Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF)-alpha has been shown to be increased in brain tissue of AIDS patients and may function as a mediator of cerebral damage. We initiated a study to determine the cellular localization and degree of protein and mRNA expression of the two specific TNF-alpha receptors (TNF-Rs), p55 and p75, in brain tissues from AIDS patients. Cerebral white matter obtained at autopsy from 13 AIDS patients, 10 unhealthy controls, and 4 healthy controls was evaluated. Double-label immunohistochemistry revealed prominent up-regulation of p55 and p75 TNF-Rs on activated macrophages and microglial cells in all AIDS patients; no increased staining was found on astrocytes. Staining was most prominent in patients with opportunistic infection of the brain and in microglial nodules of patients with HIV encephalitis. Brain tissues also showed increased expression of interleukin (IL)-1 beta, IL-6, and TNF-alpha, cytokines known to up-regulate the TNF-Rs. Increased staining for TNF-Rs was also found in patients with multiple sclerosis, chronic cerebral edema, and radiation necrosis but not in an asymptomatic HIV-positive patient without AIDS. Reverse transcriptase polymerase chain reaction performed on adjacent sections from five AIDS patients revealed up-regulation from normal for p55 in all patients and for p75 in three patients. The up-regulation of both TNF-Rs in AIDS suggests that macrophages and microglial cells may be important in amplifying the TNF-alpha response.
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PMID:Increased expression of tumor necrosis factor-alpha receptors in the brains of patients with AIDS. 854 30

Human peritoneal mesothelial cells (HPMC) respond to tumor necrosis factor alpha (TNF alpha) by releasing various cytokines that may activate the endothelium and induce recruitment of leukocytes during peristonitis. We characterized the receptors for TNF on HPMC to elucidate their functions in peritonitis. Scatchard analysis determined the presence of 70 x 10(3) TNF receptors/cell with a kDa of 0.44 nM. TNF receptor 1 (TNF-R1, p55) and TNF-R2 (p75) mRNA were demonstrated by reverse-transcriptase-PCR (RT-PCR). TNF-R1 protein was solely detected by flow cytometry (FCM). Interleukin-1 alpha (IL-1 alpha) induced down-regulation of TNF-R1. This was concomitant with accumulation of soluble TNF-R1 (sTNF-R1) detected by specific ELISA. LPS had a lower TNF-R1-shedding activity while TNF alpha did not induce shedding. The IL-1-induced-sTNF-R1-shedding was suppressed by the protein-kinase-A (PKA) inhibitor, H-8, or by H-7, the inhibitor of both PKC and PKA, but not by the specific PKC inhibitor GF. These experiments suggest a role for PKA in the IL-1-shedding signal. No change in TNF-R1 mRNA levels was observed after IL-1 alpha or TNF alpha stimulation while TNF-R2 (p75) mRNA basal levels transiently increased three to fivefold, reaching a peak after four hours followed by an accumulation of sTNF-R2 in the supernatant. Our data suggest that the main receptor expressed on HPMC is TNF-R1. Down-regulation and shedding of TNF-R1 induced by IL-1, and the transient expression of TNF-R2 induced by IL-1 and TNF, may regulate the responses to TNF by HPMC. These results may be important in understanding the inflammatory process of peritonitis were TNF plays a major role.
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PMID:TNF-receptors on human peritoneal mesothelial cells: regulation of receptor levels and shedding by IL-1 alpha and TNF alpha. 880 91

