An IL-1 receptor and an IL-1 receptor antagonist attenuate muramyl dipeptide- and IL-1-induced sleep and fever

1993 ◽  
Vol 265 (4) ◽  
pp. R907-R913 ◽  
Author(s):  
L. Imeri ◽  
M. R. Opp ◽  
J. M. Krueger
Keyword(s):  
Receptor Antagonist ◽  
Eye Movement ◽  
Brain Temperature ◽  
Interleukin 1 ◽  
Dose Range ◽  
Muramyl Dipeptide ◽  
Nrem Sleep ◽  
Type I

It is hypothesized that the somnogenic and pyrogenic effects of muramyl dipeptide (MDP) are mediated via enhanced interleukin-1 (IL-1) production. To test this hypothesis the effects of intracerebroventricular (icv) administration of a recombinant human soluble type I IL-1 receptor (sIL-1r) and of the IL-1 receptor antagonist (IL-1ra) on MDP-induced sleep and fever were evaluated in rabbits. The sIL-1r recognized rabbit IL-1 beta, but it did not affect sleep or brain temperature across the dose range tested (1-50 micrograms) when injected icv into normal rabbits. Pretreatment of rabbits with 50 micrograms sIL-1r or 10 micrograms IL-1ra blocked human recombinant IL-1-enhanced nonrapid eye movement (NREM) sleep and fever. Thus both the sIL-1r and the IL-1ra were effective antagonists of IL-1 actions. When the animals were pretreated with either 50 micrograms sIL-1r or with 10 or 100 micrograms of the IL-1ra, the somnogenic effects of 150 pmol MDP were attenuated. However, the sIL-1r had little effect on MDP-induced febrile responses. These results suggest that the sIL-1r and the IL-1ra can function as antagonists of IL-1 actions in vivo and that MDP-induced sleep and fever are partially mediated by IL-1.

Interleukin 1-receptor antagonist blocks interleukin 1-induced sleep and fever

1991 ◽  
Vol 260 (2) ◽  
pp. R453-R457 ◽  
Author(s):  
M. R. Opp ◽  
J. M. Krueger
Keyword(s):  
Receptor Antagonist ◽  
Eye Movement ◽  
Brain Temperature ◽  
Interleukin 1 ◽  
Central Administration ◽  
Rapid Eye Movement Sleep ◽  
Febrile Response ◽  
Purification And Characterization ◽  
Interleukin 1 Receptor Antagonist

The recent purification and characterization of an interleukin 1-receptor antagonist (IL-1ra) has provided an additional means of elucidating the mechanisms involved in the responses initiated by IL-1. Central administration of IL-1 to rabbits results in a characteristic febrile response and in increased non-rapid-eye-movement sleep (NREMS). In this study, rabbits received various doses of IL-1ra (10-1,000 micrograms) or pyrogen-free saline intracerebroventricularly, and sleep-wake activity and brain temperature (Tbr) were determined for the next 24 h. All doses of IL-1ra tested tended to reduce NREMS in the first postinjection hour with little effect on Tbr. When rabbits were pretreated with 100 micrograms IL-1ra and then injected with 10 ng IL-1, the characteristic IL-1-induced febrile and NREMS-promoting effects were completely blocked.

Human IL-1 receptor antagonist partially suppresses LPS fever but not plasma levels of IL-6 in Fischer rats

1992 ◽  
Vol 263 (3) ◽  
pp. R653-R655 ◽  
Author(s):  
B. K. Smith ◽  
M. J. Kluger
Keyword(s):  
Receptor Antagonist ◽  
Plasma Levels ◽  
Biological Effects ◽  
Interleukin 1 ◽  
Type I ◽  
Type Ii ◽  
Fischer 344 Rats ◽  
Fischer 344 ◽  
Fischer Rats

