Cross-linking of the beta-glucan receptor on human monocytes results in interleukin-1 receptor antagonist but not interleukin-1 production

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3695-3700 ◽  
Author(s):  
DD Poutsiaka ◽  
M Mengozzi ◽  
E Vannier ◽  
B Sinha ◽  
CA Dinarello
Keyword(s):  
Receptor Antagonist ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
Beta Glucan ◽  
Peripheral Blood Mononuclear ◽  
Naturally Occurring ◽  
Beta Glucans ◽  
Or Gene ◽  
Plastic Surfaces

Abstract The beta-glucan receptor, found on monocytes and neutrophils, binds glucose polymers derived from fungi. Ligands for the receptor have various immunomodulatory effects, including increased microbicidal killing activity. We have investigated the effect of beta-glucans on the production of interleukin-1 (IL-1) and its naturally occurring inhibitor, the IL-1 receptor antagonist (IL-1Ra). Particulate beta- glucan induced IL-1Ra production from human peripheral blood mononuclear cells (PBMC) but did not stimulate IL-1 beta synthesis or gene expression in these same cells. Monomeric (soluble) beta-glucan did not induce IL-1Ra production. However, when preincubated with PBMC, monomeric beta-glucan significantly (P <.01) reduced particulate beta- glucan induction of IL-1Ra by 40%, suggesting that crosslinking of beta- glucan receptors is required for induction of IL-1Ra. In support of this, monomeric beta-glucan immobilized on plastic surfaces stimulated IL-1Ra production. Vitamin D3, which increases the functional capacity of beta-glucan receptors, increased IL-1Ra production induced by particulate beta-glucan, whereas dexamethasone suppressed IL-1Ra synthesis. Because of their differential effects on cytokine production, beta-glucans may be used to therapeutic advantage in the diseases in which IL-1 is implicated.

scholarly journals Cross-linking of the beta-glucan receptor on human monocytes results in interleukin-1 receptor antagonist but not interleukin-1 production

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3695-3700 ◽  
Author(s):  
DD Poutsiaka ◽  
M Mengozzi ◽  
E Vannier ◽  
B Sinha ◽  
CA Dinarello
Keyword(s):  
Receptor Antagonist ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
Beta Glucan ◽  
Peripheral Blood Mononuclear ◽  
Naturally Occurring ◽  
Beta Glucans ◽  
Or Gene ◽  
Plastic Surfaces

The beta-glucan receptor, found on monocytes and neutrophils, binds glucose polymers derived from fungi. Ligands for the receptor have various immunomodulatory effects, including increased microbicidal killing activity. We have investigated the effect of beta-glucans on the production of interleukin-1 (IL-1) and its naturally occurring inhibitor, the IL-1 receptor antagonist (IL-1Ra). Particulate beta- glucan induced IL-1Ra production from human peripheral blood mononuclear cells (PBMC) but did not stimulate IL-1 beta synthesis or gene expression in these same cells. Monomeric (soluble) beta-glucan did not induce IL-1Ra production. However, when preincubated with PBMC, monomeric beta-glucan significantly (P <.01) reduced particulate beta- glucan induction of IL-1Ra by 40%, suggesting that crosslinking of beta- glucan receptors is required for induction of IL-1Ra. In support of this, monomeric beta-glucan immobilized on plastic surfaces stimulated IL-1Ra production. Vitamin D3, which increases the functional capacity of beta-glucan receptors, increased IL-1Ra production induced by particulate beta-glucan, whereas dexamethasone suppressed IL-1Ra synthesis. Because of their differential effects on cytokine production, beta-glucans may be used to therapeutic advantage in the diseases in which IL-1 is implicated.

Fibronectin modulates expression of interleukin-1 beta and its receptor antagonist in human mononuclear cells

1996 ◽  
Vol 271 (1) ◽  
pp. L61-L69 ◽  
Author(s):  
K. L. Graves ◽  
J. Roman
Keyword(s):  
Receptor Antagonist ◽  
Type I Collagen ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Human Mononuclear Cells ◽  
Naturally Occurring ◽  
Dose Dependent

Identification of factors that regulate production of proinflammatory cytokines may provide insight into mechanisms governing lung inflammation. One potential regulatory factor highly expressed in inflamed tissues is fibronectin (FN). To determine the potential effects of FN on interleukin (IL)-1 beta production, we exposed human peripheral blood mononuclear cells to soluble FN. This treatment resulted in the accumulation of IL-1 beta mRNA and enhancement of IL-1 beta protein synthesis and secretion. This effect was dose dependent and appeared to be mediated by the integrin alpha 5 beta 1. Treatment with FN also increased production of IL-1 receptor antagonist (IL-1ra), a naturally occurring inhibitor of IL-1 function. However, the stimulatory effect of FN on IL-1ra production was abolished by costimulation with type I collagen. We conclude that the increased deposition of FN in injured tissues may enhance the expression of IL-1 beta mRNA and augment the production and release of IL-1 beta protein by mononuclear cells. Differential expression of IL-1 beta and IL-1ra resulting in a high IL-1 beta-to-IL-1ra ratio in response to mixed matrices containing FN and type I collagen may be an important regulatory point in inflammation.

