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)

Distinct cytokine-producing T cell subsets are well known to play a major role in IgE production and to be differentially regulated in allergic patients, although the characterization of the type 1/type 2 cytokine pattern in PBMC during allergic responses remains to be clearly defined. The aim of this study was to determine whether different cytokine profiles are observed directly in PBMC of atopic donors. We attempted to study several cytokines (IL-2, IFN-gamma, IL-4, IL-10 and IL-13) using not only ELISA but also polymerase chain reaction (PCR) techniques, because the frequency of cytokine-producing cells in peripheral blood is very low. All the patients were selected during their acute symptomatologic phase. Data showed a significantly higher production of IL-4 (P = 0.05) and IL-10 (P < 0.005) as determined by ELISA in phytohaemagglutinin (PHA)/phorbol myristate acetate (PMA)-stimulated mononuclear cells of atopic donors compared with controls, although spontaneous IL-4 production without stimulation was never detected within either atopic or control groups. The reverse-transcriptase (RT)-PCR technique appeared to be advantageous in that it allowed the detection of the spontaneous expression of cytokine mRNA in cells without stimulation. We found a clear expression of IL-4 mRNA spontaneously in all atopic patients, whereas normal donors in most cases did not show specific signals (P < 0.0001). Less differences between atopic subjects and controls were found in IL-10 mRNA expression. Although the technique of RT-PCR amplification used in this study is semiquantitative, a reproducible and significant (P < 0.001) enhancement of IL-10 mRNA expression was observed in atopic donors. A heterogeneous expression of IL-13 mRNA was observed in individuals from the two groups studied, although mean levels in atopic donors were slightly enhanced compared with controls (P = 0.02). Furthermore, we did not observe any alteration in the expression of the type 1-derived cytokines such as IFN-gamma and IL-2. In addition, we showed a lack of correlation between the expression of serum IgE (total or specific) and spontaneous IL-4 mRNA expression. This study showed a tendency of PBMC from atopic donors to express a type 2-like cytokine pattern, with IL-4 as the most discriminatory cytokine. Additionally, as the level of serum IgE has a low predictive value in allergic disease, and as the elevated expression of IL-4 that we found was not correlated with serum IgE, we could strongly suggest that the measurement of IL-4 in blood mononuclear cells may be of great value in the analysis of allergic responses in atopic donors.
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PMID:Differential spontaneous expression of mRNA for IL-4, IL-10, IL-13, IL-2 and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) from atopic patients. 856 69

Members of the Janus kinase (Jak) family of protein tyrosine kinases have recently been implicated in the proximal signal transduction events of cytokine receptors. Jak3, a newly discovered member of this family, is believed to be normally limited in its expression to cells of the lymphoid and myeloid lineages. Herein we show that Jak3 is expressed in primary human vascular cells, as well as other non-lymphoid and non-myeloid cell types. Reverse transcriptase-polymerase chain reaction and Northern blot analysis revealed that Jak3 mRNA was expressed at low levels in human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells (HASMC), A549 (human lung carcinoma), and DLD-1 (human colon adenocarcinoma) cells. Higher basal levels of Jak3 mRNA were detected in HMEC-1 (human microvascular cell line) and HepG2 (human hepatocellular carcinoma) cells. Jak3 mRNA expression was induced in HUVEC, HMEC-1, and HASMC by treatment with interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. Jak3 protein was detectable at low levels in untreated HMEC-1, and these levels increased significantly with cytokine treatment. Furthermore, Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4. This work shows that Jak3 is expressed or inducible in human vascular endothelial, vascular smooth muscle, and other non-lymphoid and non-myeloid cells, suggesting a broader role for Jak3 in the cytokine signal transduction of these cells.
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PMID:Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. 866 78