The recently cloned cytokine interleukin-15 (IL-15) shares several functional activities with IL-2 in different cell systems. Although IL-15 does not show sequence homology with IL-2, it uses components of the IL-2 receptor (IL-2R) for binding and signal transduction, namely, p75 (beta) and the p64 (gamma) chains of IL-2R. To evaluate whether IL-15 is involved in the activation of granular lymphocytes (GL) in patients with lymphoproliferative disease of granular lymphocytes (LDGL), we evaluated the ability of IL-15 to stimulate GL proliferation, cytotoxic function, and the role of IL-2R beta and gamma molecules on relevant cells. Our results show that IL-15 stimulates cell proliferation and cytotoxic activity of GL in LDGL patients. Reverse-transcriptase polymerase chain reaction (RT-PCR) and phenotypic analyses using the anti-IL-2R gamma-chain-specific TUGh4 monoclonal antibody (MoAb) indicate that both CD3+ and CD3- GL express the p64 IL-2R, a result previously unknown. IL-15 activity was inhibited by antibodies against p75 and p64 IL-2R chains, while no inhibitory effects are detectable with anti-p55 IL-2R antibody. The association of anti-p75 and anti-p64 IL-2R MoAbs resulted in a nearly complete (95%) inhibition of IL-15-induced GL proliferation. Using RT-PCR analysis, we demonstrated that highly purified CD3+ and CD3- GL did not express mRNA for IL-15 or IL-2. By contrast, a clear-cut IL-15 mRNA signal was detected by RT-PCR in patients' peripheral blood mononuclear cells, with monocytes likely accounting for the source of IL-15 in LDGL patients. However, even in concentrated supernatants from enriched monocyte populations, we could not demonstrate the presence of IL-15 protein. Using anti-IL-15 specific MoAbs, a membrane-bound form of this cytokine was demonstrated both on CD3+ and CD3- LDGL cells. By RT-PCR analysis, purified GL from these patients were found to express the message for IL-15 receptor alpha chain. Taken together, these results indicate that both CD3+ and CD3- GL are stimulated by IL-15 and that this cytokine mediates its activity through the beta and gamma chains of the IL-2R, providing further suggestions for the interpretation of the mechanisms that lead to cell expansion in patients with LDGL.
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PMID:Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. 897 93

IL-12, a 75-kDa heterodimeric cytokine composed of two chains (p35 and p40), is a central regulator of immune responses and may be implicated in the pathogenesis of certain inflammatory diseases of the central nervous system (CNS). We have examined the capacity of two CNS APC, microglia and astrocytes, to produce IL-12 upon stimulation with cytokines, LPS, or a neurotropic virus. In purified microglial cultures from neonatal mouse brains, expression of IL-12 p35 and p40 mRNA is induced by LPS and is stimulated maximally by combined IFN-gamma/LPS treatment, as detected by semiquantitative reverse-transcriptase PCR. LPS induces secretion of IL-12 p40, but not of IL-12 p75, as detected by specific ELISA. Combined stimulation with IFN-gamma/LPS enhances IL-12 p40 secretion and induces IL-12 p75 secretion by microglia. Conversely, mouse astrocytes do not express IL-12 p35 mRNA and do not secrete IL-12 p75 under any condition tested. IL-12 production by activated microglia is inhibited by IL-10, PGE2, and cAMP-elevating agents. Coculture of microglia with astrocytes or exposure of microglia to astrocyte-conditioned medium also results in marked reduction of IL-12 p75 and p40 secretion by IFN-gamma/LPS-stimulated microglia, indicating a regulatory role of astrocytes on IL-12 production. This novel mechanism of IL-12 regulation may play an important role in the control of immune responses during infection or in Th1 cell-mediated autoimmune diseases of the CNS.
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PMID:IL-12 production by central nervous system microglia is inhibited by astrocytes. 925 19

