Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat

Luheshi, Giamal N.; Miller, A.; Brouwer, S.; Dascombe, Michael J.; Rothwell, Nancy J.; Hopkins, Stephen

doi:10.1152/ajpendo.1996.270.1.e91

Cited by 85 publications

(96 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with this effect, systemic administration of recombinant IL-1␤ exacerbated ischemic damage and neurological deficit to a similar extent as LPS, suggesting that peripheral IL-1 challenge is a similar stimulus to LPS and further supporting that IL-1 is the key mediator of LPS in this brain injury paradigm. These results parallel previous studies showing that IL-1 is important for many host defense responses to systemic LPS challenge (Long et al, 1990;Luheshi et al, 1996;Miller et al, 1997b). It is likely that IL-1␤ was acting peripherally because levels were minimal in the circulation and undetectable in the brain after intraperitoneal administration (data not shown).…”

Section: Discussionsupporting

confidence: 91%

“…IL-1 mediates several of the physiological and behavioral changes in response to a systemic inflammatory challenge induced by the bacterial endotoxin, lipopolysaccharide (LPS), or turpentine (Long et al, 1990;Luheshi et al, 1996Luheshi et al, , 1997Miller et al, 1997b). IL-1 may act by inducing the expression of an array of downstream mediators, several of which are pertinent to the systemic inflammatory response after stroke, in particular IL-6 and che-mokines (Miller et al, 1997b;Cartmell et al, 2000;Calkins et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent Mechanisms

McColl¹,

Rothwell

Allan³

2007

J. Neurosci.

Self Cite

316

339

View full text Add to dashboard Cite

Systemic inflammatory stimuli, such as infection, increase the risk of stroke and are associated with poorer clinical outcome. The mechanisms underlying the impact of systemic inflammatory stimuli on stroke are not well defined. We investigated the impact of systemic inflammation on experimental stroke and potential mechanisms involved. Focal cerebral ischemia was induced by intraluminal filament occlusion of the middle cerebral artery (MCAo). Brain damage and neurological deficit 24 h after MCAo were exacerbated by systemic lipopolysaccharide (LPS) administration. This exacerbation was critically dependent on interleukin (IL)-1, because coadministration of IL-1 receptor antagonist abolished the effect of LPS on brain damage. Systemic administration of IL-1 increased ischemic damage to a similar extent as LPS and also exacerbated brain edema. IL-1 markedly potentiated circulating levels of the acute phase proteins, serum amyloid A and IL-6, and the neutrophil-selective CXC chemokines, KC and macrophage inflammatory protein-2. Neutrophil mobilization and cortical neutrophil infiltration were aggravated by IL-1 before changes in ischemic damage. Neutropenia abolished the damaging effects of systemic IL-1. These data show for the first time that an acute systemic inflammatory stimulus is detrimental to outcome after experimental stroke and highlight IL-1 as a critical mediator in this paradigm. Our data suggest IL-1-induced potentiation of neutrophil mobilization via CXC chemokine induction is a putative mechanism underlying this effect. Our results may help to explain the poorer outcome in stroke patients presenting with infection and may have implications for neurodegenerative diseases involving neurovascular alterations, such as Alzheimer's disease, in which systemic inflammation can modulate disease progression.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent Mechanisms

McColl¹,

Rothwell

Allan³

2007

J. Neurosci.

Self Cite

316

339

View full text Add to dashboard Cite

show abstract

“…IL-6 bioactivity in plasma was measured using B-9 hybridoma cells, essentially as described by Luheshi et al (1996). TNF bioactivity was measured by virtue of its cytolytic activity on actinomycin D-treated WEHI-164 cells over a period of 24 hr.…”

Section: Cytokine Bioassaysmentioning

confidence: 99%

Long-Term Intracerebroventricular Infusion of Corticotropin-Releasing Hormone Alters Neuroendocrine, Neurochemical, Autonomic, Behavioral, and Cytokine Responses to a Systemic Inflammatory Challenge