We determined the expression of Th-2 type cytokines, interleukin-4 (IL-4) and IL-5, and of the Th-1 type cytokine, interferon-gamma (IFN-gamma), in the Brown-Norway rat. Rats were intraperitoneally sensitized with ovalbumin and 21 days later were either exposed to ovalbumin or saline aerosol. The value -log PC300 (PC300 = concentration of acetylcholine needed to increase baseline lung resistance by 300%) was 2.49 +/- 0.15 in sensitized, exposed rats, was higher than in sensitized, saline-exposed or naive rats (1.54 +/- 0.27 and 1.63 +/- 0.06 respectively, P < 0.05). There was a significant increase in eosinophils in bronchoalveolar lavage fluid and in airway submucosal airway tissues in the sensitized exposed group. Reverse-transcriptase polymerase chain reaction was performed on total lung RNA using primers for IL-4, IL-5, IFN-gamma and beta-actin. IL-4 and IL-5 mRNA levels in control and sensitized saline-exposed rats were not detectable, but increased levels were found in sensitized and ovalbumin-exposed rats with levels of 0.25 +/- 0.01 and 0.98 +/- 0.02% of beta-actin mRNA as assessed by densitometric measurements. Expression of IFN-gamma mRNA was significantly reduced in sensitized and ovalbumin-exposed rats. As in asthmatic airways, there is an increased expression of Th-2 cytokines, IL-4 and IL-5, together with a reduction in the Th-1 cytokine, IFN-gamma, thus supporting a role for Th-2 cytokines in allergic eosinophilic inflammation.
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PMID:Expression of Th-2 cytokines interleukin-4 and -5 and of Th-1 cytokine interferon-gamma in ovalbumin-exposed sensitized Brown-Norway rats. 869 Apr 57

IFN-gamma is critical for prevention of development of toxoplasmic encephalitis (TE). Since IL-4 down-regulates production of IFN-gamma, we examined its role in the pathogenesis of TE in IL-4-targeted mutant (IL-4-/-) mice. IL-4-/- mice all died from 6 to 20 wk after peroral infection with cysts of the ME49 strain of Toxoplasma gondii; control mice survived. At 4 and 8 wk after infection, significantly greater numbers of T. gondii cysts and foci of acute inflammation, and greater amounts of tachyzoite-specific mRNA (by reverse-transcriptase PCR) were in brains of IL-4-/- mice than controls. Toxoplasma IgG2b and IgG3 Ab levels were slightly but significantly higher in sera of IL-4-/- than control mice, whereas IgM and IgG2a levels did not differ between these mice. Toxoplasma IgG1 and IgE Abs were not detected in sera of either strain. Amounts of IFN-gamma, TNF-alpha, IL-6, and IL-10 mRNA detected by reverse-transcriptase PCR did not differ between brains of infected IL-4-/- and controls, although brains of the former mice had greater numbers of inflammatory mononuclear cell infiltrates. IL-4 mRNA was detected only in infected control mice. Spleen cells of control mice at 8 wk after infection produced significantly greater amounts of IFN-gamma following stimulation in vitro with soluble T. gondii Ags than did those from IL-4-/- mice. These results indicate that IL-4 is protective against development of TE by preventing formation of T. gondii cysts and proliferation of tachyzoites in the brain. The impaired ability of IL-4-/- mice in the late stage of T. gondii infection to produce IFN-gamma most likely contributes to their susceptibility for development of severe TE.
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PMID:IL-4 is protective against development of toxoplasmic encephalitis. 880 58

The role of cytokines in the regulation and function of the immune system is of great importance. In human immunodeficiency virus (HIV) infection, with progressive deterioration of cell-mediated immune response, cytokines are dysregulated. We have therefore investigated cytokine mRNA expression in type-1 and type-2 helper T cells of HIV-seropositive (HIV+) individuals, stimulated with mitogen (leukoagglutinin) and HIV-1 Tat and Rev peptides, previously found to induce proliferative T-cell responses in these individuals. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect interleukin 2 (IL-2), interferon gamma (IFN-gamma), IL-4, and IL-10 mRNAs. There was no difference in the mRNA expression of these cytokines when the cells of HIV-infected or noninfected individuals were polyclonally stimulated with the mitogen, as all cytokine mRNAs were detected in both groups. Baseline cytokine expression of unstimulated cells was, however, different in these two groups: the cells of HIV+ persons did not show comparable expression of mRNAs to HIV-seronegative (HIV+) individuals. When the cells of HIV+ individuals were stimulated with the peptides, 70% of the cases showed IL-10 mRNA expression, 20% IFN-gamma, and 10% IL-2, with no detection of IL-4 mRNA in any of the cases. Our results thus show that HIV-specific T-cell antigens induce production of IL-10 in HIV-infected individuals. The increase in IL-10 demonstrated here may have a role in hyperactivation of B cells, as well as in immunosuppression of T cells often seen in HIV-infected individuals.
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PMID:Interleukin-10 gene expression induced by HIV-1 Tat and Rev in the cells of HIV-1 infected individuals. 889 65

