Interaction Of Interleukin-1 Research Articles

Role of Datscan and Clinical Diagnosis in Pd

Interleukin-1 (IL-1), a cytokine involved in the acute phase reaction to injury and infection, has multiple effects in the central nervous system, including induction of fever and sleep and the release of several neuropeptides. We evaluated effects of IL-1 beta on inhibitory postsynaptic function at the gamma-aminobutyric acidA (GABAA) receptor. IL-1 (100 pg/ml to 10 ng/ml) augmented GABAA receptor function in cortical synaptic preparations. This effect of IL-1 was largely prevented by incubation with a specific IL-1 receptor antagonist. The related cytokines interleukin-6 and tumor necrosis factor did not augment GABA-dependent chloride transport. Similar enhancement of GABAA receptor function was observed in tissue prepared from mice previously injected intraperitoneally with IL-1 (1 microgram). Electrophysiological studies in cultured primary cortical neurons demonstrated that IL-1 enhanced the GABA-mediated increase in chloride permeability, whereas IL-1 alone produced no alterations in resting conductance. Behavioral studies indicated that IL-1 is similarly active in vivo; mice treated with IL-1 showed a decrease in open-field activity and an increase in the threshold for pentylenetetrazol-induced seizures. The interaction of IL-1 with GABAA receptors might account for the somnogenic and motor-depressant effects of this cytokine.

Interactions of Interleukin-1 With Neurotrophic Factors in the Central Nervous System: Beneficial or Detrimental?

Interleukin (IL)-1 is a multifunctional cytokine that plays a key role in mediating inflammation in the brain. Many different cell types in the brain express the IL-1 receptor and respond to this cytokine by activating cell-type-specific signaling pathways leading to distinct functional responses, which collectively comprise the inflammatory response in the brain. One key effect of IL-1 in the brain is the induction of trophic factor production by glial cells, which has traditionally been considered a neuroprotective response to injury or disease. However, recent studies have shown that nerve growth factor, which is regulated by IL-1, can induce neuronal survival or apoptosis via different receptors. This article examines the interaction of IL-1 with different trophic factors in the brain.

The immunosuppressive activity of peptide fragments of vaccinia virus C10L protein and a hypothesis on the role of this protein in the viral invasion

Our previous studies revealed that the 143–148 fragment of interleukin-1 receptor antagonist (IL-1 Ra) molecule with a Val–Thr–Lys–Phe–Tyr–Phe (VTKFYF) sequence inhibits the interleukin-1 (IL-1) interaction with its cellular receptor. The Val–Thr–Arg–Phe–Tyr–Phe (VTRFYF) sequence of the 322–327 fragment of the C-terminal domain of vaccinia virus protein related to the C10L vaccinia gene shows a very high homology to the 143–148 IL-1 Ra fragment, suggesting a similar inhibitory activity. To test this suggestion, we investigated the inhibitory activity of a series of synthetic peptides derived from 316 to 327 fragment of C10L on the interaction of IL-1 with its receptor. We also tested the peptides for their influence on the humoral and cellular immune response. The results indicate that biological activities of the C10L fragments are similar to those obtained for respective fragments of IL-1 Ra. The C-terminal domain of C10L protein can be easily folded into spatial structure similar to the crystallographic one of IL-1 Ra. Based on the crystallographic structure of IL-1 Ra, we constructed a 3-D model of the C10L protein. According to the model, the Val 322–Asn 328 sequence is localized on the surface of the molecule and, therefore, it may be involved in the interactions with receptors. Our results indicate that the C10L viral protein can play an important role in vaccinia virus evasion of the host immune system. It may consist in the blockade of IL-1 receptors by the C10L protein, a homologue of the IL-1 Ra.

Anorexia in a rat model of colitis: interaction of interleukin-1 and hypothalamic serotonin

Background and Aims: Anorexia induced by experimental colitis in rats is mediated, in part, by increased release of serotonin (5-HT) from the hypothalamic paraventricular nucleus (PVN). In this model, anorexia is attenuated by treatment with an interleukin-1 (IL)-1 receptor antagonist (ra). However, a functional link between central I l-1 receptors and 5-HT release remains unproven. We have tested the hypothesis that anorexia associated with experimental colitis is mediated by IL-1 induced release of 5-HT. Methods: In vivo 5-HT release in the PVN was measured in rats with 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colitis, treated with intracerebroventricular infusion of IL-1ra or vehicle treated controls. The effect of inhibition of tumour necrosis factor-α on food intake and PVN 5-HT release in TNBS-colitis was also tested. Results: In rats with TNBS-induced colitis, intracerebroventricular infusion of IL-1ra resulted in a 18-fold reduction in PVN 5-HT release compared to vehicle-treated controls. This was associated with a significant increase in food intake in IL-1ra treated rats. In contrast intracerebroventricular administration of anti-tumour necrosis factor antibodies had no effect on either PVN 5-HT release or food intake in rats with TNBS-induced colitis. Conclusions: In animals with TNBS-colitis, anorexia is mediated, in part, by the stimulatory effect of IL-1 on medial hypothalamic 5-HT.

