Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00017 (IFN-gamma)
 28,919 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among the important pleiotropic responses to gamma interferon (IFN-gamma) during the activation of macrophages (M phi) is the increased expression of major histocompatibility complex class II genes. In the present study, infection with Leishmania donovani was shown to inhibit in parallel the induction by IFN-gamma of H-2 A beta gene transcription, class II mRNA accumulation, and H-2 Ad protein expression in cells of the murine macrophage cell line P388D1. Treatment of P388D1 cells with either the adenylate cyclase activator cholera toxin or the protein kinase A activator N6-2'-O-dibutyryl cyclic AMP (dibutyryl cAMP) similarly inhibited the induction by IFN-gamma of class II protein expression, and in parallel with Leishmania infection, cholera toxin inhibited the induction of mRNA for the H-2 A alpha and H-2 A beta proteins. Concentrations of intracellular cAMP were significantly increased in cholera toxin-treated cells but not in leishmania-infected cells. These findings indicate that at least one mechanism by which Leishmania infection attenuates the activation of M phi by IFN-gamma involves selective, transcriptional inhibition of major histocompatibility complex class II genes via a cAMP-independent mechanism.
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PMID:Inhibition of expression of major histocompatibility complex class II molecules in macrophages infected with Leishmania donovani occurs at the level of gene transcription via a cyclic AMP-independent mechanism. 131 26

The adherence of cells to microvascular endothelium is important in a number of processes, including inflammatory responses and metastasis. It has been demonstrated that in human models, cytokines such as TNF, IL-1, IFN-gamma increase the adhesiveness of endothelium for cells of the immune and inflammatory system by stimulating the expression of cell adhesion molecules on endothelial cell surfaces. We and others have shown similar cytokine-induced endothelial adhesiveness for tumor cells in murine and human models. In contrast to the effect of those modulators, transforming growth factor-beta (TGF-beta) has been shown to inhibit the binding of human neutrophils and T lymphocytes to human endothelium, although the mechanism of TGF-beta action remains unknown. Little is known about the effect of TGF-beta on tumor cell-endothelial interaction. In the present study, we demonstrate that TGF-beta inhibits basal and TNF-enhanced binding of murine P815 mastocytoma cells to murine microvascular endothelium (MME). The alterations in MME mediated by TGF-beta, also lead to the inhibition of adherence of murine splenocytes, thymocytes, and human lymphoblastoid cells but do not inhibit adherence of murine B16 melanoma cells. The effect of TGF-beta is transient and inhibition of the endothelial adhesive phenotype is strongest 12 to 24 h after addition of the factor to MME. The TGF-beta-mediated inhibition of P815 basal binding to endothelium is dependent on protein synthesis because cycloheximide reverses the TGF-beta effect. TGF-beta does not appear to activate classical signal transduction pathways. Inhibitors of G proteins do not abolish TGF-beta action, protein kinase C and protein kinase A activators elicit an effect opposite to that of the factor, TGF-beta does not increase intracellular cAMP levels, and finally calcium-mobilizing agents do not mimic, but rather inhibit the effect of TGF-beta. However, TGF-beta-mediated inhibition of both basal binding and TNF-enhanced P815 binding to MME is completely abolished in the presence of the protein phosphatase inhibitor okadaic acid which suggests that TGF-beta may elicit its effect by stimulating protein phosphatase activity.
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PMID:Inhibition of basal and tumor necrosis factor-enhanced binding of murine tumor cells to murine endothelium by transforming growth factor-beta 1. 131 61

