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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that pretreatment of mice with keratinocyte growth factor (KGF), an epithelial tissue repair factor, can ameliorate graft-versus-host disease (GVHD) after intensive chemoradiotherapeutic conditioning and allogeneic bone marrow transplantation (BMT). To determine whether this effect was dependent on a KGF-mediated mechanism affecting repair of conditioning-induced epithelial cell injury, we studied GVHD in the absence of conditioning using BALB/c severe combined immune-deficient (SCID) recipients given C57BL/6 T cells. KGF (5 mg/kg per day, subcutaneously) given either before or after T-cell transfer enhanced body weights and extended survival. KGF-treated recipients had elevated serum levels of the Th2 cytokine interleukin 13 (IL-13) on day 6 after T-cell transfer concomitant with reduced levels of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon gamma (IFN-gamma). A 3-day KGF pretreatment also depressed the secondary in vitro mixed lymphocyte response (MLR) of C57BL/6 splenocytes taken 7 days after in vivo alloimmunization with irradiated BALB/c spleen cells. To determine whether KGF would inhibit host-antidonor-mediated BM rejection, pan-T-cell-depleted BALB/c BM cells were infused into sublethally irradiated C57BL/6 mice and administered KGF either before or before and after BMT. Surprisingly, all KGF schedules tested actually resulted in enhanced alloengraftment. The presence of KGF receptor on donor antihost alloreactive T cells could not be detected by binding studies with radiolabeled KGF, reverse transcriptase-polymerase chain reaction, and Western blotting. Therefore, the mechanism of action of KGF on inhibiting T-cell-mediated immune effects may not be due to a direct effect of KGF on T cells. These studies demonstrate that KGF, by mechanisms independent of repair of conditioning-induced injury, has great potential as an anti-GVHD therapeutic agent with the added benefit of inhibiting the rejection of pan-T-cell-depleted donor BM allografts. (Blood. 2000;96:4350-4356)
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PMID:Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury. 1111 Jul 12

The dominant view has been that there is little or no activation of Type 2 cytokine production in human tuberculosis. A novel approach to quantitative nested reverse transcriptase-polymerase chain reaction has revealed that this conclusion was based on technical inadequacies of earlier studies, particularly the failure to discriminate between IL-4 and the IL-4 splice variant, IL4delta2. A new approach reveals that the largest cytokine change in tuberculosis is a 1-2 log increase in copy number for mRNAs encoding IL-4 and IL-13, accompanied by a small decrease in expression of mRNA encoding interferon-gamma. The increased IL-4 level correlates with disease severity and with serum levels of IgE and soluble CD30, and may be attributable to the recently observed increase in conversion of cortisone into cortisol in tuberculous lesions. The implications of these findings for pathogenesis, vaccine design and immunotherapy are discussed, as effective reagents will need to downregulate this inappropriate Th2 component.
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PMID:High levels of mRNA encoding IL-4 in unstimulated peripheral blood mononuclear cells from tuberculosis patients revealed by quantitative nested reverse transcriptase-polymerase chain reaction; correlations with serum IgE levels. 1123 43

Because an airway-like inflammation has been reported in the gut of asthmatic patients, we sought to examine the expression of immunoregulatory cytokines like IL-4, IL-10, and IL-13 by gut mucosa. To establish this, we initiated this study to examine mRNA expressions of IL-4, IL-10, and IL-13 in duodenal mucosa from patients with asthma. Duodenal biopsy specimens were obtained from 20 asthmatic patients (10 allergic, 10 nonallergic) and 8 healthy controls. Cytokine mRNA was quantified with reverse transcriptase-competitive PCR, and results were expressed in proportion to the number of beta-actin mRNA in the same sample. IL-10 and IL-4 mRNA were detectable in all patients, whereas no IL-13 mRNA was detected. IL-10 mRNA concentrations were significantly higher in allergic subjects with asthma than in control subjects and nonallergic subjects with asthma. No significant difference was observed for IL-4. IL-10 mRNA expression was not related to asthma severity, FEV(1), blood eosinophilia, or IgE levels. Our results support the hypothesis that IL-10 overexpression may counterbalance the effects of proinflammatory cytokines and mitigate the inflammatory reaction found in gut mucosa of subjects with asthma.
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PMID:Overexpression of IL-10 mRNA in gut mucosa of patients with allergic asthma. 1129 68

