Involvement of IL-1β and IL-6 in antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in rats

Purpose: Evidence show that statins possess wide beneficial cardioprotective and anti-inflammatory effects; therefore, in the present experiment, we investigated the antiarrhythmic properties of atorvastatin in ouabain-induced arrhythmia in isolated rat atria and the role of several inflammatory cytokines in this effect.

Materials and methods: Male rats were pretreated with either of atorvastatin (10?mg/kg) or vehicle, orally once daily for 6 weeks. After induction of anesthesia, we isolated the atria and after incubation with ouabain, time of onset of arrhythmia and asystole as well as atrial beating rate and contractile force were recorded. We also measured the atrial levels of IL-1β, IL-6, and TNF-α after the injection of ouabain to animals.

Results: Pretreatment with atorvastatin significantly delayed the onset of arrhythmia and asystole compared with vehicle-treated group (p?p?p?p?>?.05). Injection of ouabain elevated the atrial levels of IL-1β, IL-6, and TNF-α, while pretreatment of animals with atorvastatin could reverse the ouabain-induced increase in atrial IL-1β and IL-6 (p?p?Conclusions: It is concluded that observed antiarrhythmic effects of atorvastatin might be attributed to modulation of some inflammatory cytokines, at least IL-1β and IL-6.     

IL-1可诱导产生IL-1

白细胞介素1(IL-1)作为炎症介质近来引起了人们的关注。据Dinarello等人报道,用IL-1可以诱发IL-1的产生。他们给家兔注射大量的重组IL-1α,以便观察双峰性发热现象。大约注射后3小时出现发热的第二峰,推测这就是由内源性产生的IL-1所致。用此时引起发热的血清再诱导其他家兔发热,在血清中分子量为30～40KD以及15KD的组份中可发现     

Effect of peptide aldehydes with IL-1β converting enzyme inhibitory properties on IL-1α and IL-1β production in vitro

Tripeptide and pentapeptide aldehydes as substrate-base inhibitors of cysteine proteases were designed in our laboratory for the inhibition of interleukin-lβ converting enzyme (ICE), a recently described cysteine protease responsible for the processing of IL-1β. The biological effectivity of the peptide aldehydes was studied in THP-1 cells and human whole blood. The released and cell-associated IL-1α and IL-1β levels were determined by ELISA from the supernatants and cell lysates, respectively. The total IL-1 like bioactivity was assayed by the D₁₀G₄₁ cell proliferation method. The tripeptide aldehyde (Z-Val-His-Asp-H) and pentapeptide aldehyde (Eoc-Ala-Tyr-Val-Ala-Asp-H) significantly reduced IL-1β levels in the supernatants in relatively high concentrations (10–100 μM), but the IL-1α release was unaffected by these peptides. However, a considerable decrease in the cell-associated IL-1β and IL-1α levels was observed. N-terminal extension of the tripeptide aldehyde yielded even more potent inhibitors. Amino acid substitution at the P₂ position did not cause considerable changes in the inhibitory activity. The peptide aldehydes suppressed the IL-1β production in a reversible manner, whereas dexamethasone, a glucocorticoid, had a prolonged inhibitory effect. The inhibitory effect of these peptides and that of dexamethasone appeared to be additive. These findings indicate that these peptide aldehydes might be used as IL-β inhibitory agents in experimental models in which IL-1β is a key mediator or ICE is implicated.     

Discoordinate expression of IL-1α and IL-1β in interfacial membranes of failed joint prostheses

Bone resorption following either cemented or uncemented total hip replacement has been implicated as an important etiologic factor in aseptic loosening of prostheses, the most frequent cause of clinical failure. Interleukin-1 (IL-1), collagenase and prostaglandin E₂ are considered to play key roles in pathological bone resorption. We have measured the actual levels and quantified the genes coding for several cytokines [IL-1, IL-1, IL-4, IL-6, platelet-derived growth factors (PDGF), transforming growth factor- (TGF) and tumor necrosis factor- (TNF)] in interfacial membranes obtained from cemented or uncemented loosened joint replacements. IL-1, IL-6 and TNF were barely detectable in the interfacial membranes either at protein or mRNA levels, while IL-1 and TGF were found to be expressed at the highest levels in freshly isolated tissues. However, the expression of IL-1 increased 10–1000-fold either in isolated cells or explant cultures of interfacial membranes within 24 h. The expression of other cytokines, measured directly in tissue or cells, did not suggest a discoordinate expression of bone-resorbing cellular mediators.     