Three clonally related T-cell lymphoma lines (PB-1, 2A, and 2B) were examined for expression of IL-2, IL-4, and their receptors. All three lines were derived from a single patient who had an atypical, progressive T-cell lymphoproliferative disorder involving primarily skin (Davis, T.H. et al. 1992, N. Engl. J. Med. 326:1115). The PB-1 cell line was obtained from a relatively early, clinically indolent stage of the cutaneous lymphoma, whereas the 2A and 2B lines were established from a late, aggressive stage of the lymphoma. Reverse-transcriptase PCR performed with primer pairs specific for IL-2 and IL-4 showed that no mRNA coding for these cytokines was present in any of the lines with the exception of IL-4 mRNA in the 2A line. No IL-4 protein, however, was found in any of the cell lines including 2A by immunocytochemical staining with anti-IL-4 mAb. Accordingly, no bioactive IL-4 was present in the supernatants of these lines. In contrast, all three T-cell lymphoma lines contained mRNA for IL-2R alpha, IL-2R beta, IL-4R and common gamma chain. Immunocytochemical analysis revealed that only the PB-1 line stained strongly with mAbs specific for IL-2R alpha, IL-2R beta, and IL-4R whereas the 2A and 2B lines showed only limited staining with these mAbs. In contrast to expression of IL-2R alpha and IL-4R primarily on the cell surface, IL-2R beta was localized mainly in the cell cytoplasm. Testing supernatants of the cell lines by ELISA for the presence of soluble alpha chain of the IL-2R (sIL-2R) has shown that only PB-1 secreted a large amount of sIL-2R, whereas the 2A and 2B lines secreted lesser amounts. Furthermore, the PB-1 cells expressed a relatively large number of IL-4R as determined by IL-4 binding studies using an IL-4-alkaline phosphatase fusion protein. The remaining two lines displayed only limited binding of IL-4. Addition of IL-2 and/or IL-4 to the culture medium did not modulate growth of PB-1 and the other two lines. These findings may indicate that at least some types of T-cell lymphoma evolve from cells which lose the capacity to synthesize T-cell autocrine growth factors such as IL-2 and IL-4, and show progressive loss of receptors for these cytokines.
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PMID:Analysis of IL-2, IL-4 and their receptors in clonally-related cell lines derived from a patient with a progressive cutaneous T-cell lymphoproliferative disorder. 902 95

The present study demonstrated that the administration of recombinant interleukin-4 (rIL-4) prevented overt diabetes in nonobese diabetic (NOD) mice whose T cells produced relatively low amounts of IL-4. However, massive insulitis was observed in rIL-4-treated NOD mice. The flow cytometric analysis of islet-infiltrating T cells revealed that the number of CD45RBlowCD4+ T cells was significantly increased by in vivo administration of rIL-4. By measuring the cytokine production of splenic T cells after stimulation, it was shown that CD45RBlowCD4+ T cells predominantly produced IL-4 and IL-10 but produced less IL-2 and interferon-gamma (IFN-gamma). A semiquantitative reverse-transcriptase polymerase chain reaction assay revealed a higher expression of IL-4 and IL-10 mRNA and an apparent decrease in IFN-gamma mRNA in the islets of NOD mice which were administered rIL-4. These results suggested that autoreactive CD45RBlowCD4+ T helper 2 (Th2)-like cells which developed following rIL-4 administration were predominant in the infiltrate of the islets, and overt diabetes was prevented. On the other hand, when splenocytes from rIL-4-treated NOD mice were transferred to irradiated NOD recipients, along with splenocytes from diabetic NOD mice, all of the recipient mice became diabetic within 8 weeks after transfer. Considered together, a supplement of rIL-4 administered to NOD mice may protect against autoimmune diabetes by facilitating the development of Th2-like autoreactive T cells in the islets.
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PMID:Administration of IL-4 prevents autoimmune diabetes but enhances pancreatic insulitis in NOD mice. 947 84

Inflammatory cells were obtained from the spinal cords of rats with acute experimental autoimmune encephalomyelitis (EAE) induced by inoculation with myelin basic protein (MBP) and adjuvants. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to investigate the expression of mRNA for interleukin-2 (IL-2), IL-4, IL-10 and interferon-gamma (IFN-gamma) by cells from groups of rats studied 10-21 days after inoculation. On all days of study, the inflammatory cells, which were predominantly lymphocytes, expressed mRNA for IL-2, IL-4, IL-10 and IFN-gamma. In the mRNA from normal rat spinal cord tissue, there was little expression of cytokine mRNA. Cells from a short-term MBP-reactive T cell line expressed all the cytokines. Densitometry was used to measure the products of PCR, to assess the expression of each cytokine relative to that of beta-actin. IL-2 mRNA was expressed throughout the course of disease and reached a peak on day 18, during late clinical recovery. IFN-gamma was expressed throughout the course of the disease and was also high during late recovery. IL-4 mRNA was present in the spinal cord throughout the course of the disease, with a slight rise during late recovery. Relative expression of IL-10 rose to a peak on days 17-19, during late recovery from clinical disease. This study indicates that IL-2, IL-4, IL-10 and IFN-gamma are expressed by inflammatory cells in the spinal cord in EAE, with the relative expression of all cytokines being high during late clinical recovery.
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PMID:Cytokine expression by inflammatory cells obtained from the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis induced by inoculation with myelin basic protein and adjuvants. 968 21

