Circulating concentrations of interleukin-18, interleukin-18 binding protein, and gamma interferon in patients with alcoholic hepatitis

ABSTRACT The roles of endogenous cytokines induced by either intact staphylococcal microorganisms or staphylococcal exotoxins were examined using human whole-blood cultures. To accomplish this, interleukin-18 binding protein (IL-18BP) and tumor necrosis factor binding protein (TNFbp) were used to neutralize IL-18 and TNF, respectively, whereas an anti-IL-12 monoclonal antibody was used to neutralize IL-12 and the IL-1 receptor antagonist (IL-1Ra) was used to block IL-1 receptors. Heat-killed Staphylococcus epidermidis andStaphylococcus aureus, as well as the staphylococcal superantigens toxic shock syndrome toxin-1 (TSST-1) and staphylococcus enterotoxin B (SEB) induced gamma interferon (IFN-γ) production.Staphylococcus spp.-induced production of IFN-γ required the presence of endogenous IL-18, IL-12, and TNF. In contrast, TSST-1-induced IFN-γ was not significantly reduced in the presence of IL-18BP, anti-IL-12 antibodies, IL-1Ra, or anti-TNFbp. SEB-induced IFN-γ was significantly inhibited only by anti-IL-12 antibodies, indicating that endogenous IL-18, IL-1, and TNF are not required for SEB-induced IFN-γ. In conclusion, the mechanisms of IFN-γ stimulation by intact staphylococcal microorganisms and by exotoxins differ, and this is likely due to the different receptors which are triggered on the cell membranes. In contrast to its role in the interactions between staphylococci and host cells, IL-18 does not appear to play a major role in superantigen-induced IFN-γ.

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Vaccinia Virus Interleukin-18-Binding Protein Promotes Virulence by Reducing Gamma Interferon Production and Natural Killer and T-Cell Activity

Journal of Virology ◽

10.1128/jvi.77.18.9960-9968.2003 ◽

2003 ◽

Vol 77 (18) ◽

pp. 9960-9968 ◽

Cited By ~ 70

Author(s):

Patrick C. Reading ◽

Geoffrey L. Smith

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

Cytotoxic Activity ◽

Natural Killer ◽

T Cell Activation ◽

Binding Protein ◽

Gamma Interferon ◽

Interleukin 18 ◽

Ifn Γ

ABSTRACT Interleukin-18 (IL-18) is a proinflammatory cytokine that promotes natural killer (NK) and T-cell activation. Several poxviruses, including vaccinia virus (VV), encode a soluble IL-18-binding protein (IL-18bp). The role of the VV IL-18bp (gene C12L) in vivo was studied with wild-type (vC12L), deletion mutant (vΔC12L), and revertant (vC12L-rev) viruses in a murine intranasal model of infection. The data show that vΔC12L was markedly attenuated, characterized by a mild weight loss and reduced virus titers in lungs, brain, and spleen. Three days after infection, NK cytotoxic activity was augmented in the lung, spleen, and mediastinal lymph nodes (MLNs) of vΔC12L-infected mice compared to controls. Seven days after infection, vΔC12L-infected mice displayed heightened VV-specific cytotoxic T-lymphocyte (CTL) responses in the lungs, spleen, and MLNs. Gamma interferon (IFN-γ) levels were also dramatically elevated in lavage fluids and cells from lungs of mice infected with vΔC12L. Finally, we demonstrate that IL-18 is produced in vitro and in vivo after VV infection. Taken together, these data demonstrate a role for the vIL-18bp in counteracting IL-18 in both the innate and the specific immune response to VV infection and indicate that the ability of IL-18 to promote vigorous T-cell responses (cytotoxic activity and IFN-γ production) is a critical factor in the accelerated clearance of the vΔC12L mutant.

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Faculty Opinions recommendation of The function of gamma interferon-inducible GTP-binding protein IGTP in host resistance to Toxoplasma gondii is Stat1 dependent and requires expression in both hematopoietic and nonhematopoietic cellular compartments.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1011341.179423 ◽

2003 ◽

Author(s):

Jonathan Howard

Keyword(s):

Toxoplasma Gondii ◽

Host Resistance ◽

Binding Protein ◽

Gamma Interferon ◽

Gtp Binding Protein ◽

Gtp Binding ◽

Cellular Compartments

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Faculty Opinions recommendation of A unique bivalent binding and inhibition mechanism by the yatapoxvirus interleukin 18 binding protein.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.721664649.793546662 ◽

2018 ◽

Author(s):

Antonio Alcami

Keyword(s):

Binding Protein ◽

Inhibition Mechanism ◽

Interleukin 18

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Antioxidant, Antiapoptotic and Inflammatory Effects of Interleukin-18 Binding Protein on Kidney Damage Induced by Hepatic Ischemia Reperfusion

The American Journal of the Medical Sciences ◽

10.1016/j.amjms.2016.02.017 ◽

2016 ◽

Vol 351 (6) ◽

pp. 607-615 ◽

Cited By ~ 4

Author(s):

Yucel Gonul ◽

Mustafa Ozsoy ◽

Ahmet Kocak ◽

Ziya Taner Ozkececi ◽

Afra Karavelioglu ◽

...

