation by cyclic adenosine monophosphate. 1110 33

Endothelial dysfunction anticipates the development of transplant coronary artery disease (TxCAD) observed more than 1 year after transplantation (HTx). We investigated whether in patients early after HTx myocardial inducible and constitutive nitric oxide synthases (iNOS; cNOS) are expressed and cardiac nitric oxide production occurs. Moreover, a possible relationship to alterations in endothelium dependent and independent vasomotor function was assessed. Forty-two transplant recipients were studied 37 +/- 5 days after HTx. Microvascular coronary flow velocity reserve (CFVR) was tested endothelium dependent (acetylcholine; 30 microg/min x 5 min/i.c.) and independent (adenosine; 160 microg/min x 5 min/i.c.) by Doppler flow wire. Flow velocity increase by a factor greater than 2 was considered normal. Quantitative coronary angiography was used to assess epicardial vasomotor function in response to the same stimuli. Myocardial iNOS and cNOS gene expression were detected by semiquantitative reversed transcriptase polymerase chain reaction. Plasma nitrite levels (microM) were measured by spectrophotometry. Cytokines (TNF-alpha, IL-6; pg/ml) were measured by enzyme linked immunosorbent assay. In 26.1% of patients (n = 11; group A) an impaired endothelium dependent CFVR (1.65 +/- 0.23 increase) was observed; in 73.9% (n = 31, group B) a normal endothelium dependent CFVR (3.0 +/- 0.7 increase; P = 0.003) was observed. Myocardial iNOS and cNOS gene expression did not differ between the two groups. Transcardiac cytokine production was noted in 58.8% of patients for IL-6 and in 53.3% for TNF-alpha. Coronary sinus (CS) levels of TNF-alpha, IL-6 and nitrite were higher in group A. A significant increase in nitrite production was found only in patients with impaired endothelium dependent CFVR (aorta: 43.9 +/- 3.7 vs CS: 52.8 +/- 5.6, P = 0.05), suggesting transcardiac nitric oxide production. In addition, CS nitrite levels correlated with CS TNF-alpha levels in patients with impaired CFVR (r = 0.44, P = 0.003). Microvascular endothelium dependent CFVR is impaired in 26% of patients early after HTx. Activation of cytokines and the NO pathway seem to be involved in this vasomotor dysfunction The association between cardiac nitric oxide production and TNF-alpha in this group indicates a chronic high immunologic process, which may represent an early and important target for therapy and prevention of TxCAD.
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PMID:An association between microvascular endothelial dysfunction, transcardiac nitric oxide production and pro-inflammatory cytokines after heart transplantation in humans. 1111 1


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