Interferon-β-1b and interferon-γ have similar inhibitory effects on apolipoprotein-E production in the monocyte/macrophage

2002 ◽  
Vol 8 (2) ◽  
pp. 124-129 ◽  
Author(s):  
D O'Toole ◽  
W C Love
Keyword(s):  
Apolipoprotein E ◽  
Interferon Γ ◽  
Cellular Protein ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Apo E ◽  
Reduce Relapse Rate ◽  
Ifn Γ ◽  
Remission Phase ◽  
Dose Dependent

Apolipoprotein-E (Apo-E) is the major lipid carrier in the brain, and is therefore important in the recycling of lipids and cholesterol to regenerating neurons during the remission phase of multiple sclerosis (MS). Interferon (IFN)-γ has been shown to inhibit Apo-E production by a mainly post-transcriptional method in a macrophage cell line, and reduced Apo-E in cerebrospinal fluid is noted during the remission phase in patients. IFN-β-1b is a recombinantly produced, anti-inflammatory cytokine, which has been shown to reduce the severity of MS relapses and reduce relapse rate. We have examined the effects of IFN-γ and IFN-β-1b on the production of Apo-E mRNA, cellular protein and secreted protein in primary monocytes derived from donor blood. IFN-β-1b does not relieve the dose-dependent inhibition of Apo-E seen with IFN-γ at up to 100 U/ml in these cells, and when used alone inhibits Apo-E production in a dose-dependent manner. This inhibition by IFN- β-1b was seen to be at a transcriptional level, and dose dependent up to 100 U/ml. Apo-E genotype, which has also been linked to failure to recover from MS relapses, did not affect this inhibition. The mode of action of IFN-β-1b in MS is therefore not thought to be through modification of Apo-E production.

Direct regulation of lipolysis by interleukin-15 in primary pig adipocytes

2004 ◽  
Vol 287 (3) ◽  
pp. R608-R611 ◽  
Author(s):  
Kolapo M. Ajuwon ◽  
Michael E. Spurlock
Keyword(s):  
Protein Kinase ◽  
Muscle Protein ◽  
Interferon Γ ◽  
Janus Kinase ◽  
Dependent Manner ◽  
Kinase C ◽  
Tnf Α ◽  
Interleukin 15 ◽  
Ifn Γ ◽  
Dose Dependent

We recently provided evidence that interleukin-15 (IL-15) is expressed lowly in the pig adipocyte and that interferon-γ (IFN-γ) markedly increases this expression through a pathway regulated in part by protein kinase C (Ajuwon KM, Jacobi SK, Kuske JL, and Spurlock ME. Am J Physiol Regul Integr Comp Physiol 286: R547–R553, 2004). In the present study, we tested the hypothesis that IL-15 acts directly on the adipocyte to regulate lipid accretion by enhancing lipolysis or suppressing lipogenesis. Using recombinant porcine IL-15, we determined that this cytokine stimulates lipolysis in a dose-dependent manner ( P < 0.001). Furthermore, comparative studies with other cytokines showed that IL-15 is more potent in its acute stimulation of lipolysis than either TNF-α, IL-6, or LPS ( P < 0.001). When specific inhibitors of protein kinase A or Janus kinase are present, the lipolytic effect of IL-15 is attenuated ( P < 0.01). These data indicate that, in addition to its regulation of muscle protein accretion and T-cell growth and development, IL-15 also targets the adipocyte directly to alter stimulate lipolysis. Thus, when induced by IFN-γ or other inflammatory mediators, IL-15 may be a significant homeorhetic factor that mobilizes and directs energy away from the adipocyte to other cells during the acute phase of the inflammatory response.

Protective Effects of Baicalin against Bromocriptine Induced Abortion in Mice

2009 ◽  
Vol 37 (01) ◽  
pp. 85-95 ◽  
Author(s):  
Ai-Tuan Ma ◽  
Xiu-Hui Zhong ◽  
Zhan-Min Liu ◽  
Wan-Yu Shi ◽  
Jian Du ◽  
...  
Keyword(s):  
Interleukin 10 ◽  
Interferon Γ ◽  
Induced Abortion ◽  
Dependent Manner ◽  
Protective Effects ◽  
Death Rates ◽  
Chinese Herbal ◽  
Ifn Γ ◽  
Dose Dependent ◽  
Embryonic Death