In vitro and in vivo study of regulation mechanisms of type I interleukin-1 receptor

Interleukin 1 (IL-1) is one of the inflammatory cytokines, which plays a pivotal role in both host defense and homeostasis. Its signal is transduced by type I IL-1 receptor (IL-1RI). This report gives an insight into the regulatory mechanism of IL-1RI in both in vitro and in vivo. IL-1 up-regulates IL-1RI through prostaglandin E2 (PGE2) production on human fibroblasts. However, in the presence of indomethacin, IL-1 down-regulates the receptor by destabilizing IL-1 receptor mRNA. Type I and type II interferons (IFNs) up-regulate the expression of IL-1RI. This up-regulation leads to the increasing susceptibility of IL-1RI to IL-1, as the DNA binding of IL-1-induced NF-kappa B and the production of IL-1-induced IL-6 from the fibroblasts are augmented by pretreatment with IFNs. On the other hand, the expression of cell surface IL-1RI is inhibited by tyrosine kinase inhibitors, herbimycin and genistein, resulting in reduction of the kinase activity of IRAK (IL-1 receptor associated kinase) and IL-1-induced IL-6 production from the fibroblasts. Lipopolysaccharide (LPS) augments the expression of IL-1RI mRNA and cell surface molecule in the hepatocytes of mice in vivo, and the augmentation is mediated by the interaction of IL-1, IL-6, and of glucocorticoid (GC). When hepatocytes were pretreated with dexamethasone (Dex) and IL-6, the activation of IRAK was augmented in response to IL-1, indicating that IL-1 signaling is also up-regulated. In addition, IL-1 treatment ather combined administration of Dex and IL-6 into mice markedly increased the serum level of serum amyloid A. These data suggest that the expression of IL-1RI is regulated by inflammatory cytokines, PGE2, GC and LPS in vitro and in vivo. This study shows that the biological activity of IL-1 can be controlled by regulating the expression of IL-1RI, and therefore proposes the use of pharmaceutical drugs for the regulation of cytokine expression.

Role of p53 and apoptosis in sensitization of cis-diamminedichloroplatinum antitumor activity by interleukin-1 in ovarian carcinoma cells.

We have previously reported that interleukin-1 (IL-1 ) sensitized cisplatin cytotoxicity against human ovarian NIH:OVCAR-3 tumor cells. We have further examined inter-actions of IL-1 with cisplatin in these ovarian cells. Treatment of cells with either IL-1 or CDDP or combinations resulted in a significant accumulation of cells in G1 phase and a concomitant decrease in the S phase of the cell cycle. IL-1 and CDDP treatment induced p53 protein in NIH:OVCAR-3 tumor cells. CDDP and IL-1 treatment decreased the steady-state expression of c-myc RNA and induced significant degradation of the genomic DNA into internucleosomal sized DNA fragments which was further increased in the presence of both agents in these cells. Taken together, these studies suggest that IL-1 may kill ovarian NIH:OVCAR-3 tumor cells by inducing a blockade at G1/S of the cell cycle, down-regulating c-myc gene and inducing p53-dependent apoptosis. The synergistic interactions of IL-1 with CDDP may involve the enhancement of p53-dependent apoptosis.

Role of glucocorticoid in the upregulation of type I interleukin-1 receptor mRNA expression in hepatocytes of endotoxin-administrated mice.

The interleukin-1 (IL-1) signal is transduced through type I IL-1 receptor (IL-1RI). We have recently reported that lipopolysaccharide (LPS) upregulated IL-1RI mRNA expression in mouse liver in vivo and that IL-1 and IL-6 directly upregulated IL-1RI mRNA expression in primary cultured mouse hepatocytes. Glucocorticoid (GC) has been reported to increase IL-1 binding to the cell surface and the expression level of IL-1R mRNA in a variety of cell types. As serum GC level is elevated in an inflammatory response, we evaluated the role of GC in LPS-induced upregulation of IL-1RI mRNA in the mouse liver. When LPS was administered to adrenalectomized (ADX) mice, IL-1RI mRNA was upregulated at a level comparable to those of untreated or sham-operated mice. A high dose of dexamethasone (Dex), however, caused upregulation of the mRNA. When primary cultured mouse hepatocytes were treated with Dex, only a weak upregulation of IL-1RI mRNA was observed. However, Dex in combination with IL-1 or IL-6 markedly enhanced the IL-1RI mRNA expression. A marked upregulation of the mRNA was also induced by treatment with a combination of IL-1 and IL-6 in the absence of Dex, reflecting the observation in ADX mice. These results suggest that the upregulation of IL-1RI mRNA in response to LPS is induced by the interaction of IL-1 and IL-6 and that GC augments their effect.

