Copper addition prevents the inhibitory effects of interleukin 1-β on rat pancreatic islets

Summary Since copper [Cu(II)] is a necessary cofactor for both intra-mitochondrial enzymes involved in energy production and hydroxyl scavenger enzymes, two hypothesised mechanisms for action of interleukin-Iβ (IL-1β), we studied whether CU(II) addition could prevent the inhibitory effect of IL-1β on insulin release and glucose oxidation in rat pancreatic islets. Islets were incubated with or without 50 U/ml IL-1β, in the presence or absence of various concentrations of Cu(II)-GHL (Cu(II) complexed with glycyl-l-histidyl-l-lysine, a tripeptide known to enhance copper uptake into cultured cells). CuSO₄ (1–1000 ng/ml) was used as a control for Cu(II) effect when present as an inorganic salt. At the end of the incubation period, insulin secretion was evaluated in the presence of either 2.8 mmol/l (basal insulin secretion) or 16.7 mmol/l glucose (glucose-induced release). In control islets basal insulin secretion was 92.0±11.4 pg · islet⁻¹ h⁻¹ (mean ± SEM,n=7) and glucose-induced release was 2824.0±249.0 pg · islet⁻¹ h⁻¹. In islets pre-exposed to 50 U/ml IL-1β, basal insulin release was not significantly affected but glucose-induced insulin release was greatly reduced (841.2±76.9,n=7,p<0.005). In islets incubated with IL-1β and Cu-GHL (0.4 μmol/l, maximal effect) basal secretion was 119.0±13.1 pg · islet⁻¹ h⁻¹ and glucose-induced release was 2797.2±242.2, (n=7,p<0.01 in respect to islets exposed to IL-1β alone). In contrast to data obtained with Cu(II)-GHL, increasing concentrations of CuSO4 (up to 10 μmol/l) did not influence the inhibitory effect of IL-1β on glucose-stimulated insulin release. Glucose oxidation (in the presence of 16.7 mmol/l glucose) was 31.5±2.4 pmol · islet⁻¹·90min⁻¹ in control islets and 7.0±0.9 (p<0.01) in IL-1β-exposed islets. In islets exposed to IL-1β and Cu-GHL glucose oxidation was similar to control islets (31.9±1.9). In contrast, Cu-GHL did not prevent the IL-1β-induced increase in nitric oxide production. Nitrite levels were 5±1.7, 26±5 and to 29±4 pmol · islet⁻¹·48 h⁻¹ (mean ± SEM,n=5) in the culture medium from control IL-1β and IL-1β+Cu-GHL exposed islets, respectively. These data indicate that the Cu(II) complexed to GHL is able to prevent the inhibitory effects of IL-1β on insulin secretion and glucose oxidation, but not on NO production. The mechanism of action of Cu-GHL is still unclear, but it might restore the activity of the enzymatic systems inhibited by IL-1β. [Diabetologia (1995) 38∶39–45]     

Interleukin-1β inhibition of insulin release in rat pancreatic islets: Possible involvement of G-proteins in the signal transduction pathway