The Chinese herbal medicine Huang Qin (Radix Scutellariae) had been used for restless fetus for hundreds of years in China, however, little attention had been given to the components of the herb, specifically its ability to exert abortion-preventing effects at the maternal fatal interface. The present study was carried out to investigate the protective effects of baicalin and the possible mechanisms on pregnancies. Baicalin (at 10, 20, and 50 mg/kg BW respectively) was gavaged to bromocriptine-treated mice from gestation day (GD) 1 through GD 7. Abortion rates were calculated and the changes of interferon-γ (IFN-γ), interleukin-10 (IL-10) and progesterone were assayed on different gestation days. Results showed that the embryonic death rates were significantly decreased in groups supplemented with 20 or 50 mg/kg BW of baicalin, accompanied with reduced IFN-γ and enhanced progesterone contents. Moreover, the highest levels of IFN-γ appeared on GD 5 both in the control and in baicalin treated groups. It is concluded that baicalin can exert an anti-abortive effect by cutting down the production of IFN-γ and elevating the levels of progesterone in a dose dependent manner and IFN-γ is involved in an inflammatory reaction which is beneficial for a successful implantation.

scholarly journals Effect ofTityus serrulatusvenom on cytokine production and the activity of murine macrophages

2002 ◽  
Vol 11 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Vera L. Petricevich
Keyword(s):  
Cytokine Production ◽  
Peritoneal Macrophages ◽  
Interferon Γ ◽  
Enzyme Linked Immunosorbent Assay ◽  
No Production ◽  
Dependent Manner ◽  
Immune Functions ◽  
Macrophage Activity ◽  
Ifn Γ

The purpose of this study was to investigate the effects ofTityus serrulatusvenom (TSV) on murine peritoneal macrophages evaluated in terms of activation. The effects of crude TSV were analysed by detection of cytokines, oxygen intermediate metabolites (H2O2) and nitric oxide (NO) in supernatants of peritoneal macrophages. Several functional bioassays were employed including anin vitromodel for envenomating: cytotoxicity of TSV was assessed using the lyses percentage. Tumor necrosis factor (TNF) activity was assayed by measuring its cytotoxic activity on L-929 cells, and interleukin-6 (IL-6) and interferon-γ (IFN-γ) were assayed by enzyme-linked immunosorbent assay, whereas NO levels were detected by Griess colorimetric reactions in culture supernatant of macrophages incubated with TSV and subsequently exposed to either lipopolysaccharide or IFN-γ. Incubation of macrophages with TSV increased production of IL-6 and IFN-γ in a dose-dependent manner. TNF production was not detected in supernatants treated with TSV at any concentration. The increase in IL-6 secretion was not associated with concentration-dependent cytoxicity of TSV on these cells. These data suggest that the cytotoxicity does not appear to be the main cause of an increased cytokine production by these cells. Although NO is an important effector molecule in macrophage microbicidal activity, the inducing potential of the test compounds for its release was found to be very moderate, ranging from 125 to 800 mM. Interestingly, NO levels of peritoneal macrophages were increased after IFN-γ. Moreover, NO production had an apparent effect on macrophage activity. The results obtained here also shown that the TSV induces an important elevation in H2O2release. These results combined with NO production suggest that TSV possesses significant immunomodulatory activities capable of stimulating immune functionsin vitro.

Fas/APO-1 (CD95)–Mediated Apoptosis Is Activated by Interferon-γ and Interferon- in Interleukin-6 (IL-6)–Dependent and IL-6–Independent Multiple Myeloma Cell Lines

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2914-2923 ◽  
Author(s):  
Helena Spets ◽  
Patrik Georgii-Hemming ◽  
Jan Siljason ◽  
Kenneth Nilsson ◽  
Helena Jernberg-Wiklund
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Poor Response ◽  
Antigen Expression ◽  
Myeloma Cell ◽  
Interferon Γ ◽  
Dependent Manner ◽  
Multiple Myeloma Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Abstract A poor response to Fas-induced apoptosis is evident in some multiple myeloma (MM) cell lines and primary cells. In this study, we have examined the possibility to increase the sensitivity to Fas-induced apoptosis by pretreatment of MM cells with interferon-γ (IFN-γ) or interferon- (IFN-). Both IFN-γ and IFN- markedly increased the Fas-induced apoptosis in all cell lines tested (U-266-1970, U-266-1984, and U-1958). In the U-266-1970 and U-1958 cell lines, pretreatment with either IFN-γ or IFN- also inhibited proliferation in a dose-dependent manner. In contrast, IFN-γ activation of the Fas death pathway in the U-266-1984 cells was not accompanied by growth inhibition. Incubation with the IFNs increased the Fas antigen expression in one of three cell lines but did not alter the expression of Bcl-2 or Bax. The IFNs are important regulators of growth and survival in MM cells. Our results suggest that activation of Fas-mediated apoptosis is a novel mechanism by which the IFNs exert inhibitory effects on MM cells. © 1998 by The American Society of Hematology.