et al. 1997

View full text Add to dashboard Cite

Corticotropin-releasing hormone (CRH) was infused intracerebroventricularly into rats for 7 d via a miniosmotic pump (1 g ⅐ l Ϫ1 ⅐ hr Ϫ1 ). Body temperature and locomotor activity were recorded during the treatment using biotelemetry, whereas hippocampal serotonergic neurotransmission and free corticosterone levels were monitored using in vivo microdialysis on day 7 of CRH treatment. During the microdialysis experiment, behavioral activity was scored by assessing the time during which rats were active (locomotion, grooming, eating, drinking). Continuous intracerebroventricular infusion of CRH produced a transient increase in body temperature and locomotion. Moreover, intracerebroventricularly CRH-treated rats showed elevated free corticosterone levels with no apparent diurnal rhythm.Intraperitoneal administration of bacterial endotoxin [lipopolysaccharide (LPS); 100 g/kg body weight] on day 7 of CRH/ vehicle treatment produced a marked fever response in control animals, which was significantly blunted in intracerebroventricularly CRH-treated rats. Although free corticosterone levels reached similar peak concentrations in both intracerebroventricularly vehicle-and CRH-infused groups after LPS, this response was delayed significantly by ϳ1 hr in the intracerebroventricularly CRH-treated animals. Microdialysis experiments showed no changes in basal extracellular levels of serotonin and 5-hydroxyindoleacetic acid in intracerebroventricularly CRHinfused animals. Injection of LPS in intracerebroventricularly CRHtreated rats produced a blunted 5-HT response and a delayed onset of behavioral inhibition and other signs of sickness behavior. Assessment of the endotoxin-induced cytokine responses showed significantly enhanced plasma interleukin-1 (IL-1) and IL-6 bioactivities in the intracerebroventricularly CRH-infused animals 3 hr after injection of LPS, whereas tumor necrosis factor bioactivity responses were not different.Our data demonstrate that chronically elevated brain CRH levels produce marked changes in basal (largely CRH regulated) physiological and behavioral processes accompanied by aberrant responses to an acute challenge. The present study provides evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.

show abstract

“…Studies in experimental animals have demonstrated that recombinant IL-1␤, administered either systemically or directly into the brain, induces fever (2,17) and that neutralization of endogenous IL-1␤ attenuates fever (26,32,36). The majority of these neutralization studies were conducted with a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1ra) (37,52,64), which inhibits the action of IL-1 by competing for the IL-1 receptor (16). Like IL-1, this endogenous inhibitor is induced in the periphery after LPS challenge, and its levels increase in the circulation of febrile animals in parallel with IL-1␤ (3).…”

mentioning

confidence: 99%

Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats

Ashdown¹,

Poole²,

Boksa³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Ashdown H, Poole S, Boksa P, Luheshi GN. Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats. Am J Physiol Regul Integr Comp Physiol 292: R1667-R1674, 2007. First published November 30, 2006; doi:10.1152/ajpregu.00274.2006.-Febrile responses to bacterial pathogens are attenuated near term of pregnancy in several mammalian species. It is unknown, however, whether this reflects a fundamental physiological adaptation of female rats or whether it is specific to pregnancy. The aims of this study therefore were 1) to determine whether febrile responses to the bacterial endotoxin lipopolysaccharide (LPS) are attenuated in female vs. male rats and, if so, to identify possible mechanisms involved in modulating this and 2) to assess whether plasma concentrations of the anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), an important regulator of fever, are dependent on the physiological state of the female and could therefore be involved in modulating febrile responses. We found febrile responses were attenuated in cycling female vs. male rats and also in near-term pregnant dams vs. cycling females after intraperitoneal injection of LPS (0.05 mg/kg). Plasma levels of IL-1ra were significantly greater in female rats after injection of LPS, particularly during pregnancy, than in males. This was accompanied by attenuated levels of hypothalamic IL-1␤ and cyclooxygenase-2 mRNA, two key mediators of the febrile response, in female rats. Furthermore, increasing plasma levels of IL-1ra in male rats by intraperitoneal administration of the recombinant antagonist attenuated hypothalamic mRNA levels of these mediators after LPS. These data suggest that there is a fundamental difference in febrile response to LPS between the genders that is likely regulated by IL-1ra. This may be an important mechanism that protects the developing fetus from potentially deleterious consequences of maternal fever during pregnancy.fever; pregnancy; cyclooxygenase-2; interleukin-1␤; cytokines FEVER IS A COMPLEX PHYSIOLOGICAL response mounted by the host to facilitate the resolution of infection after exposure to invading viral or bacterial pathogens. This central nervous systemorchestrated response involves the production and action of prostaglandins (PGE 2 ) on hypothalamic thermosensitive neurons, a process that is initiated through the action of systemic pyrogenic mediators of the cytokine family (16, 59). These key inflammatory proteins are readily induced after exposure to exogenous pyrogens, such as the bacterial product lipopolysaccharide (LPS), and increase in the periphery to reflect the rise in body temperature (16, 51). The proinflammatory cytokine IL-1␤ is a major peripheral mediator of LPS-induced fever, which is known to trigger increases in body temperature via cyclooxygenase-2 (COX-2)-dependent production of PGE 2 in the brain (35). Studies in experimental animals have demonstrated that recombinant IL-1␤, administered either systemically or dir...

show abstract

Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat

Cited by 85 publications

References 16 publications

Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent Mechanisms

Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent Mechanisms

Long-Term Intracerebroventricular Infusion of Corticotropin-Releasing Hormone Alters Neuroendocrine, Neurochemical, Autonomic, Behavioral, and Cytokine Responses to a Systemic Inflammatory Challenge

Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats

Contact Info

Product

Resources

About