A human recombinant interleukin-1 receptor antagonist (IL-1ra) recognizes the two known IL-1 receptors and blocks the binding and many biological effects of both IL-1 alpha and IL-1 beta. The effectiveness of IL-1ra in modifying the fever and plasma IL-6 responses elicited by lipopolysaccharide (LPS) in vivo was tested in Fischer 344 rats. Animals that received IL-1ra 0.5 mg/kg intraperitoneally followed 10 min later by 10 micrograms/kg of LPS displayed significantly lower mean fever responses 2-4 h after injection than rats that received vehicle and LPS (0.48 +/- 0.13 vs. 0.95 +/- 0.16 degrees C, P = 0.016). Plasma levels of IL-6 at 4 h after injection were not different in IL-1ra-treated rats compared with controls (407,725 vs. 729,169 U/ml). Based on our previous finding that preadministration of antiserum to IL-1 beta markedly suppressed plasma IL-6 after LPS, and recent evidence that molar excesses of IL-1ra blocked IL-1-induced circulating IL-6 levels, the possibility that IL-1 is responsible for the induction of bioactive IL-6 during inflammation cannot be ruled out. Similarly, the inability of the IL-1ra to completely suppress the febrile responses of rats to LPS in the present study may be dose related. Alternatively, the induction of bioactive IL-6 by IL-1 in the rat may be mediated primarily through some receptor other than the type I (e.g., the type II receptor).

Localisation of mRNA for interleukin-1 receptor and interleukin-1 receptor antagonist in the rat ovary

1997 ◽  
Vol 152 (1) ◽  
pp. 11-17 ◽  
Author(s):  
L-J Wang ◽  
M Brännström ◽  
K-H Cui ◽  
A P Simula ◽  
R P Hart ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Ovarian Function ◽  
Interleukin 1 ◽  
Target Cells ◽  
Corpora Lutea ◽  
Similar Distribution ◽  
Type I ◽  
Mrna Levels ◽  
Primordial Follicles

Abstract Interleukin-1 (IL-1) is a multifunctional cytokine with profound effects on ovarian function. The effects of IL-1 on ovarian steroidogenesis have been demonstrated in several species. IL-1 mRNA levels are increased in the thecal layer of the ovulating follicle and IL-1β has been shown to induce ovulations in vitro. In this study we have investigated the presence and distribution of the mRNAs for type I IL-1 receptor (IL-1RtI) and for the naturally occurring IL-1 receptor antagonist (IL-1ra) in ovaries of adult cycling rats, to elucidate the target cells for IL-1 action. We have demonstrated the presence of mRNA for both substances by in situ hybridisation and reverse transcription PCR. mRNA for IL-1RtI was not found in primordial follicles but was abundant in the granulosa and thecal layer in developing follicles with stronger signals in the granulosa layer. In the preovulatory and ovulatory follicles, there was a further increase in the signal for IL-1RtI mRNA in the thecal layer compared with the granulosa layer. Corpora lutea were weakly positive at all stages and atretic follicles were largely negative. No mRNA was detected in oocytes of any stage. mRNA for IL-1ra showed a similar distribution to that of IL-1RtI. The changes in distribution suggest an action of IL-1 on rat granulosa cells during follicular development and on thecal cells during ovulation. Journal of Endocrinology (1997) 152, 11–17

Glial cell line-derived neurotrophic factor promotes sleep in rats and rabbits

2001 ◽  
Vol 280 (4) ◽  
pp. R1001-R1006 ◽  
Author(s):  
Tetsuya Kushikata ◽  
Takeshi Kubota ◽  
Jidong Fang ◽  
James M. Krueger
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Line ◽  
Glial Cell ◽  
Eye Movement ◽  
Neurotrophic Factor ◽  
Brain Temperature ◽  
Interleukin 1 ◽  
High Dose ◽  
Sleep Regulation