Summary In vitro exposure of rat pancreatic beta cells to interleukin-1β (IL-1β) inhibits glucose-stimulated insulin release (2140 ± 239 and 323 ± 80 pg · islet^–1· h^–1 at glucose levels of 16.7 mmol/l in control and IL-1β-exposed islets, respectively, n = 7, p < 0.001). Cholera toxin (2 μg/ml) or pertussis toxin (0.5 μg/ml) potentiated, as expected, glucose-induced insulin release in control islets, but, in addition, when added together with IL-1β, were able to prevent the IL-1β mediated inhibition of glucose-stimulated insulin secretion (2087 ± 301 and 1662 ± 173 pg · islet^–1· h^–1, respectively, p < 0.05 vs islets exposed to IL-1β alone). To investigate the mechanism by which the toxins prevent the IL-1β effect, we then measured nitrite levels, glucose oxidation and Ca^{2 + uptake. Nitrite levels in the culture medium were 4.2}± 1.4 and 24.0 ± 5 pmol · islet^–1· 24 h^–1 in control islets and in IL-1β-exposed islets, respectively (n = 6, p = 0.05). In islets exposed to IL-1β and cholera or pertussis toxins, nitrite levels were 9.1 ± 3 and 12.4 ± 6 pmol · islet^–1· 24 h^–1, respectively (n = 6, NS vs control islets). Glucose oxidation at 16.7 mmol/l glucose was 31.1 ± 2.9 pmol · islet^–1· 120 min^–1 in control islets and 16.8 ± 2.7 pmol · islet^–1· 120 min^–1 in IL-1β-treated islets (p < 0.05). The addition of cholera or pertussis toxins simultaneously to IL-1β prevented the inhibition of glucose oxidation at 16.7 mmol/l glucose (32.9 ± 3.8 and 31.7 ± 3.3 pmol · islet^–1· 120 min^–1 in the presence of cholera or pertussis toxins, respectively). Glucose-stimulated ⁴⁵Ca^{2 + up-take was also significantly inhibited in IL-1}β-treat-ed islets when compared to control islets (7.1 ± 0.9 and 16.8 ± 3.2 pmol · islet^–1· 20 min^–1, respectively, p < 0.05). This inhibition was prevented by the presence of cholera or pertussis toxins (14.0 ± 3.8 and 11.2 ± 2.7 pmol · islet^–1· 20 min^–1, respectively). In conclusion, our data show that cholera and, to a lesser extent, pertussis toxins are able to partially prevent the IL-1β-induced increase in nitrite levels and block the inhibitory effects of IL-1β on different steps leading to glucose-induced insulin secretion. These findings support the possibility that in pancreatic beta cells, G-proteins may be involved or interfere with the cytokine signal transduction. [Diabetologia (1995) 38: 779–784] Received: 20 October 1994 and in revised form: 5 January 1995     

Leptin upregulates beta3-integrin expression and interleukin-1beta, upregulates leptin and leptin receptor expression in human endometrial epithelial cell cultures

Human endometrium and endometrial epithelial cells (EECs) either cultured alone or cocultured with human embryos express leptin and leptin receptor. This study compares the effect of leptin with that of interleukin-1β (IL-1β) on the expression of β3-EEC integrin, a marker of endometrial receptivity. Both cytokines increased the expression of β3-EEC at concentrations in the range of 0.06–3 nM; however, leptin exhibited a significantly greater effect than IL-1β. We also determined the regulatory effects of IL-1β on leptin secretion and on the expression of leptin and leptin receptor at the protein level in both EEC and endometrial stromal cell (ESC) cultures. In EEC cultures, IL-1β upregulated secretion of leptin and expression of both leptin and leptin receptors. No effect of IL-1β was found in the ESC cultures. However, leptin exhibited marginal upregulation of leptin receptor. The upregulation of β3-integrin and leptin/leptin receptor expression by IL-1β in EEC cultures indicates that both cytokines may be implicated in embryonic-maternal cross-talk during the early phase of human implantation. Our present data also raise the possibility that leptin is an endometrial molecular effector of IL-1β action on β3-integrin upregulation. Thus, a new role for leptin in human reproduction as an autocrine/paracrine regulator of endometrial receptivity is proposed.     

Human Lung Fibroblast Response to NGF,IL-1β, and Dexamethsone

It has been shown that lung mast cells, eosinophils, and fibroblasts are receptive to the action of nerve growth factor (NGF) and that NGF is released in to the bloodstream of subjects affected by allergic inflammatory response. The role of NGF in lung inflammatory disorders is unclear because there is evidence suggesting that NGF can be involved in both proinflammatory and anti-inflammatory responses. Lung fibroblasts play a marked role in inflammation. In this study we investigated the effect of NGF, interleukin 1β (II-1β), and dexamethasone (DEX) on human lung fibroblasts in vitro. We found that II-1β, but not NGF, promotes fibroblasts’ survival and that NGF stimulates trkA receptor expression, down regulates TFG-α, and has no effect on TNF-β immunoreactivity. Moreover, DEX exerts different effects on NGF release by fibroblasts pre-exposed to II-1β. Our findings suggest that the NGF released by lung fibroblast during inflammation is not associated with the increase of proinflammatory factors such as TNF-α and II-1β.     

