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:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor (TGF)-beta and interleukin (IL)-10 inhibited lipopolysaccharide (LPS)-induced macrophage production of the inflammatory cytokines tumor necrosis factor-alpha (TNF), IL-1 alpha, and IL-1 beta by contrasting post-transcriptional mechanisms. TGF-beta acted slowly and late, as it required 12-16 h to exert a suppressive effect, and inhibited TNF production even when added 6 h after LPS. TGF-beta affected neither the level of TNF mRNA, the release of preformed TNF nor the degradation of TNF. Thus, TGF-beta appeared to inhibit translation of TNF mRNA. IL-10 not only suppressed TNF release to a 25-fold greater extent than TGF-beta, but also inhibited release of IL-1. In contrast to TGF-beta, IL-10 acted on an early step in cytokine production, its effect being maximal 3 h after addition of LPS. Unlike TGF-beta, IL-10 markedly suppressed TNF, IL-1 alpha, and IL-1 beta mRNA levels. However, this was accomplished without suppressing transcription of the corresponding genes. Moreover, cycloheximide antagonized the IL-10-dependent reduction in cytokine mRNA levels. Thus, IL-10 may induce a ribonuclease active on cytokine transcripts or may induce a protein that enhances the susceptibility of TNF, IL-1 alpha, and IL-1 beta mRNAs to ribonucleolytic action. We conclude that IL-10 and TGF-beta induce different phenotypes of macrophage deactivation, and deactivate macrophages by different mechanisms: IL-10 promotes degradation of cytokine mRNA, while TGF-beta primarily suppresses translation.
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PMID:Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. 142 77

To delineate the scope of the human intraovarian IL-1 system we used a solution hybridization/RNase protection assay to test for expression of the genes encoding IL-1, its type I receptor (IL-1R), and its receptor antagonist (IL-1RA). IL-1 transcripts were not detected in whole ovarian material from days 4 or 12 of an unstimulated menstrual cycle but transcripts (IL-1 beta much greater than IL-11 alpha) were detected in preovulatory follicular aspirates from gonadotropin-stimulated cycles. Concurrently obtained peripheral monocytes did not contain IL-1 beta transcripts but macrophage-depleted follicular aspirates did, thus implicating the granulosa cells as the site of IL-1 expression. IL-1R transcripts were detected in RNA from whole ovaries and follicular aspirates but not in RNA from peripheral monocytes. IL-1RA transcripts were detected in whole ovarian material as well as in macrophage-free follicular aspirates. Cultured human granulosa and theca cells did not contain mRNA for IL-1 beta or IL-1RA but did contain mRNA for IL-1R. Treatment of cell cultures with forskolin (25 microM) induced IL-1 beta transcripts in granulosa but not theca cells. Forskolin also increased the basal levels of IL-1R transcripts in both granulosa and theca cells but did not induce IL-RA transcripts in either cell type. Taken together, these findings reveal the existence of a complete, highly compartmentalized, hormonally dependent intraovarian IL-1 system replete with ligands, receptor, and receptor antagonist.
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PMID:Human intraovarian interleukin-1 (IL-1) system: highly compartmentalized and hormonally dependent regulation of the genes encoding IL-1, its receptor, and its receptor antagonist. 153 16

I have previously shown that IL-1 regulates the stability of gro alpha mRNA in fibroblasts and that decay is associated with appearance of a smaller species of gro RNA that lacks poly(A). In this study, the relationship between the two species of gro RNA, which migrate at 1.3 and 0.9 kilobases, was characterized. Following withdrawal of IL-1 or addition of IL-1 receptor antagonist, 1.3 kilobase gro alpha mRNA was rapidly degraded and this was associated with increased expression of the 0.9 kilobase RNA. This increase occurred in the presence of actinomycin D, indicating that the 0.9 kilobase gro RNA was a product of a pre-existing transcript. In cells treated with 1 pg/ml IL-1, both species were induced but the 0.9 kilobase RNA appeared later, consistent with a precursor-product relationship. In cells treated with higher doses of IL-1, the 0.9 kilobase RNA was not expressed. Using an RNAase protection assay, the 0.9 kilobase poly(A)-minus gro RNA was found to be derived from gro alpha mRNA by removal of a 130-nucleotide sequence from the 3' non-coding region. This is one of few examples of formation of an mRNA decay intermediate in vivo; it indicates that degradation of the body of gro alpha mRNA is initiated by site-specific nuclease attack. Characterization of the mechanism of gro alpha mRNA degradation is a first step towards identification of the ribonuclease that controls gro alpha mRNA stability.
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PMID:Removal of a 3' non-coding sequence is an initial step in degradation of gro alpha mRNA and is regulated by interleukin-1. 154 76