Specific targeting of infectious foci with radioiodinated human recombinant interleukin-1 in an experimental model

In the present study, radioiodinated human recombinant interleukin-1 (IL-1) was investigated for its potential to image infectious foci in vivo in an animal model of infection. Twenty-four hours after induction of a Staphylococcus aureus abscess in the left calf muscle, mice were i.v. injected with both iodine-125 labelled IL-1 and iodine-131 labelled myoglobin, a size-matched control agent. The animals were killed for tissue biodistribution studies at 2, 6, 12, 24 and 48 h p.i. Gamma camera images were obtained at 6, 24 and 48 h after injecting mice with 123I-IL-1. Radioiodinated IL-1 rapidly cleared from the body; after 12 h the abscess was the organ with the highest activity. The absolute abscess uptake of 125I-IL-1 remained high compared to 131I-myoglobin, resulting in significantly higher abscess-to-muscle ratios of 125I-IL-1 compared to 131I-myoglobin. The ratios of 125I-IL-1 reached the ultimate value of 44.4+/-10.8 at 48 h p.i., whereas the ratios of 131I-myoglobin did not exceed 5.9+/-0.7. Gamma camera imaging revealed clearly visible abscesses. In conclusion, our results demonstrate specific retention of radioiodinated IL-1 in the abscess, presumably by interaction of IL-1 with its receptor on the inflammatory cells. The high target-to-background ratios that were obtained over the course of time indicate that the IL-1 receptor may be a valuable target for the imaging of infectious foci.

Permeability change of liposomal membrane induced by interleukin-1 alpha.

Interleukin-1 (IL-1) is produced and released by various cells, including activated macrophages, and plays important roles in inflammation as well as immune responses. Since the precursor of IL-1 has no signal peptide, the mechanism of IL-1 release has been an enigma. To investigate the possibility of direct interaction of IL-1 with the lipid bilayer, the interleukin-1 alpha (IL-1 alpha)- or beta (IL-1 beta)-induced permeability change of the liposomal membrane was determined. IL-1 alpha, but not IL-1 beta, caused an increase in the permeability of liposomes composed of phosphatidylserine (PS), at neutral and acidic pHs, as demonstrated by measuring the efflux of calcein. On the other hand, liposomes composed of phosphatidylcholine (PC) showed no increase in permeability when incubated with IL-1 alpha, suggesting the importance of acidic phospholipids in the interaction of IL-1 alpha with the membrane. Furthermore, permeability of liposomal membrane was markedly increased by IL-1 alpha in the presence of 1 microM calcium ions, although a permeability change was observed even in the absence of calcium ions. IL-1 alpha also induced the efflux of fluorescent dextran (average M(r) of 39,600), raising the possibility of translocation of IL-1 alpha through the cell membrane.

Interaction of interleukin-1 and interferon-gamma on fibroblast growth factor-induced angiogenesis.

The interaction of interleukin‐1 (IL‐1) and interferon‐γ (IFN‐γ) actions on several aspects of angiogenesis in vitro and in vivo was studied. The proliferation and migration of human umbilical vein endothelial cells cultured with basic fibroblast growth factor (bFGF) were synergistically inhibited by cotreatment with IL‐1 and IFN‐γ. Endothelial cell adhesion to collagen was suppressed by IL‐1 and the effect was slightly enhanced by the combination of IL‐1 and IFN‐γ. Local administration of IL‐1 (10,000 U) and IFN‐γ (1,000 U) inhibited bFGF‐induced angiogenesis in the skin of mice, and synergistic inhibitory activity of the combination was demonstrated. Expression of FGF receptors was strongly downregulated by the combination, whereas expressions of epidermal growth factor (EGF) receptors, integrin β1 and integrin β3 were not. EGF partially abrogated the growth‐inhibitory effects of IL‐1 and IFN‐γ. These findings indicate that IL‐1 and IFN‐γ are each able to act an angiogenesis inhibitor in a situation where FGF plays a major role in angiogenesis, and the activity is synergistically enhanced when they are used in combination.

Interaction of interleukin-1 with islet beta-cells. Distinction between indirect, aspecific cytotoxicity and direct, specific functional suppression

Interaction of interleukin-1 with islet beta-cells. Distinction between indirect, aspecific cytotoxicity and direct, specific functional suppression

Nuclear internalisation and DNA binding activities of interleukin-1, interleukin-1 receptor and interleukin-1/receptor complexes

This paper presents evidence to suggest that interleukin-1α as a complex with its receptor is able to express DNA binding activity. Both the interleukin-1/receptor complex and the interleukin-1 receptor appear to be able to bind to DNA, however interleukin-1 on its own showed no binding activity. Interleukin-1 was found to be internalised into the nuclei of all cells examined (EL4, MEL, HL-60, K562, THP-1 and Jurkat cells). The data suggest the possible modulation of genes by interaction of interleukin-1/receptor complexes with DNA structures.

