Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: relationship to occurrence and severity of rheumatoid arthritis.
(17/1170)
OBJECTIVE: To test if interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), IL-4, or IL-10 gene polymorphisms could be used as markers of susceptibility or severity in rheumatoid arthritis (RA). METHODS: The study included 108 patients with early RA followed up for 2 years and 128 healthy controls. From genomic DNA, 6 polymorphisms in genes for IL-1beta, IL-1Ra, IL-10, and IL-4 were typed. Allelic frequencies and carriage rates were compared between RA patients and controls, between patients with erosive and nonerosive RA, and between patients with or without sustained remission. RESULTS: The RP1 allele of the IL-4 gene was found with a significantly higher frequency in RA patients compared with controls. The combination of an RA-related HLA-DR allele expressing shared epitope and the presence of allele E2 in IL-1beta exon 5 was found to expose patients to an increased risk of erosive disease, with an odds ratio of 8.20 (95% confidence interval 2.59-25.84, P < 0.0001). No significant association was observed between polymorphisms and the occurrence of sustained remission. CONCLUSION: This report, for the first time, indicates an association between RA and a polymorphic IL-4 gene sequence located in 5q31-33. In addition, the results show the prognostic value of a polymorphism in IL-1beta exon 5, which allowed prediction of erosive disease with a specificity of 91.8% in 42.1% of patients. Although these observations are very interesting, they have to be considered preliminary and will need to be confirmed. (+info)
Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures.
(18/1170)
Using immunocytochemistry and ELISA, we investigated the production of interleukin (IL)-1beta in the rat hippocampus after focal application of kainic acid inducing electroencephalographic (EEG) seizures and CA3 neuronal cell loss. Next, we studied whether EEG seizures per se induced IL-1beta and microglia changes in the hippocampus using bicuculline as a nonexcitotoxic convulsant agent. Finally, to address the functional role of this cytokine, we measured the effect of human recombinant (hr)IL-1beta on seizure activity as one marker of the response to kainate. Three and 24 hr after unilateral intrahippocampal application of 0.19 nmol of kainate, IL-1beta immunoreactivity was enhanced in glia in the injected and the contralateral hippocampi. At 24 hr, IL-1beta concentration increased by 16-fold (p < 0.01) in the injected hippocampus. Reactive microglia was enhanced with a pattern similar to IL-1beta immunoreactivity. Intrahippocampal application of 0.77 nmol of bicuculline methiodide, which induces EEG seizures but not cell loss, enhanced IL-1beta immunoreactivity and microglia, although to a less extent and for a shorter time compared with kainate. One nanogram of (hr)IL-1beta intrahippocampally injected 10 min before kainate enhanced by 226% the time spent in seizures (p < 0.01). This effect was blocked by coinjection of 1 microgram (hr)IL-1beta receptor antagonist or 0.1 ng of 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate, selective antagonists of IL-1beta and NMDA receptors, respectively. Thus, convulsant and/or excitotoxic stimuli increase the production of IL-1beta in microglia-like cells in the hippocampus. In addition, exogenous application of IL-1beta prolongs kainate-induced hippocampal EEG seizures by enhancing glutamatergic neurotransmission. (+info)
Effects of soluble interleukin-1 type II receptor on rabbit antigen-induced arthritis: clinical, biochemical and histological assessment.
(19/1170)
OBJECTIVES: To investigate the effects of soluble interleukin-1 (IL-1) type II receptor (sIL-1RII) on a number of clinical, biochemical and histological parameters in rabbit antigen-induced arthritis. METHODS: Arthritis was induced by intra-articular injection of methylated bovine serum albumin (mBSA) into rabbits pre-sensitized to the same antigen. An initial i.v. bolus of sIL-1RII was administered, followed by s.c. mini-pump dosing for 14 days, starting at the time of the arthritis induction. Animals received vehicle (saline 500 microl + 5 microl/h), low-dose sIL-1RII (13.4 microg + 1.34 microg/h) or high-dose sIL-1RII (40.2 microg + 4.02 microg/h). RESULTS: Marked, dose-related inhibition of joint diameter, plasma prostaglandin E2 (PGE2), and synovial fluid IL-1alpha and IL-1beta concentrations were seen after administration of sIL-1RII. However, synovial fluid PGE2 concentrations and synovial fluid cell counts were not affected. A significant inhibitory effect was also seen histologically on soft-tissue swelling and joint damage with high-dose sIL-1RII. CONCLUSIONS: These results demonstrate that IL-1 plays an important role in the pathogenesis of rabbit antigen-induced arthritis, thus confirming it as an excellent animal model with respect to evaluating anti-cytokine therapies for rheumatoid arthritis. (+info)
Ovarian interleukin-1 receptor antagonist in rats: gene expression, cellular localization, cyclic variation, and hormonal regulation of a potential determinant of interleukin-1 action.
