The modulation of interleukin 1 production by interferon gamma, and the inhibitory effects of gold compounds

1990 ◽  
Vol 20 (2) ◽  
pp. 125-134 ◽  
Author(s):  
Manfred Harth ◽  
Glenn A. McCain ◽  
Keith Cousin
Keyword(s):  
Interferon Gamma ◽  
Interleukin 1 ◽  
Inhibitory Effects ◽  
Gold Compounds

scholarly journals Down regulation of myelopoiesis by mediators inhibiting the production of macrophage-derived granulomonopoietic enhancing activity (GM-EA)

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 2001-2006 ◽  
Author(s):  
SY Wang ◽  
CK Ho ◽  
LY Chen ◽  
RC Wang ◽  
MH Huang ◽  
...  
Keyword(s):  
Feedback Control ◽  
Interferon Gamma ◽  
Negative Feedback ◽  
Interleukin 1 ◽  
Optimal Conditions ◽  
Inhibitory Effects ◽  
Duration Of Treatment ◽  
Ifn Gamma ◽  
Negative Feedback Control ◽  
Macrophage Colony

Monocyte-derived lipid-containing macrophages (MDLMs) constitutively synthesize a granulomonopoietic enhancing activity (GM-EA) that potentiates the function of granulocyte-macrophage colony-stimulating activity (GM-CSA). In the study reported, we show that GM-EA is distinct from interleukin-1 (IL-1) in biochemical and functional properties and that its production is negatively regulated by several mediators. Thus, MDLM cultures pretreated with interferon-gamma (IFN- gamma, 3 to 900 U/mL), prostaglandin E2 (PGE2, 10(-13) to 10(-8) mol/L), or lactoferrin (LF, 10(-13) to 10(-8) mol/L) invariably produced less GM-EA than untreated controls. The relative potency of inhibition was in the order of IFN-gamma greater than or equal to PGE2 greater than LF. The extent of the inhibitory effects was proportional to dosage and the duration of treatment and could be observed following only a brief exposure (two hours) of the MDLMS to physiologic doses of the mediators. Under optimal conditions, IFN-gamma (300 U/mL for 24 to 48 hours) and PGE2 (10(-9) mol/L for 24 to 48 hours) could totally abrogate the ability of the MDLMs to produce GM-EA. However, the drug- inhibited MDLMs could be reactivated to produce GM-EA by treatment with zymosan (60 micrograms/mL). These results demonstrate that a mechanism for the control of myelopoiesis by mediators such as IFN-gamma, PGE2, and LF may involve the inhibition of GM-EA production. Furthermore, this negative feedback control is reversible and can be overridden when a proper stimulatory signal is given.

scholarly journals Down regulation of myelopoiesis by mediators inhibiting the production of macrophage-derived granulomonopoietic enhancing activity (GM-EA)

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 2001-2006 ◽  
Author(s):  
SY Wang ◽  
CK Ho ◽  
LY Chen ◽  
RC Wang ◽  
MH Huang ◽  
...  
Keyword(s):  
Feedback Control ◽  
Interferon Gamma ◽  
Negative Feedback ◽  
Interleukin 1 ◽  
Optimal Conditions ◽  
Inhibitory Effects ◽  
Duration Of Treatment ◽  
Ifn Gamma ◽  
Negative Feedback Control ◽  
Macrophage Colony

Abstract Monocyte-derived lipid-containing macrophages (MDLMs) constitutively synthesize a granulomonopoietic enhancing activity (GM-EA) that potentiates the function of granulocyte-macrophage colony-stimulating activity (GM-CSA). In the study reported, we show that GM-EA is distinct from interleukin-1 (IL-1) in biochemical and functional properties and that its production is negatively regulated by several mediators. Thus, MDLM cultures pretreated with interferon-gamma (IFN- gamma, 3 to 900 U/mL), prostaglandin E2 (PGE2, 10(-13) to 10(-8) mol/L), or lactoferrin (LF, 10(-13) to 10(-8) mol/L) invariably produced less GM-EA than untreated controls. The relative potency of inhibition was in the order of IFN-gamma greater than or equal to PGE2 greater than LF. The extent of the inhibitory effects was proportional to dosage and the duration of treatment and could be observed following only a brief exposure (two hours) of the MDLMS to physiologic doses of the mediators. Under optimal conditions, IFN-gamma (300 U/mL for 24 to 48 hours) and PGE2 (10(-9) mol/L for 24 to 48 hours) could totally abrogate the ability of the MDLMs to produce GM-EA. However, the drug- inhibited MDLMs could be reactivated to produce GM-EA by treatment with zymosan (60 micrograms/mL). These results demonstrate that a mechanism for the control of myelopoiesis by mediators such as IFN-gamma, PGE2, and LF may involve the inhibition of GM-EA production. Furthermore, this negative feedback control is reversible and can be overridden when a proper stimulatory signal is given.

scholarly journals Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in Alveolar Macrophages