scholarly journals PASylation of IL-1 receptor antagonist (IL-1Ra) retains IL-1 blockade and extends its duration in mouse urate crystal-induced peritonitis

2019 ◽  
Vol 295 (3) ◽  
pp. 868-882 ◽  
Author(s):  
Nicholas E. Powers ◽  
Benjamin Swartzwelter ◽  
Carlo Marchetti ◽  
Dennis M. de Graaf ◽  
Alexandra Lerchner ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Inflammatory Markers ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
The Body ◽  
Random Coil ◽  
Peripheral Blood Mononuclear

Interleukin-1 (IL-1) is a key mediator of inflammation and immunity. Naturally-occurring IL-1 receptor antagonist (IL-1Ra) binds and blocks the IL-1 receptor-1 (IL-1R1), preventing signaling. Anakinra, a recombinant form of IL-1Ra, is used to treat a spectrum of inflammatory diseases. However, anakinra is rapidly cleared from the body and requires daily administration. To create a longer-lasting alternative, PASylated IL-1Ra (PAS–IL-1Ra) has been generated by in-frame fusion of a long, defined-length, N-terminal Pro/Ala/Ser (PAS) random-coil polypeptide with IL-1Ra. Here, we compared the efficacy of two PAS–IL-1Ra molecules, PAS600–IL-1Ra and PAS800–IL-1Ra (carrying 600 and 800 PAS residues, respectively), with that of anakinra in mice. PAS600–IL-1Ra displayed markedly extended blood plasma levels 3 days post-administration, whereas anakinra was undetectable after 24 h. We also studied PAS600–IL-1Ra and PAS800–IL-1Ra for efficacy in monosodium urate (MSU) crystal-induced peritonitis. 5 days post-administration, PAS800–IL-1Ra significantly reduced leukocyte influx and inflammatory markers in MSU-induced peritonitis, whereas equimolar anakinra administered 24 h before MSU challenge was ineffective. The 6-h pretreatment with equimolar anakinra or PAS800–IL-1Ra before MSU challenge similarly reduced inflammatory markers. In cultured A549 lung carcinoma cells, anakinra, PAS600–IL-1Ra, and PAS800-IL-Ra reduced IL-1α–induced IL-6 and IL-8 levels with comparable potency. In human peripheral blood mononuclear cells, these molecules suppressed Candida albicans–induced production of the cancer-promoting cytokine IL-22. Surface plasmon resonance analyses revealed significant binding between PAS–IL-1Ra and IL-1R1, although with a slightly lower affinity than anakinra. These results validate PAS–IL-1Ra as an active IL-1 antagonist with marked in vivo potency and a significantly extended half-life compared with anakinra.

scholarly journals Antiinflammatory properties of hepatic acute phase proteins: preferential induction of interleukin 1 (IL-1) receptor antagonist over IL-1 beta synthesis by human peripheral blood mononuclear cells.

1993 ◽  
Vol 178 (5) ◽  
pp. 1629-1636 ◽  
Author(s):  
H Tilg ◽  
E Vannier ◽  
G Vachino ◽  
C A Dinarello ◽  
J W Mier
Keyword(s):  
Receptor Antagonist ◽  
Acute Phase ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Acute Phase Proteins ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

This study was undertaken to determine whether acute phase proteins (APP) induce the synthesis of interleukin 1 beta (IL-1 beta) and its specific antagonist, IL-1 receptor antagonist (IL-1Ra), in human peripheral blood mononuclear cells (PBMC). PBMC from healthy volunteers were incubated with C-reactive protein (CRP), alpha 1-antitrypsin (alpha 1-AT), or alpha 1-acid glycoprotein (AGP), and the levels of IL-1 beta and IL-1Ra produced were measured by specific radioimmunoassay. To evaluate the effects of alpha 1-AT further, a synthetic pentapeptide FVYLI corresponding to the minimal binding sequence for the serpine-enzyme complex receptor was also evaluated. PBMC incubated for 24 h with CRP, alpha 1-AT, or the pentapeptide FVYLI synthesized large quantities of IL-1Ra, 5-10-fold greater than the amount of IL-1 beta produced by these cells. AGP induced significantly less IL-1Ra than the other APP tested. These effects were shown to be specific, in that polyclonal antibodies against CRP, alpha 1-AT, and AGP eliminated the cytokine production induced by these respective proteins. CRP, alpha 1-AT, FVYLI, and AGP were synergistic with low concentrations of endotoxin in the induction of both IL-1Ra and IL-1 beta synthesis. We suggest that the preferential induction of IL-1Ra by APP may contribute to their antiinflammatory effects and provide an important regulatory signal for the acute phase response.