The distribution of myeloid lineage-associated cytokine receptors and lysosomal proteins was analyzed in human CD34+ cord blood cell (CB) subsets at different stages of myeloid commitment by reverse-transcriptase polymerase chain reaction (RT-PCR). The highly specific granulomonocyte-associated lysosomal proteins myeloperoxidase (MPO) and lysozyme (LZ), as well as the transcription factor PU.1, were already detectable in the most immature CD34+Thy-1+ subset. Messenger RNA (mRNA) levels for the granulocyte-colony stimulating factor (G-CSF) receptor, granulocyte-macrophage (GM)-CSF receptor alpha subunit and tumor necrosis factor (TNF) receptors I (p55) and II (p75) were also detected in this subset in addition to c-kit and flt-3, receptors known to be expressed on progenitor cells. By contrast, the monocyte-macrophage colony stimulating factor (M-CSF) receptor was largely absent at this stage and in the CD34+Thy-1-CD45RA- subsets. The M-CSF receptor was first detectable in the myeloid-committed CD34+Thy-l-CD45RA+ subset. All other molecules studied were found to be expressed at this stage of differentiation. Different cocktails of the identified ligands were added to sorted CD34+Thy-1+ single cells. Low proliferative capacity was observed after 1 week in culture in the presence of stem cell factor (SCF) + Flt-3 ligand (FL) + G-CSF. Addition of GM-CSF to this basic cocktail consistently increased the clonogenic capacity of single CD34+Thy-1+ cells, and this effect was further enhanced (up to 72.3 +/- 4.3% on day 7) by the inclusion of TNF-alpha. In conclusion, the presence of myeloid-associated growth factor receptor transcripts in CD34+ CB subsets does not discriminate the various stages of differentiation, with the exception of the M-CSF receptor. In addition, we show that TNF-alpha is a potent costimulatory factor of the very immature CD34+Thy-1+ CB subset.
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PMID:Analysis of myeloid-associated genes in human hematopoietic progenitor cells. 932 52

The main objective of this study was to analyze the pathogenic role of the tumor necrosis factor alpha (TNF-alpha) system in the development of nonalcoholic steatohepatitis (NASH). Fifty-two obese patients were studied. We investigated: (1) the expression of mRNA of TNF-alpha and their p55 and p75-receptors by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in hepatic and adipose tissues; and (2) the relationship between TNF-alpha, p55, and p75 and the severity of NASH. Obese patients without NASH were the control group. A remarkable increase in the expression of mRNA of TNF-alpha was found in patients with NASH in hepatic tissue (0.65 +/- 0.54) and in peripheral fat (0.43 +/- 0.45); in the control samples, the mRNA expression was 0.28 +/- 0.32, P <.007, and 0.26 +/- 0.22, P <.018, respectively. Furthermore, we found a significant increase in the mRNA levels of p55 receptor (2.42 +/- 1.81 vs. 1.56 +/- 1.17; P <.05); however, the mRNA expression of the p75 receptor was similar in both patients. Those patients with NASH with significant fibrosis presented an increase in the expression of mRNA TNF-alpha in comparison with those with a slight or nonexistent fibrosis. An overexpression of TNF-alpha mRNA is found in the liver and in the adipose tissue of NASH patients. The levels of mRNA-p55 are increased in the liver tissue of NASH patients. This overexpression is more elevated in patients with more advanced NASH. These findings suggest that the TNF-alpha system may be involved in the pathogenesis of NASH.
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PMID:Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. 1173 5

KE-758, an active metabolite of KE-298, is a novel sulfhydryl antirheumatic drug. We analyzed the effect of KE-758 on tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta production by a human monocytes cell line (THP-1 cells), stimulated with interferon-gamma (IFN-gamma) plus lipopolysaccharide (LPS). We compared the effects with other thiol-modifying antirheumatic drugs such as D-penicillamine, bucillamine and auranofin. THP-1 cells were treated with IFN-gamma for 16 h and were then exposed to LPS for an additional 6 h (for TNF-alpha detection) or 24 h (for IL-1 beta detection). The amounts of TNF-alpha and IL-1 beta in culture supernatants were measured using enzyme-linked immunosorbent assay. KE-758 and auranofin but not D-penicillamine and bucillamine significantly suppressed both TNF-alpha and IL-1 beta. Auranofin suppressed IL-1 beta production by reducing cellular viability. Reverse transcriptase-polymerase chain reaction analysis revealed that the suppressive effect of KE-758 is based on the inhibition of messenger ribonucleic acid expression of TNF-alpha and IL-1 beta. KE-758 had no effect on p75 and p55 soluble TNF receptor production in IFN-gamma and LPS-stimulated THP-1 cells. Thus, KE-758 inhibits both TNF-alpha and IL-1 beta production and its antirheumatic profile is apparently distinct from that of D-penicillamine, bucillamine and auranofin.
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PMID:KE-758, an active metabolite of the new anti-rheumatic drug KE-298, suppresses production of tumor necrosis factor-alpha and interleukin-1 beta in THP-1, a human monocyte cell line. 1263 95