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 632
Author(s):  
Stephanie B. Wall ◽  
Rui Li ◽  
Brittany Butler ◽  
Ashley R. Burg ◽  
Hubert M. Tse ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Direct Interaction ◽  
Synthesis Methods ◽  
Related Factor ◽  
Gold Compound ◽  
Nuclear Factor ◽  
Glutathione Synthesis ◽  
Gold Compounds

Background: Alveolar macrophages (AMs) are resident inflammatory cells in the lung that serve as early sentinels of infection or injury. We have identified thioredoxin reductase 1 inhibition by gold compounds increases activation of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathways to attenuate inflammatory responses. The present studies utilized murine alveolar macrophages (MH-S) to test the hypothesis that the gold compound, auranofin (AFN), decreases interleukin (IL)-1β expression through NRF2-mediated interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway genes and/or increases in glutathione synthesis. Methods: MH-S cells were treated with AFN and lipopolysaccharide (LPS) and analyzed at 6 and 24 h. The Il1b promoter was analyzed by chromatin immunoprecipitation for direct interaction with NRF2. Results: Expression of IL-1β, p-IκBα, p-p65 NF-kB, and NOD-, LRR-, and pyrin domain-containing protein 3 were elevated by LPS exposure, but only IL-1β expression was suppressed by AFN treatment. Both AFN and LPS treatments increased cellular glutathione levels, but attenuation of glutathione synthesis by buthionine sulfoximine (BSO) did not alter expression of Il-1β. Analysis revealed direct NRF2 binding to the Il1b promoter which was enhanced by AFN and inhibited the transcriptional activity of DNA polymerase II. Conclusions: Our data demonstrate that AFN-induced NRF2 activation directly suppresses IL-1β synthesis independent of NFκB and glutathione-mediated antioxidant mechanisms. NRF2 binding to the promoter region of IL1β directly inhibits transcription of the IL1β gene. Collectively, our research suggests that gold compounds elicit NRF2-dependent pulmonary protection by suppressing macrophage-mediated inflammation.

Role of Receptor Binding and Gene Transcription for Both of Stimulatory and Inhibitory Effects of Interleukin-1 In Pancreatic β-Cells

Autoimmunity ◽  
1992 ◽  
Vol 12 (2) ◽  
pp. 127-133 ◽  
Author(s):  
Décio L. Eizirik ◽  
Daniel E. Tracey ◽  
Klaus Bendtzen ◽  
Stellan Sandler
Keyword(s):  
Gene Transcription ◽  
Receptor Binding ◽  
Interleukin 1 ◽  
Inhibitory Effects ◽  
Β Cells ◽  
Pancreatic Β Cells

Low-dose gold compounds inhibit fibroblast proliferation and do not affect interleukin-1 secretion by macrophages

1988 ◽  
Vol 31 (10) ◽  
pp. 1272-1280 ◽  
Author(s):  
Tsukasa Matsubara ◽  
Yasuhiro Saegusa ◽  
Kazushi Hirohata
Keyword(s):  
Low Dose ◽  
Interleukin 1 ◽  
Fibroblast Proliferation ◽  
Gold Compounds

cAMP inhibition of interleukin-1-induced interleukin-6 production by human lung fibroblasts

1993 ◽  
Vol 264 (3) ◽  
pp. L253-L260 ◽  
Author(s):  
R. J. Zitnik ◽  
T. Zheng ◽  
J. A. Elias
Keyword(s):  
Human Lung ◽  
Interleukin 1 ◽  
Cell Number ◽  
Lung Fibroblasts ◽  
Intracellular Camp ◽  
Inhibitory Effects ◽  
Mrna Accumulation ◽  
Human Lung Fibroblasts ◽  
Dose Dependent ◽  
Necrosis Factor

We characterized the effects of agents that alter intracellular adenosine 3',5'-cyclic monophosphate (cAMP) on the interleukin (IL)-6 production of human lung fibroblasts. Unstimulated fibroblasts did not produce significant amounts of IL-6. Recombinant (r) tumor necrosis factor (TNF) weakly stimulated, recombinant interleukin-1-alpha (rIL-1 alpha) strongly stimulated, and rIL-1 alpha and rTNF in combination synergistically augmented fibroblast IL-6 production. Prostaglandin (PG)E1, forskolin, dibutyryl cAMP (DBcAMP), 3-isobutyl-1-methylxanthine (IBMX), and cholera toxin did not cause a detectable alteration in the IL-6 production of unstimulated fibroblasts. However, these agents inhibited the IL-6 production of rIL-1 and rIL-1 plus rTNF-stimulated cells. These effects were dose dependent with a concentration of 2 x 10(-9) M PGE1, 5 x 10(-6) M forskolin, 5 x 10(-4) M DBcAMP, and 1 x 10(-3) M IBMX decreasing rIL-1 alpha (2.5 ng/ml)-induced IL-6 production by approximately 50%. The inhibitory effects of these agents, correlated with their ability to induce fibroblast cAMP accumulation, could not be explained by alterations in cell number or viability and were appreciable even when cAMP modifiers were added to fibroblast culture, 1 h after rIL-1. They were also at least partly specific for rIL-1, since these agents increased the IL-6 production of rTNF-stimulated cells. These cAMP-induced alterations in IL-6 production were associated with corresponding alterations in IL-6 mRNA accumulation. Nuclear run-on analysis demonstrated that the inhibitory effects of PGE1 were associated with a comparable decrease in IL-6 transcription. Agents that increase the levels of intracellular cAMP inhibit rIL-1-induced IL-6 by human lung fibroblasts.