Regulation of complement C3 synthesis by interleukin-1 and transforming growth factor-β in rat non-transformed intestinal epithelial cell line,IEC-6

Intestinal epithelial cells are an important source of many biologically active molecules that modulate immune responses in the mucosa. The purpose of this study was to demonstrate the synthesis of complement C3 component in the rat non-transformed crypt-like intestinal epithelial cell line, IEC-6. Unstimulated IEC-6 cells secreted a low level of C3 protein and showed weak expression of C3 mRNA. The addition of interleukin (IL)-1β induced a dose- and time-dependent increase in C3 production. These effects of IL-1β were observed at a concentration as low as 0.01 ng/ml and reached a plateau at a concentration of 5 ng/ml. The effects were observed at the mRNA level as early as 6 h after the beginning of incubation. Transforming growth factor (TGF)-β alone had no effect. However, TGF-β at low concentrations (0.001–1 ng/ml) enhanced the effect of IL-1β in increasing C3 production; this enhancement was not observed at high concentrations (5–10 ng/ml). These effects of TGF-β were also observed at the mRNA level. The present findings indicate that intestinal epithelial cells are indeed capable of synthesizing complement C3 in response to IL-1β and TGF-β.     

Phytic Acid Modulates In Vitro IL-8 and IL-6 Release from Colonic Epithelial Cells Stimulated with LPS and IL-1β

Phytic acid (PA), a major fiber-associated component of wheat bran and legumes, is physiologically present in the human large gut. The aim of this study was to examine the role of PA in immunologic function of intestinal epithelial cells by analyzing its effect on interleukin (IL)-8 and IL-6 secretion by colonocytes and its role in the response of these cells to bacterial lipopolysaccharides (LPS) and IL-1β. The human colon cell line Caco-2 was exposed to LPS isolated from two strains of Desulfovibrio desulfuricans, wild intestinal and type soil strains, as well as to LPS from E. coli. Cells were also treated with IL-1β and with a combination of LPS and IL-1β. PA had a suppressive effect on IL-8 basal release and it dose dependently reduced IL-8 secretion by colonocytes stimulated with LPS and IL-1β. On the contrary, PA increased constitutive IL-6 secretion and exhibited differentiated effects on LPS responsiveness of cells depending on its concentration and LPS origin. PA was also an efficient down-regulator of IL-6 secretion stimulated by binary actions of LPS and IL-1β. The ability of PA to modulate IL-8 and IL-6 release suggests that PA present in the intestinal milieu may exert immunoregulatory effects on colonic epithelium under physiological conditions or during microbe-induced infection/inflammation in order to maintain the colonic mucosa in a noninflammatory state or to counteract infection.     

Serum levels of interleukin-1β, luteinizing hormone, and prolactin correlate with the expression of CD45 isoforms on CD4+ peripheral blood T lymphocytes in healthy women

 The expected association between age and the CD45 isoforms expression on CD4+ T-PBL is much more obvious in men than in women. We investigated whether or not circulating factors influence the differentiation of CD4+ T-PBL. Peripheral blood samples were obtained from 56 healthy age-matched subjects (28 men and 28 women, 21–55 years old). Mononuclear leukocytes were analyzed by three-color flow cytometry. The serum concentrations of interleukin-1β (IL-1β), interleukin-6, tumor necrosis factor-α (TNF-α), GM colony-stimulating factor, prolactin (Prl), and luteinizing hormone (LH) were determined by ELISA. The expected age-related decrease of naive (CD45RA+,RO–) cells and increase of memory (CD45RA–,RO+) cells among CD4+ T-PBL were observed in men only (p<0.001 and 0.005). In women, these correlations were not significant. On the other hand, in women only, elevated IL-1β was associated with fewer naive and more memory cells among CD4+ T-PBL (p<0.001). In both sexes, IL-1β correlated with the expression of CD25 on CD4+ T-PBL (on either naive or memory cells, p<0.001). Other cytokines or the CD8+ T-PBL showed no significant correlation. In women, the elevation of LH at mid-cycle inversely correlated with the proportion of naive CD4+ T-PBL (p<0.01). Elevated LH was associated with more CD25 on memory CD4+ T-PBL (p<0.01). A significant correlation exists between IL-1β and LH (p<0.001). Furthermore, in both sexes, Prl correlated with the proportion of CD4+ cells among T-PBL. In men, elevated Prl was associated with more naive CD4+ T-PBL (p<0.005), while in women, Prl correlated with more transient CD45RA+, RO+ cells among CD4+ T-PBL and increased TNF-α (p<0.05 for both). Thus, circulating IL-1β could be involved in the expression of CD25 on CD4+ T-PBL and favors the generation of memory CD4+ T-PBL. In women, the IL-1β- and/or mid-cycle-dependent processes seem to overwhelm the age-related changes. Elevated Prl might exert a dual influence: it favors the development of naive CD4+ T lymphocytes and possibly acts in, synergy with other cytokines during immune stimulation. Received: 20 June 1997 / Accepted: 1 August 1997     