scholarly journals Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: II. IL-1 receptor antagonist inhibits lipopolysaccharide-induced cytokine synthesis by human monocytes

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2364-2369 ◽  
Author(s):  
EV Granowitz ◽  
E Vannier ◽  
DD Poutsiaka ◽  
CA Dinarello
Keyword(s):  
Receptor Antagonist ◽  
Messenger Rna ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Cytokine Synthesis

Abstract Lipopolysaccharide (LPS) stimulates interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) gene expression and synthesis in human peripheral blood mononuclear cells (PBMC). IL-1 can also induce PBMC to synthesize IL-1 and TNF alpha. In the present study, we used IL- 1 receptor antagonist (IL-1ra) to determine the relative contribution of an IL-1-positive feedback loop to the total amount of LPS-induced cytokine synthesis. Pretreatment of PBMC with human recombinant IL-1ra reduced LPS-induced cytokine synthesis in a dose-dependent manner (P less than .001). Maximal inhibition was 33% for IL-1 alpha (P less than .01), 43% for IL-1 beta (P = .001), and 20% for TNF alpha (P less than .05). We consistently observed IL-1ra suppression of LPS-induced cytokines in PBMC of 38 volunteers. However, this phenomenon was not specific for LPS; 1 microgram/mL IL-1ra inhibited IL-1 beta synthesized in response to human recombinant IL-2 by 44% (P less than .001), toxic shock syndrome toxin-1 by 26% (P less than .05), and phorbol 12- myristate 13-acetate by 76% (P less than .001). IL-1ra added to PBMC 4 or 8 hours after stimulation with LPS still inhibited IL-1 beta synthesis by 44% (P less than .001) or 25% (P = .01), respectively. The steady state messenger RNA levels of IL-1 beta were reduced in PBMC stimulated by LPS in the presence of IL-1ra. In monocytes isolated by elutriation, IL-1ra reduced LPS-induced IL-1 alpha by 16% (P less than .001), IL-1 beta by 14% (P less than .05), and TNF alpha by 24% (P = .01). We conclude that IL-1-induced IL-1 significantly contributes to LPS-induced cytokine synthesis.

scholarly journals Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: II. IL-1 receptor antagonist inhibits lipopolysaccharide-induced cytokine synthesis by human monocytes

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2364-2369
Author(s):  
EV Granowitz ◽  
E Vannier ◽  
DD Poutsiaka ◽  
CA Dinarello
Keyword(s):  
Receptor Antagonist ◽  
Messenger Rna ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Cytokine Synthesis

Lipopolysaccharide (LPS) stimulates interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) gene expression and synthesis in human peripheral blood mononuclear cells (PBMC). IL-1 can also induce PBMC to synthesize IL-1 and TNF alpha. In the present study, we used IL- 1 receptor antagonist (IL-1ra) to determine the relative contribution of an IL-1-positive feedback loop to the total amount of LPS-induced cytokine synthesis. Pretreatment of PBMC with human recombinant IL-1ra reduced LPS-induced cytokine synthesis in a dose-dependent manner (P less than .001). Maximal inhibition was 33% for IL-1 alpha (P less than .01), 43% for IL-1 beta (P = .001), and 20% for TNF alpha (P less than .05). We consistently observed IL-1ra suppression of LPS-induced cytokines in PBMC of 38 volunteers. However, this phenomenon was not specific for LPS; 1 microgram/mL IL-1ra inhibited IL-1 beta synthesized in response to human recombinant IL-2 by 44% (P less than .001), toxic shock syndrome toxin-1 by 26% (P less than .05), and phorbol 12- myristate 13-acetate by 76% (P less than .001). IL-1ra added to PBMC 4 or 8 hours after stimulation with LPS still inhibited IL-1 beta synthesis by 44% (P less than .001) or 25% (P = .01), respectively. The steady state messenger RNA levels of IL-1 beta were reduced in PBMC stimulated by LPS in the presence of IL-1ra. In monocytes isolated by elutriation, IL-1ra reduced LPS-induced IL-1 alpha by 16% (P less than .001), IL-1 beta by 14% (P less than .05), and TNF alpha by 24% (P = .01). We conclude that IL-1-induced IL-1 significantly contributes to LPS-induced cytokine synthesis.

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