scholarly journals Studies on the Interaction between Poly-Phosphane Gold(I) Complexes and Dihydrofolate Reductase: An Interplay with Nicotinamide Adenine Dinucleotide Cofactor

2019 ◽  
Vol 20 (7) ◽  
pp. 1802
Author(s):  
Stefania Pucciarelli ◽  
Silvia Vincenzetti ◽  
Massimo Ricciutelli ◽  
Oumarou Camille Simon ◽  
Anna Teresa Ramadori ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Protein Interactions ◽  
Dissociation Constants ◽  
Gold Compound ◽  
Inhibitory Effects ◽  
Binding Properties ◽  
Enzyme Active Site ◽  
E Coli ◽  
Kd Values ◽  
Gold Compounds

A class of gold(I) phosphane complexes have been identified as inhibitors of dihydrofolate reductase (DHFR) from E. coli, an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), using NADPH as a coenzyme. In this work, to comprehend the nature of the interaction at the basis of these inhibitory effects, the binding properties of bis- and tris-phosphane gold(I) chloride compounds in regards to DHFR have been studied by emission spectroscopy and spectrophotometric assays. The lack of cysteine and seleno-cysteine residues in the enzyme active site, the most favorable sites of attack of Au(I) moieties, makes this work noteworthy. The interaction with the gold compounds results into the quenching of the DHFR tryptophan’s emissions and in an enhancement of their intrinsic emission intensities. Moreover, a modulating action of NADPH is highlighted by means of an increase of the gold compound affinity toward the enzyme; in fact, the dissociation constants calculated for the interactions between DHFR and each gold compound in the presence of saturating NADPH were lower than the ones observed for the apo-enzyme. The fluorimetric data afforded to Kd values ranged from 2.22 ± 0.25 µM for (PPh3)2AuCl in the presence of NADPH to 21.4 ± 3.85 µM for 4L3AuTf in the absence of NADPH. By elucidating the energetic aspects of the binding events, we have attempted to dissect the role played by the gold phosphane/protein interactions in the inhibitory activity, resulting in an exothermic enthalpy change and a positive entropic contribution (ΔH° = −5.04 ± 0.08 kcal/mol and ΔS° = 7.34 ± 0.005 cal/mol·K).

Inhibition of mouse placental lactogen-II release from placental cells by interleukin-1 after mid-pregnancy

1995 ◽  
Vol 147 (3) ◽  
pp. 423-429 ◽  
Author(s):  
M Yamaguchi ◽  
M Sakata ◽  
K Ogura ◽  
K Adachi ◽  
A Mammoto ◽  
...  
Keyword(s):  
Blot Analysis ◽  
Interleukin 1 ◽  
Placental Lactogen ◽  
Inhibitory Effects ◽  
Gm Csf ◽  
Placental Cells ◽  
Steady State Levels ◽  
Combined Action ◽  
Factor Α

Abstract The effects of interleukin (IL)-1 and granulocytemacrophage colony stimulating factor (GM-CSF), which are present in the mouse placenta, on the secretion of mouse placental lactogen (mPL)-1 and mPL-II by placental cells were tested in vitro. IL-lα and IL-1β, 2·5 nmol/l each, significantly inhibited mPL-II secretion by cells from days 9 and 12 of pregnancy, but did not affect mPL-II secretion by cells from day 7 of pregnancy or mPL-I secretion by cells from days 7, 9 or 12 of pregnancy. GM-CSF had no effect on mPL-I and mPL-II secretion by cells from days 7, 9 or 12 of pregnancy. The inhibitory effects of IL-1α and IL-1β on mPL-II secretion were completely eliminated by the addition of antibodies to IL-1α and IL-1β respectively. Western blot analysis for mPL-II indicated that IL-1α significantly reduced the intensity of the mPL-II band. Steady-state levels of mPL-II mRNA, assessed by Northern blot analysis, were reduced by incubation of placental cells from day 12 of pregnancy with 2·5 nmol/l IL-1α for 5 days. Co-incubation of 0·25 pmol/l IL-1α, 25 pmol/l IL-6, and 25 pmol/l tumor necrosis factor-α, each of which did not significantly inhibit mPL-II secretion by itself, together inhibited mPL-II secretion. These results suggest that IL-1, but not GM-CSF, is a potent inhibitor of mPL-II secretion after mid-pregnancy, and that the combined action of cytokines can inhibit mPL-II secretion. Journal of Endocrinology (1995) 147, 423–429

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