Targeted inhibition of tumour necrosis factor-alpha (TNF-alpha) is an effective therapy in rheumatoid arthritis and Crohn's disease (CD). Infliximab, a monoclonal murine-human chimeric antibody to TNF-alpha, and etanercept, a fusion protein of two p75 chains of the TNF receptor II and the Fc portion of IgG1, are generally well tolerated. Rarely does clinically significant autoimmunity, including drug-induced lupus and vasculitis occur. Immunologic mechanisms underlying the development of autoimmunity in the presence of such powerful immunosuppressants are unknown. We describe a patient with CD, who developed cutaneous vasculitis on etanercept, which worsened significantly with switch to infliximab. Investigation of the associated systemic and local immune response demonstrated the absence of human antichimera antibodies, but mRNA for T-helper 1 cytokines, chemokines and defensins in the skin and elevated angiogenesis factors in the serum, as determined by reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Histopathology revealed a lymphocytic vasculitis composed of T cells. A permanent B-cell line (MD-B) producing extremely high amounts of chemokines and interleukin-6 was established from this patient's peripheral blood. Lesions progressed despite discontinuation of the drugs and (40 mg/day) prednisone but almost completely resolved with single dose of (0.1 mg/kg) intravenous dexamethasone, which may be therapy of choice for this reaction. A few lesions (<10) have recurred intermittently over 4 years of follow-up, suggesting possible persistence of this TNF-inhibitor-triggered autoimmune disease.
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PMID:Immunology of cutaneous vasculitis associated with both etanercept and infliximab. 1585 15

Interaction of CD40L and its cognate receptor is an essential component of B-lymphocyte signaling, affecting various aspects of B-cell differentiation pathways and immunoglobulin gene expression. However, much less is known about the biological consequences of B-cell signaling through tumor necrosis factor (TNF)-alpha and its cognate receptors TNF-R1 and 2. We used Ramos Burkitt's lymphoma cell line as a model system to study the direct effects of these cytokines on B cells. Treatment of Ramos cells with either TNF-alpha or CD40L, but not with interleukin (IL)- 4, interferon (IFN)-gamma and transforming growth factor (TGF)-beta, resulted in enhanced cell aggregation and enhancement of adherence to glass cover-slips. Scanning electron microscopy showed that Ramos cells have a polarized cell surface morphology and exhibit at least 3 cell surface morphological domains: microvilli, filopodia and ruffled membranes. The cells adhered to the glass matrix through multiple filopodia/podopodia-like cell processes and demonstrated distinct ruffled-like membrane projections on their opposite pole. Induction by TNF-alpha or CD40L, but not with IL-4, IFN-gamma and TGF-beta, resulted in increased number and complexity of both types of membrane projections. TNF-alpha and CD40L upregulated the expression of the adhesion molecule intercellular adhesion molecule-1 and the Fas receptor on Ramos cells, without affecting the expression levels of membrane immunoglobulin M or its secretion rate. Reverse transcriptase-polymerase chain reaction, and flow cytometry demonstrated that Ramos cells expressed TNF-R1 but very little if any TNF-R2, indicating that TNF-alpha exerted its effects on Ramos cells through the former receptor.
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PMID:Tumor necrosis factor-alpha and CD40L modulate cell surface morphology and induce aggregation in Ramos Burkitt's lymphoma cells. 1652 91