IFN-gamma secretion by Th1 cells has been shown to preferentially promote the production of IgG2a in LPS-stimulated murine B lymphocytes. We recently reported that PGE2 potentiated the ability of IFN-gamma to augment IgG2a production in both Ag-specific and polyclonal systems via a cAMP-dependent pathway. Because antibodies (Ab) directed against class II MHC molecules have been shown to induce a rise in B cell cAMP, we hypothesized that this event, like PGE2 treatment, would promote the production of IgG2a. In this manuscript, cultures of small and large B cells treated with anti-Ia Ab are shown to produce significantly higher levels of IgG2a, compared with cultures treated only with IFN-gamma and LPS. Moreover, the combined treatment of B lymphocytes with IFN-gamma and PGE2 followed by anti-Ia and LPS resulted in a fourfold rise in IgG2a levels compared with IFN-gamma and LPS. Only anti-class II, but not anti-class I Ab, stimulated IgG2a production. Utilizing an ELISA spot assay, the frequency of IgG2a-secreting B cells was determined to be elevated fourfold in anti-Ia treated B cells. B cell cultures incubated with either PGE2 or anti-Ia exhibited elevated levels of cAMP and treatment with IFN-gamma primed these lymphocytes to the cAMP-elevating effects of either PGE2 or anti-Ia. Finally, RpcAMP, a cAMP antagonist that blocks cAMP from activating protein kinase A, prevented the increased production of IgG2a induced by anti-Ia Ab. These results support the theory that a cAMP pathway exists that promotes B cell IgG2a production. Within this pathway, IFN-gamma sensitizes B lymphocytes to cAMP elevators such as anti-class II Ab, and in conjunction with LPS, causes an increase in the frequency of IgG2a-secreting cells and the amount of IgG2a produced. These observations suggest that, after exposure to viral Ag in vivo, interaction between IFN-gamma-primed murine B cells and T cells will potentiate production of IgG2a, the predominant murine anti-viral Ig.
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PMID:Anti-class II antibodies potentiate IgG2a production by lipopolysaccharide-stimulated B lymphocytes treated with prostaglandin E2 and IFN-gamma. 131 36

A molecular cDNA clone (P1 KIN) was isolated that encodes the human RNA-dependent P1/eIF-2 alpha protein kinase. The complete cDNA sequence of the P1 KIN cDNA was determined; the longest open reading frame (ORF) encoded a 551 amino acid protein with a deduced molecular weight of 62055 Da. Transcripts prepared from the P1 KIN cDNA by transcription in vitro with T7 RNA polymerase programmed the cell-free synthesis of a protein indistinguishable by immunoprecipitation and immunoblot gel analyses from the authentic 67-kDa P1 protein synthesized in human U cells treated with interferon (IFN). Furthermore, by use of a sensitive primer extension assay with T7 DNA polymerase, the major site of translation initiation within the deduced ORF of the P1 KIN cDNA was directly identified. Northern RNA gel-blot analysis revealed that the P1 KIN cDNA strongly hybridized to two IFN-induced mRNAs present in both human amnion U cells and HeLa cells; their sizes were 2.5 and 6 kb. Both transcripts were efficiently induced by IFN-alpha, but poorly by IFN-gamma. Polyclonal antibody was prepared against the product of the P1 KIN cDNA expressed in Escherichia coli. In Western blot analysis the antibody recognized a 67-kDa protein induced in human cells by IFN-alpha and, in addition, a 90-kDa protein whose level was not greatly altered by IFN treatment. The IFN-induced 67-kDa protein was found associated with the ribosomal salt-wash fraction of IFN-treated human cells, whereas the 90-kDa protein was predominantly in the S100 soluble fraction. The time course for the induction by IFN-alpha of RNA-dependent protein P1 kinase activity measured by immunoprecipitation was comparable to the time course for protein P1 induction measured by Western immunoblot analysis. The amino acid sequence of P1/eIF-2 alpha protein kinase deduced from the cDNA was 62% identical with the 518-residue murine TIK kinase and contained, within the carboxy-terminal half of the protein, the motifs commonly conserved among protein-serine/threonine kinases. The amino-terminal half of the P1 protein did not possess conserved kinase motifs, but did show extensive homology with vaccinia virus-predicted protein E3L.
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PMID:Mechanism of interferon action: cDNA structure, expression, and regulation of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from human cells. 137 53