Mediators released from injured human skin that initiate the inflammatory response have not been adequately identified. Organ culture of full-thickness skin explants enables us to do so, because injury to the skin can be made in vitro, eliminating the rapid leakage of serum and infiltration of leukocytes that occur in vivo. In our studies, the military vesicant sulfur mustard (SM) (10 microliters of a 0.01 to 1.0% dilution) was topically applied to injure the epidermis of the explant. Then, the explants were cultured in small Petri dishes, usually for 18 h at 36 degrees C, and the organ-culture fluids were assayed for various inflammatory mediators. We found that the culture fluids from SM-exposed and control explants contained similar amounts of angiotensin-converting enzyme, trypsin-like and chymotrypsin-like proteases, acid phosphatase, beta-glucuronidase, beta-galactosidase, lysozyme, deoxyribonuclease, ribonuclease, interleukin 1, and lactic dehydrogenase. However, the culture fluids from SM-exposed explants contained increased amounts of histamine and plasminogen-activating activity, and often prostaglandin E2, when compared to culture fluids from control explants. After 3 to 4 d in culture, full-thickness human skin explants, when exposed to 0.2% SM (but not when exposed to 1.0% SM), sometimes showed separation of the epidermis and increased collagenase activity (i.e., hydroxyproline release). Thus, histamine (from local mast cells), and prostaglandin E2 and plasminogen-activating activity (probably from both mast cells and epidermal cells) are apparently involved in early mediation of the inflammatory response.
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PMID:Mediators, initiating the inflammatory response, released in organ culture by full-thickness human skin explants exposed to the irritant, sulfur mustard. 171 Jun 39

Granulocyte-macrophage CSF (GM-CSF) is a potent stimulator of macrophages and neutrophils and is produced by rheumatoid arthritis (RA) synovium. We now report studies that identify some of the synovial cells and cytokines responsible for local GM-CSF production and gene expression in RA. GM-CSF was assayed by ELISA in supernatants from cultured RA fibroblast-like synoviocytes stimulated with various cytokines (IL-1 beta, TNF-alpha, macrophage-CSF, IFN-gamma, IL-6, and TGF-beta). Immunoreactive GM-CSF was detected in IL-1 beta and TNF-alpha-stimulated cultures, but not in cells cultured in medium or stimulated with any of the other cytokines. IL-1 and TNF-alpha had a synergistic effect on GM-CSF production. GM-CSF gene expression by fibroblast-like synoviocytes was analyzed by ribonuclease protection assay, Northern blot analysis, and in situ hybridization. Both IL-1 beta and TNF-alpha induced GM-CSF mRNA accumulation, with a maximum effect after 4 h of stimulation. We then studied GM-CSF production by macrophage-like synoviocytes (MLS) isolated from fresh synovial specimens by flow microfluorimetry. Fresh MLS spontaneously secreted the cytokine and exogenous IL-1 beta or TNF-alpha had no effect. After 1 wk in culture, additional stimulation with IL-1 beta or TNF-alpha was required for GM-CSF production. Finally, in situ hybridization performed on freshly isolated subpopulations of synovial cells, identified GM-CSF RNA transcripts in MLS.
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PMID:Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. 202 69