scholarly journals Deacetylation of p53 induces autophagy by suppressing Bmf expression

2013 ◽  
Vol 201 (3) ◽  
pp. 427-437 ◽  
Author(s):  
Amelia U. Contreras ◽  
Yohannes Mebratu ◽  
Monica Delgado ◽  
Gilbert Montano ◽  
Chien-an A. Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Messenger Rna ◽  
Histone Deacetylase Inhibitors ◽  
Interferon Γ ◽  
Airway Epithelial Cells ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Independent Manner ◽  
Rich Domain ◽  
Ifn Γ

Interferon γ (IFN-γ)–induced cell death is mediated by the BH3-only domain protein, Bik, in a p53-independent manner. However, the effect of IFN-γ on p53 and how this affects autophagy have not been reported. The present study demonstrates that IFN-γ down-regulated expression of the BH3 domain-only protein, Bmf, in human and mouse airway epithelial cells in a p53-dependent manner. p53 also suppressed Bmf expression in response to other cell death–stimulating agents, including ultraviolet radiation and histone deacetylase inhibitors. IFN-γ did not affect Bmf messenger RNA half-life but increased nuclear p53 levels and the interaction of p53 with the Bmf promoter. IFN-γ–induced interaction of HDAC1 and p53 resulted in the deacetylation of p53 and suppression of Bmf expression independent of p53’s proline-rich domain. Suppression of Bmf facilitated IFN-γ–induced autophagy by reducing the interaction of Beclin-1 and Bcl-2. Furthermore, autophagy was prominent in cultured bmf−/− but not in bmf+/+ cells. Collectively, these observations show that deacetylation of p53 suppresses Bmf expression and facilitates autophagy.

scholarly journals Streptococcus pneumoniae Autolysis Prevents Phagocytosis and Production of Phagocyte-Activating Cytokines

2009 ◽  
Vol 77 (9) ◽  
pp. 3826-3837 ◽  
Author(s):  
Anna Martner ◽  
Susann Skovbjerg ◽  
James C. Paton ◽  
Agnes E. Wold
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 12 ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Exact Function ◽  
Ifn Γ ◽  
Dose Dependent

ABSTRACT Streptococcus pneumoniae is a major pathogen in humans. The pathogenicity of this organism is related to its many virulence factors, the most important of which is the thick pneumococcal capsule that minimizes phagocytosis. Another virulence-associated trait is the tendency of this bacterium to undergo autolysis in stationary phase through activation of the cell wall-bound amidase LytA, which breaks down peptidoglycan. The exact function of autolysis in pneumococcal pathogenesis is, however, unclear. Here, we show the selective and specific inefficiency of wild-type S. pneumoniae for inducing production of phagocyte-activating cytokines in human peripheral blood mononuclear cells (PBMC). Indeed, clinical pneumococcal strains induced production of 30-fold less tumor necrosis factor (TNF), 15-fold less gamma interferon (IFN-γ), and only negligible amounts of interleukin-12 (IL-12) compared with other closely related Streptococcus species, whereas the levels of induction of IL-6, IL-8, and IL-10 production were similar. If pneumococcal LytA was inactivated by mutation or by culture in a medium containing excess choline, the pneumococci induced production of significantly more TNF, IFN-γ, and IL-12 in PBMC, whereas the production of IL-6, IL-8, and IL-10 was unaffected. Further, adding autolyzed pneumococci to intact bacteria inhibited production of TNF, IFN-γ, and IL-12 in a dose-dependent manner but did not inhibit production of IL-6, IL-8, and IL-10 in response to the intact bacteria. Fragments from autolyzed bacteria inhibited phagocytosis of intact bacteria and reduced the in vitro elimination of pneumococci from human blood. Our results suggest that fragments generated by autolysis of bacteria with reduced viability interfere with phagocyte-mediated elimination of live pneumococci.