Cellular immune responses of BALB/c mice infected with 80 or 160 L3 of Litomosoides sigmodontis were studied over a period of 200 days postinfection (p.i.) by stimulating spleen cells with specific microfilariae and adult antigens and Concanavalin A (Con A). Effects were determined as the level of transcription of cytokine genes [interleukin (IL)-2, interferon (IFN)-gamma, IL-4, IL-5, IL-10, IL-13] employing a semiquantitative reverse transcriptase-polymerase chain reaction technique. Con A stimulation resulted in generally enhanced transcription levels in infected animals. Exposure to filarial antigens stimulated T cells of infected animals dependent on time p.i. There was a general strong response in the early prepatency (24 days p.i.), a temporary almost complete downregulation of cytokine gene transcription except IL-10 towards the end of prepatency (45 days p.i.), and subsequently strong reactions particularly concerning IFN-gamma and IL-13 during patency and postpatency. The dose of infection as well as the mode of antigenic stimulation had generally only small effects on the cytokine gene transcription: following the same type of kinetics, infection with 160 L3 as well as the use of microfilarial antigen generally induced lower levels of cytokine gene transcription compared with infection with 80 L3 and stimulation with female antigen, respectively.
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PMID:Cellular immune responses of filaria (Litomosoides sigmodontis) infected BALB/c mice detected on the level of cytokine transcription. 1148 69

Development of a novel group of antiviral agents, acyclic nucleoside phosphonates, has provided a new perspective for treating human immunodeficiency virus (HIV) infection. One of the compounds, 9-(R)-[2-(phosphonomethoxy)propyl]adenine (PMPA) (tenofovir), has been shown to confer complete protection against AIDS in a simian model of the infection. The aim of our study was to investigate whether the antiviral efficacy of PMPA, which depends mainly on inhibition of virus-induced DNA polymerase or of reverse transcriptase, could be contributed by immunomodulatory potential of this drug. We screened for its ability to activate production of cytokines and chemokines that are known to interfere with the replication and/or the entry of HIV in cells. Using the in vitro test system of mouse macrophages and lymphocytes, it has been found that PMPA stimulates macrophage secretion of interleukin-1beta (IL-1beta), IL-10, and tumor necrosis factor alpha. Production of the chemokines RANTES and macrophage inflammatory protein 1alpha was activated in both macrophages and lymphocytes, and also in human cell line U937. Other cytokines--i.e., IL-2, IL-12, IL-13, and gamma interferon-remained uninfluenced by PMPA. The cytokines were stimulated in a dose-dependent fashion, with rapid onset, and peak concentrations were achieved within 5 to 24 h. The findings contribute to a more complex understanding of mechanisms of antiviral effectiveness of PMPA and support the view that this drug could become a promising candidate for therapeutic exploitation in anti-HIV preventive medicine.
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PMID:Activation by 9-(R)-[2-(phosphonomethoxy)propyl]adenine of chemokine (RANTES, macrophage inflammatory protein 1alpha) and cytokine (tumor necrosis factor alpha, interleukin-10 [IL-10], IL-1beta) production. 1170 12