Association between interleukin-1β-511C/T polymorphism and reflux esophagitis in Japan

Background Interleukin-1β (IL-1β) gene polymorphisms are related to hypochlorhydria and increase the risk of gastric cancer in the presence of Helicobacter pylori infection. However, little information is available about the genetic risk factors of reflux esophagitis. In this study we investigated its association with the IL-1β polymorphisms. Methods We examined 48 patients with reflux esophagitis and 96 control subjects, 89 with gastric cancer. IL-1β-511C/T genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results The frequency of IL-1β-511T alleles was significantly higher in reflux esophagitis patients (57.3%) than in controls (41.1%) (P = 0.0215, χ² = 5.289). The frequency of IL-1β-511T/T genotypes was also significantly higher in reflux esophagitis patients (31.3%) than in controls (15.6%). The odds ratio and the 95% confidence interval were 4.000 and 1.393–11.486, respectively. The frequency of IL-1β-511T/T genotypes was significantly higher in reflux esophagitis patients (31.3%) than in gastric cancer patients (21.4%). The odds ratio and the 95% confidence interval were 2.961 and 1.054–8.316, respectively. Conclusions IL-1β-511T was associated with reflux esophagitis having hyperacidity. Differences of genetic background regarding gastric acid secretion may exist between Japanese and Caucasians.     

Regulation of expression of cytokines and growth factors in osteoarthritic cartilage explants

Osteoarthritis (OA) is a degenerative joint disease characterised by the breakdown of the extracellular matrix of chondrocytes in the affected joints. Cytokines and growth factors which are known to play a role in the synthesis and degradation of cartilage matrix have been shown to be upregulated in osteoarthritic cartilage. This upregulation resulted in two different phenotypes, overexpressing either TNF-α and IL-6 or IL-1β, TGFβ₁, IL-4 and IL-10. To investigate the hierarchy among growth factors and cytokines involved in cartilage metabolism, we analysed osteoarthritic cartilage explants for their responses to human recombinant (rh) cytokines and growth factors. The cytokine expression patterns of the explants before and after in vitro culture were compared by immunohistological staining of cartilage sections. We found a coordinate expression of TNF-α and IL-6 on the one hand, and of IL-1β, TGFβ₁, IL-4 and IL-10 on the other. Although TNF-α and IL-6 stimulated each other’s expression, they downregulated TGF β₁, IL-4 and IL-10 or IL-1β, TGF β₁ and IFNg, respectively. IL-1β upregulated the expression of TGF β₁, IL-4 and IL-10, and jointly these four cytokines and growth factors downregulated IL-6. Both of the expression patterns described for OA cartilage can be explained by these regulatory mechanisms. Interestingly, no cytokine efficiently downregulated TNF-α, and even though IL-1β is upregulated in one of the OA phenotypes, none of the growth factors and cytokines tested – except for IL-1β itself – seemed capable of mediating this upregulation. This unresponsiveness to cytokine stimulation might hint at a genetic cause for the elevated expression in the respective phenotypes. Received: 15 September 2000 / Accepted: 17 April 2001     

Transforming growth factor-beta1 modulates chondrocyte responsiveness to 17beta-estradiol

This study examined the interrelationship between transforming growth factor-betal (TGF-β1) and 17β-estradiol (E₂) in the regulation of growth plate chondrocytes. To determine whether TGF-β1 modulates chondrocyte response to E₂, we used cells isolated from the resting zone (RC) and growth zone (GC) of costochondral cartilage. Confluent, fourth-passage cultures were pretreated with rhTGF-β1 for 24 h, followed by treatment with E₂ for 24h. The effect of TGF-β1 and E₂ alone, or the sequential combination, were examined by measuring [³H]-thymidine incorporation (proliferation), alkaline phosphatase (AP) specific activity (differentiation), and [³⁵S]-sulfate incorporation (matrix synthesis). TGF-β1 alone increased [³H]-thymidine incorporation in both female and male RC and GC cells, but E₂ affected this parameter only in RC cells, causing a dose-dependent decrease. At the highest concentration of TGF-β1 and E_2′ [³H]-thymidine incorporation in female GC cells was the same as seen in untreated control cultures. In male GC cells, [³H]-thymidine incorporation in cultures treated with TGF-β1 and E₂ exhibited a comparable increase, as was seen in cultures treated with TGF-β1 alone. TGF-β1 caused a biphasic stimulation in AP that was maximal at 0.22 ng/mL, in both female and male RC and GC cells. E_2′ however, affected only female cells. Whereas the effect of TGF-β1 predominated in RC and GC male cells, the biphasic stimulation caused by E₂, maximal at 10⁻⁹ M, predominated in female RC cells. In female GC cells, however, TGF-β1 caused a synergistic response, resulting in enhanced AP specific activity in cultures pretreated with 0.22 ng/mL of TGF-β1 and 10⁻⁸ M E₂. TGF-β1 alone caused dose-dependent increases in [³⁵S]-sulfate incorporation in female RC and GC cells, as well as in male GC cells, but had no effect on male RC cells. E₂ affected only female cells. TGF-β1 potentiated the effect of E₂ on this parameter, resulting in synergistic increases in the female cells. This is the first demonstration of a gender-specific response to TGF-β1 in chondrocytes. These results suggest that chondrocyte response to a systemic hormone such as E₂ can be modulated by local regulatory agents such as TGF-β1.     