Vandellia Cordifolia Regulated Cell Proliferation and Cytokines Production in Human Mononuclear Cells

2000 ◽  
Vol 28 (03n04) ◽  
pp. 313-323 ◽  
Author(s):  
An-Pang Lin ◽  
Wei-Jern Tsai ◽  
Chi-Yen Fan ◽  
Ming-Jen Lee ◽  
Yuh-Chi Kuo
Keyword(s):  
Cell Cycle Progression ◽  
Mononuclear Cells ◽  
Tritiated Thymidine ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Thymidine Uptake ◽  
Dependent Manner ◽  
Human Mononuclear Cells ◽  
Tritiated Thymidine Uptake ◽  
Ifn Γ

Vandellia cordifolia (V. cordifolia) used for treatment inflammation in traditional Chinese medicine was selected for immunopharmacological activity test. The effects of V. cordifolia extracted fractions on human mononuclear cells (HMNC) proliferation were determined by tritiated thymidine uptake. The results indicated that VC-ME fraction suppressed HMNC proliferation activated with phytohemagglutinin (PHA) and stimulated cell cycle progression was arrested at the G0/G1 stage. The inhibitory mechanisms may involve the blocking of interleukin-2 (IL-2) and interferon-γ (IFN-γ) production, since VC-ME suppressed IL-2 and IFN-γ production of HMNC in a dose-dependent manner. Therefore, it is suggested that immunomodulatory agents are contained in V. cordifolia.

Lenalidomide Strongly Enhances Natural Killer (NK) Cell Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC) of Rituximab Treated Non-Hodkin’s Lymphoma Cell Lines In Vitro.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3714-3714 ◽  
Author(s):  
Lei Wu ◽  
Peter Schafer ◽  
George Muller ◽  
David Stirling ◽  
J. Blake Bartlett
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Nk Cell ◽  
Dependent Manner ◽  
Activation Markers ◽  
Early Results ◽  
Ifn Γ ◽  
Dose Dependent

Abstract Lenalidomide (Revlimid® is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone is for the treatment of multiple myeloma patients who have received at least one prior therapy. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin’s lymphoma (NHL). Potential mechanisms of action include anti-angiogenic, anti-proliferative and immunomodulatory activities. Lenalidomide has been shown to enhance Th1-type cytokines and T cell and NK cell activation markers in patients with advanced cancers. Furthermore, lenalidomide has been shown to enhance rituximab-mediated protection in a SCID mouse lymphoma model in vivo. We have utilized an in vitro ADCC system to assess the ability of lenalidomide to directly enhance human NK cell function in response to therapeutic antibodies, such as rituximab (chimeric anti-CD20 mAb). Isolated NK cells produced little or no IFN-γ in response to IgG and/or IL-2 or IL-12. However, pre-treatment of NK cells with lenalidomide greatly enhanced IFN-γ production by NK cells in a dose-dependent manner. In a functional ADCC assay, NHL cell lines (Namalwa, Farage & Raji) were pre-coated with rituximab and exposed to NK cells pre-treated with lenalidomide in the presence of either exogenous IL-2 or IL-12. After 4 hours in culture the viability of the tumor cells was assessed. Lenalidomide consistently and synergistically increased the killing of tumor cells in a dose-dependent manner and up to >4-fold compared to rituximab alone. Rituximab alone had only a small effect in this model and there was no killing of cells in the absence of rituximab. The presence of either exogenous IL-2 or IL-12 was required to see enhanced killing by lenalidomide. In cancer patients lenalidomide has been shown to increase serum IL-12 levels and is also known to induce IL-2 production by T cells in vitro. Potential mechanisms for enhanced ADCC include increased signaling through NK FCγ receptors and/or IL-2 or IL-12 receptors. However, we found that these receptors are unaffected by lenalidomide, although downstream effects on NK signaling pathways are likely and are being actively investigated. In conclusion, we have shown that lenalidomide strongly enhances the ability of rituximab to induce ADCC mediated killing of NHL cells in vitro. This provides a strong rationale for combination of these drugs in patients with NHL and CLL.