It has previously been shown that a single intravenous injection of freshly heparinized donor-specific blood transfusion (DST) before transplantation significantly prolongs the survival of fully allogeneic ACI (RT1a)-to-LEW(RT1(1)) rat hepatic allografts. Additionally, we have shown that pretreatment of LEW rats with PVG.r1 blood, which shares only the RT1.A major histocompatibility complex (MHC) region with ACI, significantly prolongs the survival of ACI hepatic allografts. In this study, we report the cellular identity of hepatic allograft leukocyte infiltrates following transplantation. Fluorescence-activated cell sorting (FACS) analysis revealed that CD4+ T cells infiltrating liver allografts could be divided into two subsets, CD45RC- CD4+ and CD45RC+ CD4+ T cells, and that the ratio of CD45RC- CD4+/CD45RC+ CD4+ T cells was significantly higher in hepatic allografts of recipients pretreated with DST or PVG.r1 blood as compared to untreated allografts. Further, CD8+ T cells that accumulated in the liver grafts could be similarly divided into two subsets, and the ratio of CD45RC- CD8+/CD45RC+ CD8+ T cells was also significantly higher in hepatic allografts of recipients pretreated with DST or PVG.r1 blood. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that CD45RC- CD4+ T cells harvested from hepatic allografts pretreated with PVG.r1 blood expressed interleukin-4 (IL-4) and interleukin-10 (IL-10), but not interleukin-2 (IL-2) or interferon-gamma (IFN-gamma). In contrast, CD45RC- CD8+ T cells from hepatic allografts pretreated with PVG.r1 blood expressed IL-4, IL-10, and IFN-lambda, but not IL-2. These results indicate that the CD45RC leukocyte common antigen could be used to differentiate CD4+ and CD8+ T cells following pretreatment with DST or PVG.r1 blood. Persistent infiltration of CD45RC- CD4+ and CD45RC- CD8+ T cells, capable of secreting Th2-type cytokines may prevent allograft rejection by causing immunologic unresponsiveness.
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PMID:Infiltrating CD45RC- T cells are associated with immunologic unresponsiveness induced by donor class I major histocompatibility complex antigens in rats. 969 11

Activated CD4-positive T cells are essential in the early stages of arteriosclerotic lesion development after cardiac transplantation. Besides its parenchymal effects, transforming growth factor-beta1 (TGF-beta1) mediates immunosuppressive effects on proliferation and activation of CD4 cells. This study was designed to assess immune contributions of TGF-beta1 to arteriosclerosis by comparing the effect of TGF-beta1-deficient and -competent infiltrating inflammatory cells on the development of intimal thickening in a heterotopic mouse transplant model (CBA to C57B6). Transplant arteriosclerosis was evaluated in cardiac grafts placed into knockout recipients heterozygous for TGF-beta1 (n=7) and was compared with those placed into wild-type recipients (n=11). At 55 days, allografts in TGF-beta1-deficient recipients had increased concentric intimal thickening. Computer-assisted analysis of all elastin-positive vessels (n=173) showed significantly increased luminal occlusion (67.8+/-5.6%) in grafts from TGF-beta1-deficient recipients compared with wild-type recipients (47.4+/-4.1%, P=0.003). To determine whether TGF-beta1 deficiency altered CD4 activation patterns, we studied intragraft cytokine expression. Using 32P-reverse-transcriptase polymerase chain reaction assays, we show that TGF-beta1-deficient recipients had an increased expression of the transcription factor STAT 4, interferon gamma, and interleukin-2 (Th1-type response) and unaltered or reduced expression of the transcription factor STAT 6, interleukin-4, and interleukin-10 (Th2-type response). Hence, when present, immune sources of TGF-beta1 attenuate transplant arteriosclerosis. This effect is associated with attenuation of Th1 forces.
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PMID:Immune sources of transforming growth factor-beta1 reduce transplant arteriosclerosis: insight derived from a knockout mouse model. 974 61


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