(20/1170)
It is hypothesized that the intraovarian interleukin (IL)-1 system plays a prominent role in the regulation of follicular development and ovulation. A central component of the intraovarian IL-1 system is the IL-1 receptor antagonist (IL-1RA), a protein acting as a pure IL-1 receptor antagonist and one for which intracellular (icIL-1RA) and secretory (sIL-1RA) varieties have been described. It was the objective of this study to explore rat ovarian IL-1RA gene expression, to establish the identity and relative abundance of its alternative transcripts, to study its cellular localization, to determine its cyclic variation, and to assess its hormonal regulation. Protected IL-1RA cDNA fragments corresponding to either sIL-1RA or icIL-1RA were barely detectable in untreated whole ovarian tissue of immature rat origin. However, sIL-1RA transcripts reached a maximal value (3.3-fold increase over untreated control values; p < 0.05) 12 h after hCG administration (time of projected ovulation). In situ hybridization localized IL-1RA to mural, antral, and cumulus granulosa cells. Modestly intense staining was also apparent in oocytes. The basal pattern of sIL-1RA expression by cultured whole ovarian dispersates was characterized by a spontaneous increase to a peak value at 4 h. The early (4 h) sIL-1RA burst proved IL-1-, nitric oxide-, and protein biosynthesis-independent. However, treatment with IL-1beta led to a secondary sIL-1RA peak at 48 h, an effect that was substantially reversed by IL-1RA. This stimulatory effect of IL-1beta on IL-1RA expression proved relatively specific, and nitric oxide independent, but contingent upon de novo protein biosynthesis. The in vitro expression of icIL-1RA was barely detectable. Taken together, these in vivo and in vitro observations 1) document the rat ovary as a site of IL-1RA (sIL-1RA > cIL-1RA) expression, 2) localize the relevant transcripts to the granulosa cell, 3) disclose peak expression at the time of ovulation, and 4) establish IL-1 dependence. (+info)
Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1beta on tuberculosis.
(21/1170)
Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The proinflammatory cytokine interleukin (IL)-1beta and its antagonist, IL-1Ra (IL-1 receptor agonist), are strongly induced by M. tuberculosis and are encoded by polymorphic genes. The induction of both IL-1Ra mRNA and secreted protein by M. tuberculosis in IL-1Ra allele A2-positive (IL-1Ra A2(+)) healthy subjects was 1.9-fold higher than in IL-1Ra A2(-) subjects. The M. tuberculosis-induced expression of mRNA for IL-1beta was higher in subjects of the IL-1beta (+3953) A1(+) haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1beta induced by M. tuberculosis was markedly higher in IL-1Ra A2(+) individuals (P < 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1beta (+3953) A2 alleles. In M. tuberculosis-stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon gamma increased and IL-10 decreased IL-1beta production, indicative of a differential influence on the IL-1Ra/IL-1beta ratio by cytokines. In a study of 114 healthy purified protein derivative-reactive subjects and 89 patients with tuberculosis, the frequency of allelic variants at two positions (-511 and +3953) in the IL-1beta and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2(-)/IL-1beta (+3953) A1(+) haplotype was unevenly distributed, being more common in patients with tuberculous pleurisy (92%) in comparison with healthy M. tuberculosis-sensitized control subjects or patients with other disease forms (57%, P = 0.028 and 56%, P = 0. 024, respectively). Furthermore, the IL-1Ra A2(+) haplotype was associated with a reduced Mantoux response to purified protein derivative of M. tuberculosis: 60% of tuberculin-nonreactive patients were of this type. Thus, the polymorphism at the IL-1 locus influences the cytokine response and may be a determinant of delayed-type hypersensitivity and disease expression in human tuberculosis. (+info)
Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo.
(22/1170)
This study examined the influence of low-dose aspirin on interleukin (IL)-1alpha , IL-1 receptor antagonist (IL-1ra), and soluble receptor type II (sIL-1RII) secretion in vivo and in vitro. Blood mononuclear cells were isolated from healthy young men who ingested 81 mg of aspirin on alternate days for 2 weeks and from unmedicated controls. Aspirin had minor effects on ex vivo secretion of IL-1beta and no influence on IL-1ra. In contrast, unstimulated ex vivo secretion of sIL-1RII was over twice as high by cells from aspirin-treated subjects (1115+/-123 vs. 460+/-77 pg/mL, P = 0.02). Lipopolysaccharide-stimulated sIL-1RII secretion was influenced similarly. Plasma sIL-1RII concentrations were 23% higher in aspirin-treated subjects (10.2+/-0.6 vs. 8.4+/-0.3 ng/mL, P = 0.03). In addition, cells from unmedicated subjects cultured in vitro with aspirin (10 microg/mL) secreted significantly greater amounts of sIL-1RII. Thus, low-dose aspirin therapy may prevent inflammation by increasing soluble receptor secretion, thereby preventing IL-1 from binding target cells. (+info)
Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis.
(23/1170)
Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-alpha therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and included serum amyloid A, haptoglobin, and fibrinogen. The latter reduction could be of importance, as it is a risk factor for atherosclerosis, which is augmented in RA patients. (+info)
Relationship of plasma leptin to plasma cytokines and human survivalin sepsis and septic shock.
(24/1170)
Leptin production is increased in rodents by administration of endotoxin or cytokines. To investigate whether circulating leptin is related to cytokine release and survival in human sepsis, plasma concentrations of leptin, interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, soluble TNF receptor type I, IL-1 receptor antagonist (IL-1ra), and the inflammatory modulator IL-10 were measured as soon as severe sepsis (n=28) or septic shock (n=14) developed and every 6 h for 24 h. Patients with sepsis or septic shock had leptin concentrations 2.3- and 4.2-fold greater, respectively, than the control group. There was an independent association for leptin with IL-1ra and IL-10 in both patient groups. By discriminant analysis, leptin and IL-6 were independent predictors of death. These findings suggest that increases in leptin levels may be a host defense mechanism during sepsis. (+info)