Various growth factors (e.g., growth hormone-releasing hormone, acidic fibroblast growth factor, nerve growth factor, brain-derived neurotrophic factor, and interleukin-1) are implicated in sleep regulation. It is hypothesized that neuronal activity enhances the production of such growth factors, and they in turn form part of the sleep regulatory mechanism. Glial cell line-derived neurotrophic factor (GDNF) promotes development, differentiation, maintenance, and regeneration of neurons, and its production is induced by well-characterized sleep regulatory substances such as interleukin-1 and tumor necrosis factor. Therefore, we investigated whether GDNF would promote sleep. Twenty-six male Sprague-Dawley rats and 30 male New Zealand White rabbits were surgically implanted with electroencephalogram (EEG) and electromyogram (EMG; rats only) electrodes, a brain thermistor, and a lateral intracerebroventricular cannula. The animals were injected intracerebroventricularly with pyrogen-free saline and on a separate day with one of the following doses of GDNF: 5, 50, and 500 ng in rabbits and 50 and 500 ng in rats. The EEG, brain temperature, EMG (in rats), and motor activity (in rabbits) were recorded for 23 h after the intracerebroventricular injection. GDNF (500-ng dose) increased the time spent in nonrapid eye movement sleep in both rats and rabbits. Rapid eye movement sleep was not affected by the lower doses of GDNF but was inhibited in rabbits after the high dose. EEG slow-wave activity was not affected by GDNF. The current results provide further evidence that various growth factors are involved in sleep regulation.

An interleukin-1 receptor fragment inhibits spontaneous sleep and muramyl dipeptide-induced sleep in rabbits

1996 ◽  
Vol 271 (1) ◽  
pp. R101-R108 ◽  
Author(s):  
S. Takahashi ◽  
L. Kapas ◽  
J. Fang ◽  
J. M. Seyer ◽  
Y. Wang ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Interleukin 1 ◽  
Muramyl Dipeptide ◽  
Type I ◽  
Amino Acid Residues ◽  
Central Administration ◽  
Sleep Regulation ◽  
Systemic Injection ◽  
Normal Sleep ◽  
Receptor Fragment

Interleukin-1 (IL-1) is hypothesized to be involved in physiological sleep regulation and in sleep responses occurring during infectious disease. If this hypothesis is correct, then inhibition of endogenous IL-1 should reduce both normal sleep and N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)-induced sleep. MDP is a somnogenic substance derived from bacterial cell walls. We report here the effects of a synthetic IL-1 receptor fragment corresponding to amino acid residues 86-95 of the human type I IL-1 receptor (IL-1RF) on spontaneous sleep and IL-1 beta- and MDP-induced sleep and fever in rabbits. Two doses of the IL-1RF (25 and 50 micrograms) were injected into normal rabbits intracerebroventricularly (icv). Both doses significantly decreased spontaneous non-rapid eye movement sleep (NREMS) across a 22-h recording period. Pretreatment of rabbits with 25 micrograms of IL-1RF blocked the somnogenic actions of 10 ng icv IL-1. Similarly, central pretreatment of animals with 25 micrograms IL-1RF significantly attenuated the NREMS-promoting and REMS-suppressive actions of 150 pmol MDP injected centrally. The increase in NREMS and decrease in REMS induced by systemic injection of 12.5 micrograms/kg MDP were also significantly suppressed by central administration of 50 micrograms IL-1RF. In contrast, the febrile response induced by either intracerebroventricularly or intravenously injected MDP were not significantly affected by IL-1RF. These results support the hypothesis that endogenous, brain-derived IL-1 contributes to the maintenance of normal sleep and may mediate sleep responses to systemic as well as central bacterial infections.

Microparticles Locally Deliver Active Interleukin-1 Receptor Antagonist In Vivo

2018 ◽  
Vol 7 (16) ◽  
pp. 1800263 ◽  
Author(s):  
Anna E. B. Clements ◽  
Emily R. Groves ◽  
Connie S. Chamberlain ◽  
Ray Vanderby ◽  
William L. Murphy
Keyword(s):  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Interleukin 1 Receptor Antagonist

Inhibition of nitric oxide synthesis suppresses sleep in rabbits

1994 ◽  
Vol 266 (1) ◽  
pp. R151-R157 ◽  
Author(s):  
L. Kapas ◽  
M. Shibata ◽  
M. Kimura ◽  
J. M. Krueger
Keyword(s):  
Nitric Oxide ◽  
Eye Movement ◽  
Brain Temperature ◽  
Interleukin 1 ◽  
Systemic Blood Pressure ◽  
Common Mechanism ◽  
Rapid Eye Movement ◽  
Nitric Oxide Synthesis ◽  
Rapid Eye Movement Sleep ◽  
Intracerebroventricular Injections