IL-22 Enhances CCL20 Production in IL-1β-Stimulated Human Gingival Fibroblasts

CC chemokine ligand 20 (CCL20) is involved in the recruitment of Th17 cells and thus in the exacerbation of periodontal disease, but the effect of simultaneous interleukin (IL)-22 and IL-1β stimulation on CCL20 production in human gingival fibroblasts (HGFs) is uncertain. In this study, we investigated the mechanisms of IL-1β- and/or IL-22-induced CCL20 production in HGFs. A single stimulation of IL-22 could not induce CCL20 production. On the other hand, IL-22 could increase CCL20 production from IL-1β-stimulated HGFs in a dose-dependent manner. C-Jun N terminal kinase (JNK) and inhibitor of nuclear factor κB (IκB)-α phosphorylation were increased in IL-1β- and IL-22-stimulated HGFs. An inhibitor of nuclear factor (NF)-κB decreased IL-1β- and IL-22-induced CCL20 production, though an inhibitor of JNK did not modulate CCL20 production. These data suggest that IL-1β in cooperation with IL-22 could increase Th17 cell accumulation in periodontally diseased tissues to enhance CCL20 production in HGFs.     

Lung inflammation induces IL-1β expression in hypoglossal neurons in rat brainstem

Perinatal inflammation is associated with respiratory morbidity. Immune modulation of brainstem respiratory control centers may provide a link for this pathobiology. We exposed 11-day old rats to intratracheal lipopolysaccharide (LPS, 0.5 μg/g) to test the hypothesis that intrapulmonary inflammation increases expression of the proinflammatory cytokine IL-1β within respiratory-related brainstem regions. Intratracheal LPS resulted in a 32% increase in IL-1β protein expression in the medulla oblongata. In situ hybridization showed increased intensity of IL-1β mRNA but no change in neuronal numbers. Co-localization experiments showed that hypoglossal neurons express IL-1β mRNA and immunostaining showed a 43% increase in IL-1β protein-expressing cells after LPS exposure. LPS treatment also significantly increased microglial cell numbers though they did not express IL-1β mRNA. LPS-induced brainstem expression of neuronal IL-1β mRNA and protein may have implications for our understanding of the vulnerability of neonatal respiratory control in response to a peripheral proinflammatory stimulus.     

IL-1β/IL-6 network in the tumor microenvironment of human colorectal cancer

Objectives

Recent studies suggest that the interaction between interleukin (IL)-1β and IL-6 in the microenvironment might be involved in the development and progression of human colorectal cancer (CRC). However, the expression of IL-1β/IL-6 network within the CRC microenvironment is not fully understood.

Membrane interleukin-18 revisits membrane IL-1α in T-helper type 1 responses

Although all structural studies on cytokine-cytokine receptor interactions are based on a crystallized cytokine binding to its specific receptor, there is no dearth of evidence that membrane-embedded cytokines are biologically active by virtue of cell-cell contact. Clearly the orientation of the membrane cytokine is such that it allows binding to the receptor, as takes place with the soluble form of the cytokine. In this issue, Bellora et al. [Eur. J. Immunol. 2012. 42: 1618-1626] report that interleukin-18 (IL-18) exists as an integral membrane protein on M-CSF-differentiated human macrophages and that upon LPS stimulation, IL-18 induces IFN-γ from NK cells in a caspase-1-dependent fashion. The immunological and inflammatory implications for this finding are considerable because of the role of IL-18 as the primary IFN-γ inducing cytokine in promoting Th1 responses.     

Short-term IL-1β blockade reduces monocyte CD11b integrin expression in an IL-8 dependent fashion in patients with type 1 diabetes

Objective

Interleukin 1-beta (IL-1β) is a major inflammatory cytokine. Blockade of the IL-1β pathway is therapeutically efficacious in type 2 diabetes, but the mechanistic effects on the immune system are incompletely understood.

Research design

We administered an IL-1 receptor antagonist, anakinra, to 7 type 1 diabetes patients in order to investigate the immunologic and metabolic effects of this drug. Mechanistic assays were performed before and after drug administration.

Results

A novel signature was observed, with reduced serum interleukin 8 (IL-8) levels and reduced CD11b integrin expression on monocytes associated with increased CXCR1 expression.

Conclusions

This set of linked phenotypes suggests that blockade of the IL-1β pathway results in the reduced ability of mononuclear cells to traffic to sites of inflammation. Mechanistic studies from large scale trials using IL-1 blockade in type 1 diabetes should focus on changes in monocyte trafficking and the IL-8 pathway.     