Effect of environmental estrogens on IL-1β promoter activity in a macrophage cell line

Environmental estrogens or estrogen disrupters have recently received a great deal of attention because of their potential health impact on reproductive tissues. Few, if any, studies have been made on the impact of these compounds on the immune system. We sought to determine the activities of various environmental estrogens on the modulation of the interleukin-1β (IL-1β) gene in a model monocytic cell line, hER+IL-1β-CAT+. This cell line stably transfected with the human estrogen receptor, and an IL-1β promoter construct fused to the CAT reporter gene allows us to monitor the effect of estrogenic compounds on IL-1β promoter activity. 17β-Estradiol (E₂) markedly enhanced lipopolysaccharide-(LPS) induced IL-1β promoter-driven CAT activity in a dose-dependent manner. The mycotoxins α-zearalenol and zearalenone both exhibited full agonist activity, but at lower potencies, with EC₅₀ values of 1.8 and 54 nM, respectively, compared with E₂ at 0.5 nM. In addition, genistein was a very low-potency agonist, having an EC₅₀ of 1.5 μM. Similar to the E₂ response, the slope factors for α-zearalenol, zearalenone, and genistein were close to 3.0, suggesting positive cooperativity in the estrogenic response. The activity of the mycotoxins appeared to be mediated through the estrogen receptor, since both the antiestrogens H1285 and ICI 182,780 effectively inhibited their agonist activity in a dose-dependent manner. Representative environmental estrogenic compounds both from plant and industrial sources were also tested. Unlike the mycoestrogens, none of the compounds, with the exception of genistein, synergized with LPS to enhance IL-1β promoter activity. When tested for antiestrogenic activity, the industrial compound 4-octylphenol was able to antagonize the response to E₂; however, the response was three orders of magnitude less potent than H1285. Naringenin, a plant flavonoid, showed little or no ability to antagonize the response to E₂. Overall, the results show that some environmental estrogens that display agonist activity in reproductive tissue also have an effect on IL-1 gene expression in hemopoietic-derived tissue.     

Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-α in patients with recent-onset type 1 diabetes

Aims/hypothesis Type 1A diabetes results from autoimmune destruction of pancreatic beta cells. We examined the involvement of TNF-α and IL-1β, as well as of T cells, macrophages and dendritic cells, in the destruction of beta cells in patients with recent-onset type 1 diabetes. Materials and methods We obtained pancreatic biopsy specimens from six patients with recent-onset type 1 diabetes and analysed these by immunohistochemistry. Results T cell infiltration was less common in islets without beta cells (12.5 [0–33.3]%) than in those with beta cells (46.0 [17.4–83.3]%), while macrophages and dendritic cells showed a similar extent of infiltration into islets both with or without beta cells. TNF-α was detected in 25.0 (4.3–46.9)% of macrophages and 11.8 (0–40.0)% of dendritic cells infiltrating the islets in samples from each patient, but not at all in T cells. IL-1β was detected in 1.8 (0–11.3)% of T cells infiltrating the islets with beta cells, while it was found in 19.2 (0–35.3)% of macrophages or 10.7 (0–31.3)% of dendritic cells infiltrating the islets in samples from each patient (all values median [range]). Conclusions/interpretation Macrophages and dendritic cells infiltrate the islets and produce inflammatory cytokines (TNF-α and IL-1β) during the development of type 1A diabetes.     