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, on spontaneous and interleukin-1 (IL-1)-induced sleep were examined in rabbits. Animals were injected intracerebroventricularly or intravenously during the light phase with vehicle, L-NAME, IL-1, or the combination of L-NAME and IL-1. Injection of L-NAME (5 mg icv and 100 mg/kg iv) suppressed both non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) for 4-6 h. The sleep-suppressive effects are unlikely due to pressor responses to L-NAME because administration of L-NAME (5 mg icv) produced only a transient (3-4 min) slight increase in systemic blood pressure. Injection of IL-1 (20 ng icv) elicited fever, suppressed REMS, and increased NREMS for 6 h. NREMS was suppressed for 3 h after the combined intracerebroventricular injections of 5 mg L-NAME and 20 ng IL-1 and was elevated during postinjection hours 4-6. Administration of IL-1 (30 ng/kg iv) increased NREMS and brain temperature for 2 h. After the combined injection of IL-1 and L-NAME (100 mg/kg), NREMS was significantly suppressed during postinjection hours 1-5. It is not known whether the interactions between the sleep-suppressive effects of L-NAME and the NREMS-promoting effects of IL-1 are specific, being mediated via a common mechanism, or whether they are additive, being mediated via independent mechanisms. The pyrogenic and REMS-suppressive actions of either intracerebroventricularly or intravenously injected IL-1 were not affected by L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy

1997 ◽  
Vol 40 (6) ◽  
pp. 1012-1019 ◽  
Author(s):  
Jean-Pierre Pelletier ◽  
John P. Caron ◽  
Christopher Evans ◽  
Paul D. Robbins ◽  
Helga I. Georgescu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Receptor Antagonist ◽  
Interleukin 1 ◽  
Interleukin 1 Receptor Antagonist ◽  
Experimental Osteoarthritis

scholarly journals Counter-regulation in the IKK family

2011 ◽  
Vol 434 (1) ◽  
pp. e1-e2 ◽  
Author(s):  
Luke A. J. O'Neill
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Control Mechanisms ◽  
Biochemical Journal ◽  
Regulatory Feedback Loop

The human IKK [IκB (inhibitor of NF-κB) kinase] family has four members; they are the central kinases of innate immunity. Two members, IKKα and IKKβ, the so-called canonical members, phosphoryate IκBα, leading to activation of the transcription factor NF-κB (nuclear factor κB), which controls the expression of many immune and inflammatory genes. The IKK-related proteins TBK-1 (TANK-binding kinase 1) and IKKϵ have a different substrate – IRF3 (interferon regulatory factor 3) – which regulates a different set of genes, the products of which include Type I interferons. Toll-like receptors (TLRs) such as the lipopolysaccharide receptor TLR4 or the poly(I:C) receptor TLR3 activate each of the IKKs, but the pro-inflammatory cytokine IL-1 (interleukin 1), which signals in a broadly similar way to the TLRs, has so far been shown to activate only the canonical IKKs. In this issue of the Biochemical Journal, Clark et al. bring new insights into the regulation of IKKs. They demonstrate that IL-1 is in fact able to activate IKKϵ/TBK-1, which occurs via IKKα/IKKβ. The consequence of this is not IRF3 activation, but a negative feedback effect on IKKα/IKKβ. This provides us with yet another regulatory feedback loop in a system already replete with control mechanisms. It attests yet again to the importance of keeping these innate immune pathways in check, since if they proceed uncontrolled, inflammatory diseases can occur. Importantly, this study utilized new and specific inhibitors of these kinases, suggesting that the interpretation of any effects the compound might have in vivo may be complex, since for example the inhibition of IKKϵ/TBK-1 might actually have a pro-inflammatory effect.

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