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.

scholarly journals Brain-specific interleukin-1 receptor accessory protein in sleep regulation

2012 ◽  
Vol 112 (6) ◽  
pp. 1015-1022 ◽  
Author(s):  
Ping Taishi ◽  
Christopher J. Davis ◽  
Omar Bayomy ◽  
Mark R. Zielinski ◽  
Fan Liao ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Nrem Sleep ◽  
Adaptor Proteins ◽  
Accessory Protein ◽  
Type I ◽  
Sleep Regulation ◽  
Brain Functions ◽  
Inflammatory Stimuli ◽  
Rat Somatosensory Cortex ◽  
Complex Signaling

Interleukin (IL)-1β is involved in several brain functions, including sleep regulation. It promotes non-rapid eye movement (NREM) sleep via the IL-1 type I receptor. IL-1β/IL-1 receptor complex signaling requires adaptor proteins, e.g., the IL-1 receptor brain-specific accessory protein (AcPb). We have cloned and characterized rat AcPb, which shares substantial homologies with mouse AcPb and, compared with AcP, is preferentially expressed in the brain. Furthermore, rat somatosensory cortex AcPb mRNA varied across the day with sleep propensity, increased after sleep deprivation, and was induced by somnogenic doses of IL-1β. Duration of NREM sleep was slightly shorter and duration of REM sleep was slightly longer in AcPb knockout than wild-type mice. In response to lipopolysaccharide, which is used to induce IL-1β, sleep responses were exaggerated in AcPb knockout mice, suggesting that, in normal mice, inflammation-mediated sleep responses are attenuated by AcPb. We conclude that AcPb has a role in sleep responses to inflammatory stimuli and, possibly, in physiological sleep regulation.

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.

scholarly journals Akkermansia Muciniphila induces chronic extramedullary hematopoiesis through cooperative IL-1R and TLR signals

2022 ◽  
Author(s):  
Yuxin Wang ◽  
Tatsuya Morishima ◽  
Maiko Sezaki ◽  
Gaku Nakato ◽  
Shinji Fukuda ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Interleukin 1 ◽  
Extramedullary Hematopoiesis ◽  
Commensal Bacteria ◽  
Host Immune System ◽  
Systemic Injection ◽  
Hematopoietic Stem ◽  
Akkermansia Muciniphila ◽  
Degrading Bacterium ◽  
The Impact

Bacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to spleen, which is termed as extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria, particularly the microbiota, regulates not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbial species on hematopoietic pathology remains largely unknown. Here we found that systemic injection of Akkermansia muciniphila (A. m.), a mucin-degrading bacterium abundantly existing in the human gut rapidly activates BM myelopoiesis, and induces a slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we termed chronic EMH. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) partially diminished A. m.-induced chronic EMH, while additional pharmacological inhibition of the interleukin-1 receptor (IL-1R) completely alleviated splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated innate immune signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders.

scholarly journals Study of 2'-macrolide phosphotransferase selectivity for different substrates

2014 ◽  
Vol 70 (a1) ◽  
pp. C703-C703
Author(s):  
Jonathan Blanchet ◽  
Desiree Fong ◽  
Albert Berghuis
Keyword(s):  
Bacterial Infections ◽  
Respiratory Infections ◽  
Kinetic Studies ◽  
Binding Pocket ◽  
Nucleoside Triphosphate ◽  
Type I ◽  
Amino Acid Residues ◽  
Wide Range ◽  
The Family ◽  
Phosphate Donor

Macrolides are antibiotics that have been in use since the late 1950s to treat a wide range of bacterial infections (e.g. upper respiratory infections, skin and soft–tissue infections, stomach ulcers and some venereal diseases). The structure of these antibiotics contains a lactone ring of either 14, 15, or 16 members, with a variety of sugar moieties attached. Resistance to this class of antibiotics may result from the reaction carried out by macrolide phosphotransferases [MPHs]. MPHs belong to the family of antibiotic kinases which catalyzes the transfer of a phosphate group from a nucleoside triphosphate to a specific hydroxyl on the antibiotic. However, unlike most antibiotic kinases, MPHs utilize GTP as the phosphate donor. Specifically, 2'-macrolide phosphotransferase type I [MPH(2')-I] transfers the gamma-phosphate from GTP to the 2'-hydroxyl of 14- and 15-membered ring macrolides. Crystal structure of the ternary complexes of MPH(2')-I with both 14- and 15-membered lactone macrolides have been determined. To study the basis of substrate selectivity, we have generated mutations of several amino acid residues in the macrolide-binding pocket and examined the catalytic activities of these mutants on the different classes of macrolides, including those containing a 16-membered lactone. Furthermore, we will present kinetic studies of MPH(2')-I containing mutations in the nucleoside-binding pocket in order to study the mechanism for the enzyme's preference for GTP.