IL-1刺激内皮细胞产生 IL-6

白细胞与血管内皮细胞在炎症及免疫反应中的关系相当密切,淋巴因子在介导两者     

Differential Regulation of IL-8 by IL-1β and TNFα in Hyaline Membrane Disease

Mechanisms that regulate cytokine-mediated inflammation in the lungs of preterm infants, including factors which regulate production of the chemokine IL-8, remain poorly defined. Sequential bronchoalveolar lavage samples were obtained from preterm newborns with hyaline membrane disease over a 28-day period. Bronchoalveolar lavage cell cytokine relationships were evaluated and the differential regulation of IL-8 by IL-1 and TNF was studied in a short-term culture system. In vivo, IL-8 and IL-l protein levels correlated closely with each other and with macrophage counts. In cell culture, exogenous anti-IL-1 antibody led to a 40% maximum inhibition (approximately) of IL-8 production by lipopolysaccharide stimulated lung inflammatory cells. Comparable amounts of exogenous anti-TNF antibodies achieved a 15% maximum inhibition (approximately) of IL-8 production. Anti-IL-1 and anti-TNF antibodies in combination did not inhibit IL-8 production beyond that achieved by anti-IL-l antibody alone. These results, in preterm newborns, support the concept of lung inflammation mediated in part by a macrophage, IL-1, and IL-8 cell cytokine pathway. The results also suggest that factors other than IL-1 and TNF regulate IL-8 expression in the lungs of preterm infants.     

IL-1β in eosinophil-mediated small intestinal homeostasis and IgA production

Eosinophils are multifunctional leukocytes that reside in the gastrointestinal (GI) lamina propria, where their basal function remains largely unexplored. In this study, by examining mice with a selective deficiency of systemic eosinophils (by lineage ablation) or GI eosinophils (eotaxin-1/2 double deficient or CC chemokine receptor 3 deficient), we show that eosinophils support immunoglobulin A (IgA) class switching, maintain intestinal mucus secretions, affect intestinal microbial composition, and promote the development of Peyer's patches. Eosinophil-deficient mice showed reduced expression of mediators of secretory IgA production, including intestinal interleukin 1β (IL-1β), inducible nitric oxide synthase, lymphotoxin (LT) α, and LT-β, and reduced levels of retinoic acid–related orphan receptor gamma t–positive (ROR-γt⁺) innate lymphoid cells (ILCs), while maintaining normal levels of APRIL (a proliferation-inducing ligand), BAFF (B cell–activating factor of the tumor necrosis factor family), and TGF-β (transforming growth factor β). GI eosinophils expressed a relatively high level of IL-1β, and IL-1β–deficient mice manifested the altered gene expression profiles observed in eosinophil-deficient mice and decreased levels of IgA⁺ cells and ROR-γt⁺ ILCs. On the basis of these collective data, we propose that eosinophils are required for homeostatic intestinal immune responses including IgA production and that their affect is mediated via IL-1β in the small intestine.     

The levels of IL-1β and soluble IL-1 receptors in patients with IgG4-related periaortitis/periarteritis

PurposeIgG4-related disease (IgG4-RD) is a chronic fibrotic inflammatory and an immune-mediated disease characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system, and its pathogenesis and characteristics remain unclear.The inflammatory cytokine IL-1β is involved in a variety of cellular activities including inflammation, fibrosis, and angiogenesis. The present study compared the levels of the inflammatory cytokine IL-1β and two soluble IL-1 receptors, IL-1R1 and IL-1R2, between IgG4-RD patients with and without IgG4-related periaortitis/periarteritis.MethodsThe patients with IgG4-related periaortitis/periarteritis (n ?= ?38), those without (n ?= ?66) and healthy (n ?= ?33) were recruited to measure cytokines of IL-1β and soluble receptors (sIL-1R1 and sIL-1R2) in sera by ELISA assay.ResultsSerum IgG4 was significantly higher in patients with periaortitis/periarteritis compared to non-periaortitis/periarteritis (p ?= ?0.0074), while serum IL-1β was significantly lower in patients with periaortitis/periarteritis (p ?= ?0.00037).The three groups did not show significant difference in sIL1-R1, while sIL-1R2 in the periaortitis/periarteritis and healthy group was higher than in the group without periaortitis/periarteritis (p ?= ?0.00001).ConclusionsThe characteristic changes in IL-1β, sIL-1R1, and sIL-1R2 levels in IgG4-RD patients with and without IgG4-related periaortitis/periarteritis may indicate an active phase of the inflammatory process in these diseases.     

