Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor

Hannum, Charles; Wilcox, Carol; Arend, William P.; Joslin, Fenneke G.; Dripps, David J.; Heimdal, P; Armes, Lyman G.; Sommer, Andreas; Eisenberg, Stephen P.; Thompson, Robert C.

doi:10.1038/343336a0

Cited by 1,077 publications

(411 citation statements)

References 13 publications

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“…Recently, a newly described receptor antagonist to IIr1(II., Ira) produced from IgG-adherent human monocytes has been purified, sequenced, and cDNA for the 18-kD protein expressed in Escherichia coli (14,15) . The protein binds to the ILI receptor but has no agonist activity, nor does it bind to the cytokine.…”

Section: Resultsmentioning

confidence: 99%

A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice.

Alexander

Doherty

Buresh

et al. 1991

The Journal of Experimental Medicine

271

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Interleukin 1 (IL-1) is an endogenously produced cytokine that mediates a variety of physiological effects that may be beneficial or deleterious to the host. C57Bl/6 mice treated intravenously with a recently characterized human recombinant receptor antagonist protein to IL-1 (IL-1ra) had improved survival when treated after a lethal Escherichia coli endotoxin (lipopolysaccharide [LPS]) challenge. IL-1ra was effective when treatment was initiated after LPS, and intravenous administration every 4 h for 24 h was required. Serum levels of tumor necrosis factor (TNF) activity after LPS and in vitro TNF cytotoxicity were not altered by treatment with IL-1ra. These experiments provide direct evidence that the lethal effects of LPS may be mediated through the action of IL-1 and that the IL-1ra can provide a new treatment strategy for disease processes mediated via this cytokine.

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Section: Resultsmentioning

confidence: 99%

A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice.

Alexander

Doherty

Buresh

et al. 1991

The Journal of Experimental Medicine

271

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“…The IL-1 receptor antagonist (IL-1Ra) is a naturally occurring, competitive inhibitor of IL-1 action, which is highly selective. There is considerable preclinical and clinical evidence showing that IL-1Ra is a promising candidate for the treatment of stroke and related disorders (Banwell et al, 2009;Emsley et al, 2005;Hannum et al, 1990;Rothwell, 2003). In experimental stroke, endogenous IL-1Ra is upregulated and protects the brain (Denes et al, 2008;Pinteaux et al, 2006), while administration of exogenous IL-1Ra reduces ischemic injury, even when administered 3 hours after the insult (Garcia et al, 1995;Loddick and Rothwell, 1996;Mulcahy et al, 2003;Relton et al, 1996;Stroemer and Rothwell, 1997).…”

Section: Introductionmentioning

confidence: 99%

Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

Pradillo

Greenhalgh

Boutin

et al. 2012

J Cereb Blood Flow Metab

124

108

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Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood-brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

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“…A related receptor ligand molecule, which can be made by cells in several alternatively spliced forms, is known as the IL-1 receptor antagonist or IL-1ra (4-6, 17, 18). This family of molecules binds to IL-1R1, but receptor occupancy by IL-1ra does not result in signal transduction (18). Thus, blockade of the IL-1R1 is an important means of limiting IL-1 activity (10,16,19), and under many circumstances, IL-1 gene expression appears to be paralleled by expression of the IL-1ra gene (5).…”

mentioning

confidence: 99%

Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

Rauschmayr

Groves

Kupper

1997

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal keratinocytes can express two types of interleukin 1 (IL-1) receptors: IL-1R1, which is active in signal transduction, and the less well characterized IL-1R2, which is incapable of transducing a signal and can be shed from cells. The binding of IL-1 in solution by IL-1R2 has been demonstrated, and it has been proposed to inhibit IL-1-mediated responses through this mechanism. We and others have reported that keratinocytes can be induced to express IL-1R2 both in vitro and in vivo, often under conditions that also favor IL-1 gene expression. We hypothesized that production of IL-1R2 by keratinocytes would be an efficient means to achieve local inhibition of IL-1-mediated responses without systemic consequences. To test this hypothesis, we have generated transgenic mice that constitutively express IL-1R2 on basal keratinocytes. Keratinocytes cultured from these animals shed the soluble form of the receptor into culture supernatants, and IL-1-inducible production of granulocyte͞macrophage colony-stimulating factor was markedly inhibited. In vivo, acute cutaneous vascular leakage, as well as chronic inf lammation induced by a well characterized IL-1-dependent stimulus, was significantly inhibited in IL-1R2 transgenic animals. In contrast, contact hypersensitivity was unaffected, suggesting that overexpression of IL-1R2 did not inhibit all types of inf lammation globally. Finally, systemic injection of IL-1 induced equivalent levels of plasma IL-6 in IL-1R2 transgenic and nontransgenic mice, suggesting that the activity of the transgenic IL-1R2 remained predominantly local and did not inf luence systemic IL-1 responses. We conclude that tissue-specific production of IL-1R2 can mediate IL-1 antagonism in tissue microenvironments without systemic consequences. Our transgenic mice may be a useful tool for determining the degree to which different types of cutaneous inf lammation depend on the IL-1 system.

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Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor

Cited by 1,077 publications

References 13 publications

A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice.

A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice.

Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

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