Cytokines derived from lymphocytes are believed to play key roles in a variety of diseases, including airway diseases such as asthma. The current study was designed to evaluate the hypothesis that cytokines derived from Th2 cells, interleukin (IL)-4 and IL-13, might contribute to tissue remodeling by modulating the production of transforming growth factor (TGF)-beta. In addition, the ability of interferon (IFN)-gamma, a cytokine derived from Th1 cells that can antagonize many effects of IL-4 and IL-13, was also assessed for its effects on TGF-beta production. IL-4 and IL-13 both stimulated production of TGF-beta2 release from human bronchial epithelial cells in a time- and concentration-dependent manner. Both with and without acidification, TGF-beta2 were detected. Neither TGF-beta1 nor TGF-beta3 was released. In contrast to the stimulatory effect on human bronchial epithelial cells, neither IL-4 nor IL-13 stimulated release of any TGF-beta isoform from human lung fibroblasts. IFN-gamma reduced both basal, IL-4-, and IL-13-stimulated release of TGF-beta2 in human bronchial epithelial cells. The stimulatory effects of IL-4 and IL-13 and the inhibitory effect of IFN-gamma on TGF-beta2 release were paralleled by mRNA levels, as assessed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). In summary, the Th2-derived cytokines, IL-4 and IL-13, can stimulate production of TGF-beta from airway epithelial cells but not from lung fibroblasts. IFN-gamma, in contrast, can inhibit TGF-beta2 release both under basal conditions and following IL-4 or IL-13 stimulation. The ability of these cytokines to modulate TGF-beta release may contribute to both normal airway repair and to the development of subepithelial fibrosis in asthma.
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PMID:Interleukin-4- and interleukin-13-enhanced transforming growth factor-beta2 production in cultured human bronchial epithelial cells is attenuated by interferon-gamma. 1191 85

The CC chemokine thymus- and activation-regulated chemokine (TARC/CCL17) acts on CC chemokine receptor 4 (CCR4), which is known to be selectively expressed in Th2 cells. In order to compare the regulatory profiles of TARC production by tumor necrosis factor-alpha (TNF-alpha), IFN-gamma, interleukin-4 (IL-4) and IL-13 in keratinocytes and fibroblasts, HaCaT cells, a human keratinocyte cell line, and NG1RGB cells, a human skin fibroblast cell line, were used. The expression of TARC protein was measured using enzyme-linked immunosorbent assay (ELISA), and the mRNA level was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The spontaneous expression of TARC protein and mRNA levels were augmented by TNF-alpha and IFN-gamma and were inhibited by IL-4 and IL-13 in the keratinocytes. The fibroblasts expressed the TARC protein and mRNA only in the presence of IL-4+TNF-alpha or IL-13+TNF-alpha stimulation. IFN-gamma further enhanced the IL-4+TNF-alpha or IL-13+TNF-alpha-induced TARC production in the fibroblasts. Thus, TNF-alpha and IFN-gamma -induced TARC production was differentially regulated by IL-4 and IL-13 in human keratinocytes and fibroblasts.
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PMID:Differential regulation of thymus- and activation-regulated chemokine induced by IL-4, IL-13, TNF-alpha and IFN-gamma in human keratinocyte and fibroblast. 1235 17

Type 1 diabetes is an autoimmune disease with an inflammatory process directed against the beta cells in pancreas. This investigation aimed at studying the immune response during the first 3 months after the diagnosis of type 1 diabetes, with focus on the balance of T-helper 1 (Th1)- and Th2-like cytokines, produced spontaneously and in response to relevant autoantigens. Peripheral blood mononuclear cells (PBMCs) were collected from type 1 diabetic children (10-17 years) at 5, 20, 35 and 90 days after diagnosis. Expression of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) mRNA were detected by real-time reverse transcriptase polymerase chain reaction and IFN-gamma, IL-10 and IL-13 by enzyme-linked immunosorbent assay in cell supernatant after stimulation with a glutamic acid decarboxylase 65 (GAD(65))-peptide [amino acid (a.a.) 247-279], insulin, the ABBOS-peptide (a.a. 152-169), phytohaemagglutinin and keyhole limpet haemocyanin. Spontaneous and antigen-induced expression and secretion of cytokines were low at the diagnosis of type 1 diabetes. During the first month, after diagnosis, the GAD(65)-peptide caused an increased ratio of IFN-gamma/IL-4 mRNA expression (P < 0.05) and increased secretion of IFN-gamma (P = 0.07). Expression of IFN-gamma mRNA did also increase from stimulation with insulin (P < 0.05), even though cytokine secretion remained low. Thus, duration after diagnosis as well as metabolic state should be carefully considered both in studies of the pathogenesis of type 1 diabetes and in immune intervention studies at onset.
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PMID:Cytokine profile in children during the first 3 months after the diagnosis of type 1 diabetes. 1514 63