The B lymphoproliferative disorders B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) produce a number of autocrine growth factors, including tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-1, all of which may induce positive feedback growth loops. If such malignancies depend on these autocrine growth loops for survival, their interruption may be therapeutically valuable. Interferon alpha (IFN-alpha) abrogates TNF- or IL-6-induced proliferation of HCL and B-CLL cells in vitro and has therapeutic activity in these diseases. We have investigated the possibility that IFN-alpha may act by interrupting autocrine growth factor loops. If purified B-CLL or HCL cells are cultured in the presence of TNF, there is induction of mRNA for TNF, IL-1 alpha, IL-1 beta, and IL-6. However, culture in the presence of IFN-alpha in addition to TNF reduced the level of mRNA for all these cytokines, compared with cells cultured in TNF alone. While cytokine mRNA levels were diminished, levels of mRNA for the ribonuclease activator 2-5A synthetase were increased. Analysis of the kinetics of cytokine mRNA production showed that levels fall shortly after the rise of 2-5A synthetase mRNA. IFN-alpha may produce these effects by shortening the half-life of cytokine mRNA, since TNF mRNA half-life in B-CLL and HCL cells is substantially reduced when the cells are cultured with IFN-alpha. These data suggest that IFN-alpha may mediate its therapeutic effects in these malignancies by blocking autocrine growth factor loops.
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PMID:Effects of interferon alpha on autocrine growth factor loops in B lymphoproliferative disorders. 225 3

We have investigated the requirements for the induction of the acute phase response to inflammation using the FAZA rat hepatocyte cell line which can be induced to activate the acute phase response genes with supernatants from human or rat monocytes. Using ribonuclease mapping of fibrinogen transcripts, we find that the tumor promoter 12-O-tetradecanoylphorbol-13-acetate can induce a 10-20-fold increase in properly initiated and spliced fibrinogen mRNA. This response is likely to be mediated by protein kinase C (Ca2+/phospholipid-dependent enzyme) since the synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol, can also induce fibrinogen mRNA. In addition to the alpha, beta, and gamma chains of fibrinogen, other acute phase response mRNAs are induced by 12-O-tetradecanoylphorbol-13-acetate including alpha 2-macroglobulin. The active agent capable of inducing the fibrinogen mRNAs in the monocyte supernatants is clearly not interleukin 1 (IL-1) or tumor necrosis factor. The FAZA cell line does not have detectable IL-1 receptors and does not respond to either murine or human IL-1 or the 30-kDa precursor for IL-1. In addition, fibrinogen cannot be induced by tumor necrosis factor alpha in this cell line, and the active agent in monocytes supernatants cannot be neutralized with polyclonal or monoclonal antibodies to tumor necrosis factor alpha. We conclude that a third as yet uncharacterized agent is responsible for the induction of fibrinogen during the acute phase response and that this agent transduces its signal to the fibrinogen genes by a mechanism involving protein kinase C.
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PMID:Induction of fibrinogen and a subset of acute phase response genes involves a novel monokine which is mimicked by phorbol esters. 244 Aug 78

Supernatants from PHA-activated human peripheral blood mononuclear cells, depleted of virtually all IL-2 activity by an anti-rIL-2 immunoadsorbent column, contain a factor(s) which synergizes with rIL-2 in facilitating the generation of allogeneic human CTL responses in vitro. This factor, provisionally termed CTL maturation factor (TcMF), did not appear to promote CTL responses in the absence of rIL-2. Furthermore, it acted later than IL-2 in facilitating CTL responses and could not be replaced by recombinant IFN-gamma. In this report we show that rIFN-alpha, rIL-1 alpha, and rIL-1 beta likewise lack TcMF activity. The TcMF activity in lymphokine-containing culture supernatants could be eliminated by trypsin or pronase but not by neuraminidase or RNase. Gel filtration revealed two peaks of TcMF activity, one at 12,000 to 25,000 Da and the other at 45,000 to 65,000 Da. Isoelectrofocusing demonstrated substantial charge heterogeneity. The majority of TcMF activity was recovered between pI 4.0 and pI 5.5 with a minor component at pI 6.5, corresponding to the areas in which IL-1 activity was also found. However, TcMF activity could be separated from IL-1 by reverse-phase HPLC. Moreover, TcMF recovered following reverse-phase HPLC was also found to be depleted of IL-4 activity. These studies suggest that TcMF activity is mediated by a protein(s) distinct from IL-1, IL-2, IL-4, and interferon-alpha or-gamma.
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PMID:Characterization of a factor(s) which synergizes with recombinant interleukin 2 in promoting allogeneic human cytolytic T-lymphocyte responses in vitro. 327 3