Inhibition of brain interleukin-1 attenuates sleep rebound after sleep deprivation in rabbits

1997 ◽  
Vol 273 (2) ◽  
pp. R677-R682 ◽  
Author(s):  
S. Takahashi ◽  
J. Fang ◽  
L. Kapas ◽  
Y. Wang ◽  
J. M. Krueger
Keyword(s):  
Sleep Deprivation ◽  
Eye Movement ◽  
Intravenous Injection ◽  
Slow Wave ◽  
Interleukin 1 ◽  
Wave Activity ◽  
Rapid Eye Movement Sleep ◽  
Sleep Regulation ◽  
Receptor Fragment ◽  
Physiological Sleep

It is hypothesized that interleukin-1 (IL-1) is involved in physiological sleep. If this hypothesis is correct, inhibition of IL-1 should attenuate sleep responses after sleep deprivation. We tested the effect of intracerebroventricular or intravenous injection of an IL-1 inhibitor, an IL-1 receptor fragment (IL-1RF), on sleep rebound after sleep deprivation in rabbits. Six hours of total sleep deprivation significantly increased non-rapid eye movement sleep (NREMS) and enhanced electroencephalogram slow-wave activity during NREMS. Intracerebroventricular treatment with the IL-1RF (50 micrograms) significantly attenuated the sleep responses after sleep deprivation. Furthermore, 1.0 mg/kg i.v. injection of the IL-1RF significantly suppressed spontaneous NREMS in rabbits that were not sleep deprived. However, intravenous administration of the IL-1RF (1.0 mg/kg) failed to attenuate the sleep responses following the 6-h sleep deprivation period. These results support the hypothesis that central pools of IL-1 are important for physiological sleep regulation.

scholarly journals Interleukin-1 receptor antagonist mediates type I interferon-driven susceptibility to Mycobacterium tuberculosis

2018 ◽  
Author(s):  
Daisy X. Ji ◽  
Katherine J. Chen ◽  
Naofumi Mukaida ◽  
Igor Kramnik ◽  
K. Heran Darwin ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Receptor Antagonist ◽  
Bacterial Infections ◽  
Type I Interferon ◽  
Inbred Mouse ◽  
Interleukin 1 ◽  
Mouse Strains ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns

AbstractThe bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and is responsible for more human mortality than any other single pathogen1. Although ~1.7 billion people are infected with Mtb2, most infections are asymptomatic. Progression to active disease occurs in ~10% of infected individuals and is predicted by an elevated type I interferon (IFN) response3–8. Type I IFNs are vital for antiviral immunity, but whether or how they mediate susceptibility to Mtb has been difficult to study, in part because the standard C57BL/6 (B6) mouse model does not recapitulate the IFN-driven disease that appears to occur in humans3–5,8. Here we examined B6. Sst1S congenic mice that carry the C3H “sensitive” allele of the Sst1 locus that renders them highly susceptible to Mtb infections9,10. We found that B6.Sst1S mice exhibit markedly increased type I IFN signaling, and that type I IFNs were required for the enhanced susceptibility of B6. Sst1S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections11,12. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, IL-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb. As even a partial reduction in IL-1Ra levels led to significant protection, we hypothesized that IL-1Ra may be a plausible target for host-directed anti-TB therapy. Indeed, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6. Sst1S mice. Our results illustrate how the diversity of inbred mouse strains can be exploited to better model human TB, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo.

scholarly journals Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 788
Author(s):  
Hava Peretz ◽  
Ayala Lagziel ◽  
Florian Bittner ◽  
Mustafa Kabha ◽  
Meirav Shtauber-Naamati ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Heterologous Protein ◽  
Heterologous Protein Expression ◽  
Type I ◽  
Type Ii ◽  
Amino Acid Residues ◽  
Cysteine Desulfurase ◽  
Cofactor Binding ◽  
Pathogenic Variants ◽  
Expression Studies

Classical xanthinuria is a rare autosomal recessive metabolic disorder caused by variants in the XDH (type I) or MOCOS (type II) genes. Thirteen Israeli kindred (five Jewish and eight Arab) and two isolated cases from Germany were studied between the years 1997 and 2013. Four and a branch of a fifth of these families were previously described. Here, we reported the demographic, clinical, molecular and biochemical characterizations of the remaining cases. Seven out of 20 affected individuals (35%) presented with xanthinuria-related symptoms of varied severity. Among the 10 distinct variants identified, six were novel: c.449G>T (p.(Cys150Phe)), c.1434G>A (p.(Trp478*)), c.1871C>G (p.(Ser624*)) and c.913del (p.(Leu305fs*1)) in the XDH gene and c.1046C>T (p.(Thr349Ileu)) and c.1771C>T (p.(Pro591Ser)) in the MOCOS gene. Heterologous protein expression studies revealed that the p.Cys150Phe variant within the Fe/S-I cluster-binding site impairs XDH biogenesis, the p.Thr349Ileu variant in the NifS-like domain of MOCOS affects protein stability and cysteine desulfurase activity, while the p.Pro591Ser and a previously described p.Arg776Cys variant in the C-terminal domain affect Molybdenum cofactor binding. Based on the results of haplotype analyses and historical genealogy findings, the potential dispersion of the identified variants is discussed. As far as we are aware, this is the largest cohort of xanthinuria cases described so far, substantially expanding the repertoire of pathogenic variants, characterizing structurally and functionally essential amino acid residues in the XDH and MOCOS proteins and addressing the population genetic aspects of classical xanthinuria.

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