Macrophages are activated by a variety of microbial and cytokine stimuli. One feature of activation is the induction of class II Ag (Ia) on the cell surface. To understand the intracellular events that occur during activation, we investigated various agents with intracellular activities, and examined their effects on the induction of Ia. We first noted that several agents that activate protein kinase C (PKC) induced Ia, and that several inhibitors of PKC inhibited Ia induction by IFN-gamma. To directly test whether PKC induced Ia, we microinjected normal peritoneal macrophages with this enzyme and other intracellular mediators, then examined Ia expression. We observed that injection of PKC itself, or of other intracellular proteins thought to participate in the PKC pathway (Ras or phospholipase C gamma) strongly induced Ia expression. The Ia-inducing activity of transforming Ras protein was blocked by kinase inhibitor treatment of cells, suggesting that Ras signal transduction requires kinase activity. On the other hand, components of the protein kinase A pathway (phospholipase A2 and protein kinase A itself) did not induce Ia. Thus, the PKC pathway can control expression of macrophage surface Ia, possibly by regulating the genes of the MHC, and may play many other roles in the activation of macrophages.
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PMID:Components of the protein kinase C pathway induce Ia expression after injection into macrophages. 138 38

Treatment of human HeLa and amnion U cells with gamma interferon (IFN-gamma), either alone or in combination with alpha interferon (IFN-alpha), reduced the steady-state level of mRNA encoding the catalytic (C) subunit of protein kinase A (PKA) as measured by Northern gel-blot (RNA) analysis. In addition, IFN-gamma treatment increased the ratio of C alpha to C alpha 2 (the two splice-site variants of PKA C alpha subunit mRNA produced in HeLa cells) as measured by a polymerase chain reaction assay. IFN-gamma greatly reduced the amount of a novel splice-site variant of PKA, C alpha 2, which retains introns G and H, relative to the amount of C alpha, which lacks introns G and H. IFN-alpha treatment in combination with IFN-gamma did not further reduce the level of PKA C alpha transcripts beyond that of IFN-gamma alone, as measured by Northern blots; however, IFN-alpha in combination with IFN-gamma did cause a synergistic increase in the level of human Mx transcripts.
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PMID:Mechanism of interferon action: alpha and gamma interferons differentially affect mRNA levels of the catalytic subunit of protein kinase A and protein Mx in human cells. 154 77

Treatment of human colorectal tumor cells (LS174T, HT-29, and WiDr) with analogues of cyclic AMP (cAMP) (dibutyryl-cAMP and 8-Cl-cAMP) selectively enhances the expression of carcinoembryonic antigen (CEA). Dose and temporal kinetics results revealed that 8-Cl-cAMP was approximately 100-fold more potent than dibutyryl-cAMP for increasing CEA expression. Results demonstrated that 8-Cl-cAMP treatment of LS174T quantitatively increased CEA levels in cell extracts 2-fold, increased anti-CEA monoclonal antibody (MAb) binding to the tumor cell surface, and induced the appearance of CEA-related mRNA transcripts. The findings suggest that 8-Cl-cAMP is capable of regulating CEA expression at transcriptional and/or post-transcriptional levels. Other human tumor cells, as well as normal cell types which do not constitutively express CEA, remained CEA-negative following 8-Cl-cAMP treatment. Moreover, the level of expression of other human tumor antigens as well as antigens of the major histocompatibility complex were not changed by 8-Cl-cAMP treatment, suggesting some selectivity for CEA regulation by this cAMP analogue. In vivo administration of 8-Cl-cAMP to athymic mice bearing LS174T tumor xenografts increased the amount of anti-CEA MAb bound to tumor extracts as well as the tumor localization of a radionuclide-conjugated anti-CEA MAb. The results indicate that 8-Cl-cAMP can selectively upregulate CEA expression on human colorectal tumor cells in vitro and in vivo. Interestingly, IFN-gamma treatment of the LS174T cells fails to enhance or induce expression of CEA or any of the histocompatibility leukocyte antigens. Thus, 8-Cl-cAMP treatment regulates CEA expression through another cellular pathway which may involve cAMP-dependent protein kinase.
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PMID:Carcinoembryonic antigen regulation in human colorectal tumor cells by a site-selective cyclic AMP analogue: a comparison with interferon-gamma. 164