Interleukin 1 interacts synergistically with forskolin and isobutylmethylxanthine in stimulating bone resorption in organ culture

This study examined the interaction of interleukin 1 (IL-1) with forskolin and isobutyl-methylxanthine (3-isobutyl-1-methyl-xanthine) (IBMX) in stimulating bone resorption in 5-day fetal rat long bone organ culture. Forskolin and IBMX are pharmacologic agents that elevate cyclic adenosine monophosphate (AMP) levels in many cell types, including osteoblasts and osteoclasts. The interaction of IL-1 with forskolin and IBMX are synergistic when submaximal resorptive concentrations of agonists were examined. Stimulated resorption was 2 to 5 times that expected for an additive response. When maximally resorptive concentrations of agonists were examined, the interaction between IL-1 and the other agents was, at most, additive. We have previously reported that parathyroid hormone and prostaglandin E, agents that also activate the cyclic AMP pathway in bone cells, interact synergistically with IL-1 in stimulating bone resorption. The results of this study, together with our previous studies, suggest that activation of the cyclic AMP pathway is a sufficient signal for an agent to interact synergistically with IL-1 in stimulating bone resorption.

Human alveolar macrophage and blood monocyte inhibition of fibroblast proliferation. Evidence for synergy between interleukin-1 and tumor necrosis factor.

Stimulated human blood monocytes and alveolar macrophages are known to elaborate a soluble factor(s) that inhibits fibroblast proliferation by stimulating fibroblast prostaglandin (PG) production. However, the factor(s) mediating these effects has never been completely characterized and its relationship to known cytokines has never been fully defined. In this study, we demonstrate that this factor(s) is partially trypsin-sensitive, is between 16 and 24 kilodaltons molecular weight, and elutes between 0.13 and 0.25 M NaCl and 24 and 38% 1-propanol from anion exchange and reverse phase columns, respectively. In addition, we demonstrate that interleukin-1 (IL-1) and tumor necrosis factor (TNF) have similar patterns of elution and that the fibroblast growth-inhibiting and PGE-stimulating activities in monocyte and alveolar macrophage supernatants are partially reversed with neutralizing antibodies against IL-1-beta or TNF. However, this inhibition is not due to IL-1-beta or TNF, alone, because each has a mild stimulatory effect on fibroblast proliferation. In contrast, a dose-dependent inhibition of fibroblast proliferation is noted when fibroblasts are simultaneously exposed to recombinant IL-1 and TNF. This inhibition is reversed when fibroblast PG production is blocked and appears to result from IL-1 and TNF synergistically stimulating fibroblast PGE production. Thus, the PG-mediated inhibition of fibroblast proliferation caused by stimulated human mononuclear phagocytes is not the result of a single cytokine but is instead at least partly mediated by an interaction of IL-1 and TNF.

Self-regulation of procoagulant events on the endothelial cell surface.

Interleukin 1 (IL-1) is a potent mediator of inflammatory and immunologic phenomena. In addition, IL-1 may be intimately involved in the regulation of hemostasis, since interaction of IL-1 with endothelial cells has been reported to induce tissue factor activity. We demonstrate that perturbation of the endothelial cell induces augmented IL-1 release. Human umbilical vein endothelial cells perturbed by treatment with lipopolysaccharide produced enhanced amounts of IL-1 activity. IL-1 activity from lipopolysaccharide-treated endothelial cell supernatants could be absorbed by an antibody to IL-1 coupled to Sepharose. Elaboration of IL-1 activity was dependent on the dose of lipopolysaccharide and occurred in a time-dependent manner. Addition of cycloheximide blocked generation of IL-1 activity. A physiological vessel wall perturbant, the coagulation enzyme thrombin, induced comparable amounts of IL-1 activity in endothelial cell cultures. This effect was specific for the enzyme, since active site-blocked thrombin and prothrombin had no effect on IL-1. In addition, IL-1-containing supernatants from thrombin-stimulated endothelial cells induced tissue factor procoagulant activity in fresh endothelial cell cultures. Thus, in contrast to the multiple, known inhibitory mechanisms that block thrombin procoagulant activity, these data suggest a circle of interaction in which thrombin induces endothelial cell elaboration of IL-1, a mediator of endothelial cell procoagulant activity. Endothelial cell production of IL-1 in response to perturbation allows these cells to play an integral role in the regulation of the inflammatory and coagulation systems.