Expression of Proteinase Inhibitor-9 in Primary AML Blasts and Its Regulation by Interferon-γ: A Potential Immune Escape Mechanism after Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3687-3687
Author(s):  
Sabine Hoves ◽  
Alexandra Kolbeck ◽  
Krishna Mondal ◽  
Reinhard Andreesen ◽  
Andreas Mackensen
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Escape ◽  
Immune Surveillance ◽  
Hematologic Malignancies ◽  
Interferon Γ ◽  
Dependent Manner ◽  
Ifn Γ ◽  
Immune Escape Mechanisms

Abstract It is well established, that the curative potential of allogeneic peripheral blood stem cell transplantation (allo PBSCT) is due to immunocompetent donor T cells inducing potent anti-neoplastic effects against host tumor cells. This reaction, which is termed graft-versus-leukemia (GVL) effect, is clinically effective against a number of different hematologic malignancies such as myeloid and lymphoid leukemias. Despite great efforts of allo PBSCT in treatment of CML, the 5-year survival rate of AML patients after allo PBSCT is only about 30% due to relapsing disease. The recurrent disease is inefficiently controlled by the immune system, due most likely to the various immune escape mechanisms described for AML blasts including upregulation of anti-apoptotic molecules. Since cytotoxic T lymphocytes (CTL) and natural killer cells are the cells responsible for eliminating leukemic blasts, the most important effector molecule is Granzyme B (GrB). Misdirected GrB is quenched by its specific physiological inhibitor Protease Inhibitor-9 (PI-9) leading to inactivation of GrB. PI-9 expression by tumour cells can be used to escape immune surveillance and its presence has been shown for different tumors e.g. melanoma, colon carcinoma and lymphoma. Despite other regulators, interferon-γ (IFN-γ) has been shown to upregulate PI-9 expression in hepatocytes. Here, we wanted to investigate the expression of PI-9 in primary AML blasts and its regulation by IFN-γ. Using CD34+ positive magnetic selection, we isolated primary blasts with a purity of >90% from 20 AML patients with different FAB subtypes. For detection of PI-9 expression by Western Blotting, whole cell lysates were made from freshly purified blasts and after 24 h +/− 200 IU/ml IFN-γ. In some patients, PI-9 expression was confirmed by FACS analysis with an anti- PI-9 specific monoclonal antibody. Here we describe for the first time, that PI-9 is constitutively expressed in 16/20 (80%) of AML blasts. Treatment of AML blasts with IFN-γ could upregulate PI-9 expression in a dose-dependent manner (2–2,000 IU/ml) and strong expression of PI-9 was detectable in 6/18 patients within 4–5 h after IFN-γ exposure. Of note, a mild upregulation of PI-9 upon 24 h incubation w/o IFN-γ could be detected in 4/18 (22%) patients. We conclude, that cytokines such as IFN-γ which are secreted during the cytokine storm of acute graft-versus-host disease can contribute to the development of immune escape mechanisms in AML blasts.

scholarly journals Choline Induces Transcriptional Repression and Proteasomal Degradation of the Malarial Phosphoethanolamine Methyltransferase

2007 ◽  
Vol 6 (9) ◽  
pp. 1618-1624 ◽  
Author(s):  
William Harold Witola ◽  
Choukri Ben Mamoun
Keyword(s):  
Transcriptional Repression ◽  
Morphological Changes ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Wild Type ◽  
Active Synthesis ◽  
Rapid Multiplication ◽  
Gene And Protein Expression ◽  
Transgenic Parasites ◽  
Dose Dependent

ABSTRACT During its intraerythrocytic life cycle, the malaria parasite Plasmodium falciparum undergoes dramatic metabolic and morphological changes and multiplies to produce up to 36 new daughter parasites. This rapid multiplication of the parasite requires an active synthesis of new membranes. The major component of these membranes, phosphatidylcholine, is synthesized via two metabolic routes, the CDP-choline pathway, which uses host choline as a precursor, and the plant-like serine decarboxylase-phosphoethanolamine methyltransferase (SDPM) pathway, which uses host serine as a precursor. Here we provide evidence indicating that the activity of the SDPM pathway is regulated by the CDP-choline precursor, choline. We show that the phosphoethanolamine methyltransferase, Pfpmt, a critical enzyme in the SDPM pathway, is down-regulated at the transcriptional level as well as targeted for degradation by the proteasome in the presence of choline. Transcript analysis revealed that PfPMT transcription is repressed by choline in a dose-dependent manner. Immunoblotting, pulse-chase experiments, and immunoprecipitation studies demonstrated that Pfpmt degradation occurs not only in wild-type but also in transgenic parasites constitutively expressing Pfpmt. The proteasome inhibitor bortezomib inhibited choline-mediated Pfpmt degradation. These data provide the first evidence for metabolite-mediated transcriptional and proteasomal regulation in Plasmodium and will set the stage for the use of this system for conditional gene and protein expression in this organism.

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