A review was made on the recent advances in the study on the pathogenesis of silica-induced pulmonary fibrosis. Alveolar macrophages which ingest silica particles liberate a fibrogenic factor, which stimulates the production of collagen of cultured fibroblasts. Silica deposited in the alveoli augments the demand of macrophages, the supply of which is maintained by monocytes recruited from the bone marrow. Attempts to demonstrate in vitro the presence of a fibrogenic factor in the supernatant of macrophages have been made in many laboratories, and an in vivo model utilizing diffusion chambers implanted in mice has been used by some investigators. A fibrogenic factor has been isolated and purified from the medium of silica-treated macrophages. Recent advances in immunological studies have demonstrated that silica stimulates macrophages to release monokines such as interleukin 1 (IL-1) and that IL-1 has chemical properties identical to the fibrogenic factor, which enhances the level of collagen production by modulating the proliferation of fibroblasts. Silica inhibits the suppressive effects of macrophages on fibroblasts. The increased protein synthesis in the fibroblasts is due partly to increase in mRNA. Collagen synthesis is stimulated not only by the fibrogenic factor released from silica-treated macrophages but also by the inhibition of macrophage ribonuclease activity. Information on the number of cells, collagen content and protease activity in the lung as well as in the bronchopulmonary lavage fluid has provided us a better understanding of the mechanisms involved in silica-induced pulmonary fibrosis.
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PMID:[Recent advances in the study of the mechanisms of silica-induced pulmonary fibrosis]. 391 86

Rabbit mononuclear cells from oil-induced peritoneal exudates were purified by centrifugation on Percoll gradients, suspended in tissue culture medium, and stimulated with opsonized Staphylococcus epidermidis. The supernatants from these macrophages caused fever when injected intravenously into rabbits (endogenous pyrogen [EP] activity). The EP activity was contained in two protein fractions, with pIs of 7.3 and ca. 5.0. The same fractions caused mouse thymocytes to incorporate tritiated thymidine when incubated in vitro with small quantities of phytohemagglutinin (interleukin 1 [IL-1] activity). The pI 5.0 form of EP was purified to apparent homogeneity by sequential use of ammonium sulfate precipitation, gel filtration, ion-exchange chromatography, hydrophobic chromatography, and high-resolution isoelectric focusing. EP and IL-1 activities were not separable by any of these procedures. Active fractions from isoelectric focusing were analyzed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Only one band was visible as judged by a silver staining method, and IL-1 activity could be recovered by renaturing eluates from the same region of sodium dodecyl sulfate gels run in parallel. An estimate of specific activity was made by comparing the intensity of stained bands of EP with the intensity of bands containing known quantities of lysozyme or RNase. By this criterion, the specific activity of purified pI 5 EP was between 17,000 and 58,000 degrees C U/mg of protein, and the specific activity in terms of IL-1 was between 59 million and 360 million U per mg of protein. These observations suggest that both EP and IL-1 activities can be expressed by a single molecular species. The implications of this coincidence are discussed. It was also shown that highly purified pI 5 EP obtained from macrophages stimulated in the presence of 14C-labeled amino acids contained significant 14C radioactivity. This suggests that the pI 5.0 EP, like the pI 7.3 form, was synthesized de novo from amino acid precursors.
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PMID:Demonstration of interleukin 1 activity in apparently homogeneous specimens of the pI 5 form of rabbit endogenous pyrogen. 661 12


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