Previous studies have implicated protein kinase C (PKC) as a mediator in the activation of macrophages by interferons. In order to probe further into the suspected role of protein kinase C in mouse peritoneal macrophage activation, the effects of protein kinase inhibitors in macrophage Fc gamma R and Ia Ag expression were studied. The protein kinase inhibitor, H7, reduced basal levels, and inhibited IFN-alpha-induced expression of Fc gamma R significantly. The concentration of H7 required to inhibit 50% of the Fc gamma R induction was approximately 12 microM, which reflects the previously reported affinity of this compound for PKC in vitro. H7 had only a minimal effect on IFN-gamma-induced Fc gamma R, suggesting different pathways of Fc gamma R induction by the two types of IFN. Ia induction by IFN-gamma was also inhibited by H7, indicating that both types of IFN can utilize PKC to mediate at least part of the signal required for Fc gamma R or Ia expression. HA-1004, a derivative of H7 which possesses high affinity for cyclic nucleotide-dependent protein kinases, but low affinity for PKC, did not alter induction, while H8, a slightly less effective PKC inhibitor than H7, was effective at higher concentrations. Another structurally distinct PKC antagonist, staurosporine, was also effective inhibiting IFN-alpha-induced Fc gamma R and IFN-gamma-induced Ia Ag expression, providing additional evidence that PKC is important. H7 was found to be effective when added as late as several hours after IFN treatment, indicating a prolonged or delayed requirement of PKC for optimal induction of Ia and Fc gamma R by IFN.
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PMID:Pharmacologic evidence for the requirement of protein kinase C in IFN-induced macrophage Fc gamma receptor and Ia antigen expression. 170 Sep 95

The effects of combinations of interferons (IFNs) and cAMP-inducing agents on the induction of differentiation of human monocytic leukemia U-937 cells were examined. IFN-gamma induced nitro blue tetrazolium (NBT) reducing activity of U-937 cells in a dose-dependent manner, while cAMP-inducing agents such as cholera toxin, prostaglandin E1, forskolin, and isoproterenol only marginally induced NBT reducing activity. However, they all synergistically increased IFN-gamma induction of NBT reducing activity. Cholera toxin was the most potent of the cAMP-inducing agents. Combination effects of IFN-gamma and cholera toxin on other differentiation-associated markers of alpha-naphthyl acetate esterase activity, morphological maturation, Fc receptors, and surface phenotype were also observed. IFN-alpha and -beta, either alone or in combination with cAMP-inducing agents, did not induce NBT reducing activity. IFN-gamma and cholera toxin also synergistically induced differentiation-associated markers in another human monocytic leukemia cell line, THP-1, and a human myeloblastic leukemia cell line, ML-1. These results suggest that cAMP/A-kinase may be an important but insufficient signal for the maturation process of myelogenous leukemia cells.
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PMID:Enhancement of interferon-gamma-induced differentiation of human monoblastic leukemia U-937 cells by cAMP-inducing agents. 170 96

We have previously described an Ia-expressing macrophage hybridoma clone, termed clone 59, which attains the ability to induce Ts cells after activation with murine rIFN-gamma. In this report, we show that a protein kinase C (PKC) activator, PMA (10 ng/ml) can replace IFN-gamma in inducing this form of macrophage competence. IFN-gamma-induced cellular competence was abrogated specifically by a PKC inhibitor but not by inhibitors that have specificity for cyclic nucleotide-dependent protein kinases. Furthermore, PGE2 known to induce protein kinase A in murine macrophages also failed to induce competence. In contrast, the ability to induce Th responses was neither dependent on IFN-gamma nor inhibited by prior treatment with protein kinase inhibitors. Furthermore, PKC depletion of macrophages by treatment with high doses (100 ng/ml) of PMA abrogated their ability to induce Ts cells. In addition, PKC-depleted macrophages failed to regain the ability to stimulate Ts cells after further treatment with IFN-gamma. The ability of IFN-gamma to modulate macrophage-mediated induction of Ts cells does not clearly correlate with an increased Ia expression as inducible expression of Ia was not consistently abrogated by PKC inhibitor treatment. In addition, PKC inhibitors failed to prevent the production of the cytokines IL-1 and IL-6. However, incubation of IFN-gamma or PMA-treated macrophages with antibodies recognizing the putative IJ ligand blocked the ability to induce Ts cells, suggesting the expression of these determinants on accessory cells is responsible for Ts induction.
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PMID:Involvement of protein kinase C in competence induction of macrophages to generate T suppressor cells. 171 Feb 37


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