The high degree of immunity induced by the bovine lungworm, Dictyocaulus viviparus, makes it an ideal model in which to study nematode-induced protective immune responses. Here, cytokine responses were measured over the course of an experimental infection of D. viviparus. Local cytokine messenger RNA (mRNA) transcripts were measured in lung parenchyma, tracheal rings and draining lymph nodes using semi-quantitative reverse transcriptase-polymerase chain reaction. Responses were measured in animals necropsied at 15, 22 and 43 days post-infection (DPI). The responses elicited at these time points were compared with cytokine levels observed in uninfected animals. Interleukin (IL)-4, IL-5, IL-10, IL-12p35, IL-13 and interferon gamma (IFNgamma) mRNA levels were measured in duplicate at each site. By 42 DPI, very few parasites were recovered, either from faeces or lungs. Transcripts of all cytokines increased in the lung parenchyma, tracheal rings and caudal mesenteric lymph nodes by 15 DPI. The response was rapid and peaked during the time of larval migration through the lungs. By 42 DPI, expression levels of most cytokines were reduced to levels similar to, or below, base line values measured in uninfected animals. Highest levels of IL-10, IL-12p35, IL-13 and IFNgamma transcript were measured in the bronchial lymph nodes of uninfected animals. IgG1 levels were negatively correlated with expression levels of all cytokines. The results demonstrate that a mixed cytokine response occurs over the course of a primary infection during which the parasites were eliminated by day 43 DPI. These results agree with those obtained for other helminths in cattle and challenge the hypothesis that polarised Th2 responses are essential for protection against nematodes in this species. These observations are important in the development of recombinant vaccines, particularly when considering adjuvant choice.
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PMID:Local cytokine responses in Dictyocaulus viviparus infection. 1574 Aug 68

Skin lesions are a frequent manifestation of Leishmania infantum infections in Mediterranean countries. This study demonstrates by real-time reverse transcriptase-polymerase chain reaction the local cytokine response in skin biopsies from Leishmania-infected dogs (n=10). As controls, we investigated skin biopsies from healthy (n=10) and fleabite hypersensitive dogs (n=10). We established a quantitative PCR to determine the parasite burden in biopsies. The objective was to elucidate whether a correlation exists between parasite number, histologic response, and T helper-1 (TH1)/T helper-2 (TH2) cytokine expression in lesional skin of naturally infected dogs. In Leishmania-infected dogs, interleukin-4 (IL-4), tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) messenger RNA production was significantly higher than controls. Furthermore, dogs with a high Leishmania burden had a significantly higher IL-4 expression, whereas no difference was noted with regard to expression of other cytokines. By comparing the pattern of inflammation and cytokine expression, a clear trend became evident in that levels of IL-4, TNF-alpha, and IFN-gamma were elevated in biopsies with a periadnexal nodular pattern and in biopsies where the severity of the periadnexal infiltrate was equal to the perivascular to interstitial infiltrate. Expression of IL-4, IL-13, and TNF-alpha was slightly increased in biopsies where plasma cells prevailed on lymphocytes, whereas expression of IFN-gamma was moderately higher when lymphocytes were predominating. In summary, the present study demonstrates that the local immune response in naturally occurring leishmaniasis includes TH1 as well as TH2 cytokine subsets. Furthermore, respective data suggest that increased expression of the TH2-type cytokine IL-4 is associated with both severe clinical signs and a high parasite burden in the skin lesions.
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PMID:Cutaneous leishmaniasis in naturally infected dogs is associated with a T helper-2-biased immune response. 1575 70


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