Keyword(s):

Binding Protein ◽

Ischemia Reperfusion ◽

Kidney Damage ◽

Interleukin 18 ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

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A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site.

Molecular and Cellular Biology ◽

10.1128/mcb.14.2.1364 ◽

1994 ◽

Vol 14 (2) ◽

pp. 1364-1373 ◽

Cited By ~ 37

Author(s):

A Eilers ◽

M Baccarini ◽

F Horn ◽

R A Hipskind ◽

C Schindler ◽

...

Keyword(s):

Growth Factor ◽

Dna Binding ◽

Binding Protein ◽

Trna Synthetase ◽

Gamma Interferon ◽

U937 Cells ◽

Gamma Activation ◽

Ifn Gamma ◽

Differentiation Factors ◽

Activation Site

Rapid transcriptional induction of genes in response to gamma interferon (IFN-gamma) is mediated by the IFN-gamma activation site (GAS) and its cognate protein, the IFN-gamma activation factor (GAF). We describe a GAS-associated, differentiation-induced factor (DIF) as a potential molecular link between the activities of IFN-gamma and of growth and differentiation factors. DIF DNA binding was activated by colony-stimulating factor 1 in murine macrophages and also during tetradecanoyl phorbol acetate-induced differentiation or IFN-gamma treatment in myeloid U937 cells. IFN-gamma activation of DIF decreased significantly upon monocytic differentiation. DIF binding to DNA was inhibited by antiphosphotyrosine antibodies and could be induced by treatment of U937 cells with vanadate. Unlike GAF, DIF-DNA complexes did not contain the 91-kDa protein (p91) from ISGF-3. DIF bound with high affinity to GAS from the promoters of the IFP 53/tryptophanyl-tRNA synthetase and Fc gamma RI genes, intermediate affinity to the Ly6A/E GAS, and low affinity to the guanylate-binding protein GAS. DIF may belong to a family of cytokine- or growth factor-induced factors binding with variable affinities to GAS-related elements: the interleukin-6-responsive acute-phase response factor associated with GAS from different IFN-inducible promoters but with a different preference of binding compared with DIF. The sis-inducible element of the c-fos promoter bound GAF but not DIF. However, the sis-inducible element could be changed by point mutation to compete for GAF and DIF binding. Our data show DIF to be a novel DNA-binding protein which is activated in response to differentiating signals. Moreover, they suggest that a family of cytokine- or growth factor-regulated proteins integrates and coordinates the responses to cytokines and to growth and differentiation factors by binding to GAS-related elements.

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Interleukin-18 Binding Protein

Encyclopedia of Inflammatory Diseases ◽

10.1007/978-3-0348-0620-6_217-1 ◽

2014 ◽

pp. 1-7

Author(s):

Daniela Novick ◽

Soohyun Kim ◽

Charles A. Dinarello

Keyword(s):

Binding Protein ◽

Interleukin 18

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The Role of Interleukin 18/Interleukin 18-Binding Protein in Adult-Onset Still’s Disease and Systemic Juvenile Idiopathic Arthritis

Journal of Clinical Medicine ◽

10.3390/jcm11020430 ◽

2022 ◽

Vol 11 (2) ◽

pp. 430

Author(s):

Charlotte Girard-Guyonvarc’h ◽

Mathilde Harel ◽

Cem Gabay

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Binding Protein ◽

Systemic Juvenile Idiopathic Arthritis ◽

Free Form ◽

Adult Onset Still’S Disease ◽

Adult Onset ◽

Still’S Disease ◽

Interleukin 18 ◽

Still's Disease ◽

Adult Onset Still's Disease

Interleukin 18 (IL-18) is a pro-inflammatory cytokine of the IL-1 family, whose activity is tightly controlled at the level of production, as well as signalization. Notably, it is buffered by its natural inhibitor, IL-18 binding protein (IL-18BP), which is massively present in circulation in normal and in most pathological conditions, thus preventing harmful pro-inflammatory systemic effects of IL-18. IL-18 has long been considered to be involved in the pathophysiology of various inflammatory diseases. However, a first clinical trial using recombinant IL-18BP for the treatment of rheumatoid arthritis and psoriasis gave disappointing results. Direct measurements of unbound, bioactive, free form of circulating IL-18 demonstrated that IL-18 was more specifically involved in adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) but also in their most severe complication, macrophage activation syndrome (MAS). More importantly, administration of recombinant IL-18BP to patients with AOSD, and sJIA with MAS, showed promising results. This review summarizes available data regarding IL-18 and IL-18BP in AOSD and sJIA in mouse models and humans and shows the importance of IL-18/IL-18BP imbalance in these conditions, leading to the conclusion that IL-18, particularly free IL-18, may be a useful biomarker in these diseases and an interesting therapeutic target.

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