Proinflammatory cytokine IL-1 β polymorphisms in sudden sensorineural hearing loss

The cause and pathogenesis of sudden sensorineural hearing loss (SSNHL) remain unknown. IL-1β is one of the most powerful inflammatory cytokines. The aim of this study was to evaluate the relationships between interleukin-1 β (IL-1β) gene polymorphisms (?511 C/T and +3953 C/T) in patients with SSNHL. One hundred two patients affected by SSNHL and 595 controls were genotyped for IL-1β gene polymorphisms. The polymorphisms were analyzed by polymerase chain reaction amplification and DNA fragment separation via electrophoresis. Compared to controls, the IL-1β (+3953) T allele increased the relative risk of SSNHL in subjects with IL-1β (?511) TT genotype (p = 0.022, OR = 9.111, 95% CI = 1.441–57.618). In this study, polymorphisms in the IL-1β ?511 and IL-1β +3953 loci were assessed for evidence of association with SSNHL. From this assessment, a significant difference in carriage of both the IL-1β ?511 T allele and the IL-1β +3953 T allele was observed between SSNHL and controls. This suggests that the IL-1β ?511 and +3953 loci may play an important role in the etiopathogenesis of SSNHL.     

Blood Serum Levels of IL-2, IL-6, IL-8, TNF-α and IL-1β in Patients on Maintenance Hemodialysis

Cytokines are essential mediators of immune response and inflammatory reactions. Patients with chronic renal failure (CRF) commonly present with abnormalities of immune function related with impaired kidney function and the accumulation of uremic toxins in addition to bioincompatibility of dialyzer membranes. During a hemodialysis (HD) session, cytokines are released mainly by monocytes activated by endotoxin-type compounds in dialyzer fluid, complement factors and direct contact with dialyzer membrane. The study included 15 CRF patients, aged 36.4±2.9 years, on regular HD maintenance therapy for mean 68±10 months and 15 healthy controls. It was designed to assess serum levels of a panel of inflammatory cytokines: IL-1β, IL-2, IL-6, IL-8 and TNF-αin CRF patients on regular maintenance HD before, 20, 60 and 240 minutes of a single HD session in parallel with C-reactive protein (CRP) as an additional parameter. CRP concentration was increased in HD patients when compared with healthy controls. The concentrations of IL-1, IL-6, IL-8 and TNF-αwere increased, whereas the serum level of IL-2 was not altered during a single HD session.     

IL-33 enhances macrophage release of IL-1β and promotes pain and inflammation in gouty arthritis

Inflammation Research - To investigate the role of IL-33 in gouty arthritis. 174 Balb/c (wild-type) and 54 ST2?/? mice were used in this study. In vitro experiments were conducted in...     

Effect of IL-1β Receptor Antagonist on Lipid Peroxidation in the Liver in Stress

The content of molecular LPO products increased in the liver of rats exposed to daily 1-h immobilization. IL-1β receptor antagonist limited the stress-induced intensifi cation of LPO.     

Enhancement of in vivo production of IL-1α and IL-6 in mice by Y-25510, a 1H-pyrazolo[3,4-b]pyridine-1-acetic acid derivative

The serum concentrations of interleukin(IL)-lα and IL-6 in C57BL/6 and C3H/HeN mice reached the maximum at 12–16h after the intravenous treatment with (±)-3-[4-(2-dimethylamino-l-methylethoxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-1-acetic acid (Y-25510) at a dose of 3 mg/kg, and the concentration of IL-10 did at 20h after the treatment. By repeated treatments with Y-25510 to C57BL/6 mice for 14 days, the maximal values of IL-lα and IL-6 at day 14 were respectively 6.6 times and 5.7 times relative to those on day 1. Neither the counts of peripheral leukocytes nor those of platelets were, however, increased until day 15. The repeated treatment with Y-25510 followed by anti-IL-10 antibody for 14 days was significantly more effective than that with Y-25510 alone in increasing the concentrations of IL-lα and IL-6 in C3H/HeN mice. In addition, both the counts of peripheral leukocytes and platelets were significantly increased at day 18. In conclusion, Y-25510 enhanced not only the production of endogenous IL-1α and IL-6 but also that of IL-10 in healthy mice. As a result, in normal conditions, both the counts of peripheral leukocytes and platelets were never increased because of the inhibitory effect of endogenously produced IL-10.