Protective effects of phytoestrogen alpha-zearalanol on beta amyloid25-35 induced oxidative damage in cultured rat hippocampal neurons

Although experimental evidence has shown that the neuroprotective effect from estrogen may benefit postmenopausal women, but the clinical use of estrogen was limited by the risk of increasing the cases of mammary and endometrial cancer. This study was designed to evaluate the neuroprotective effects of a novel phytoestrogen α-zearalanol (α-ZAL), on the cultured rat hippocampal neurons. Following a 24-h exposure of the cells to amyloid β-peptide fragment 25–35 (Aβ_25–35), a significant reduction in cell survival and activities of total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as increased of malondialdehyde (MDA) were observed. Preincubation of the cells with α-ZAL or 17β-estradiol(17β-E2) prior to Aβ_25–35 exposure elevated the cell survival and SOD and GSH-Px activities, and decreased the level of MDA. These data suggested that the phytoestrogen α-ZAL, like estrogen, may effectively antagonize Aβ_25–35-induced cell toxicity, which might be beneficial for neurons.     

Suppressive effect of ethanol on the expression of hepatic asialoglycoprotein receptors augmented by interleukin-1β, interleukin-6, and tumor necrosis factor-α

Blood levels of inflammatory-related cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, are elevated in patients with alcoholic liver diseases. We investigated the effects of these cytokines and ethanol on the expression of hepatic asialoglycoprotein receptors (AGPRs) in a human hepatoblastoma cell line, HepG2. An [¹²⁵I]-asialo-orosomucoid binding assay showed significant increases in surface AGPR numbers in HepG2 cells by treatment with IL-1β, IL-6, and TNF-α, to levels which were approximately 130% of the values in untreated control cells. However, the enhanced AGPR numbers induced by treatment with these cytokines were markedly suppressed, to 70%–80% of the number in the untreated cells, by treatment with ethanol. Immunological detection of AGPR with a specific antibody demonstrated that the modulation of surface AGPR numbers was correlated with the cellular expression levels of AGPR. These results suggest that, although IL-1β, IL-6, and TNF-α stimulate the synthesis of hepatic AGPR, ethanol suppresses the expression of AGPR augmented by these cytokines. This leads to an increase in serum asialo-orosomucoid levels caused by the disordered catabolism mediated by AGPR in patients with alcoholic liver disease. (Received Dec. 5, 1997; accepted May 22, 1998)     

Detection of anti-recombinant ββ2-glycoprotein 1 and anti-recombinant ββ2-glycoprotein 1 fifth-domain antibodies in sera from patients with systemic lupus erythematosus

Two kinds of plasmid expression vectors which expressed β ₂-glycoprotein 1(β ₂GP1) and the fifth domain of β ₂-glycoprotein 1 (β ₂GP1-D5) were constructed respectively in this study. The antigenicity of recombinant β ₂GP1 (rβ ₂GP1) and β ₂GP1-D5 (rβ ₂GP1-D5) was identified by immunoblots using rabbit anti-β ₂GP1 antibodies, and the recombinant proteins were purified. Both anti-rβ ₂GP1 and anti-β ₂GP1-D5 antibodies in 112 patients were detected by ELISA using rβ ₂GP1 and rβ ₂GP1-D5 as coating antigens. A significant statistical correlation (r=0.667, P<0.01) between the levels of anti-β ₂GP1 and anticardiolipin (ACL) antibodies was found. The presence of anti-rβ ₂GP1 antibodies was associated with an increased frequency of history of thrombosis and/or recurrent abortion; hence anti-rβ ₂GP1 assay provided better specificity than conventional ACL assay. Detection of anti-rβ ₂GP1 antibodies may be of potential value in evaluating the risk of thrombosis and/or symptoms associated with other antiphospholipid syndromes (APS). The binding of anti-rβ ₂GP1 from the sera of patients with APS to rβ ₂GP1 was inhibited by rβ ₂GP1-D5. Meanwhile, of 28 patients who had positive anti-rβ ₂GP1 antibodies in sera, 27 (96.4%) had positive anti-rβ ₂GP1-D1 antibodies. This indicated that the antigenic epitope of β ₂GP1 may be located in its fifth domain. Received: 10 November 1997 / Accepted: 2 March 1998     

The preventive factors for aspirin-induced peptic ulcer: aspirin ulcer and corpus atrophy

Purpose  Interleukin-1β (IL-1β) polymorphisms are associated with peptic ulcer and atrophic gastritis. This study aimed to examine effects of corpus atrophy and the genotypes of genes related to peptic ulcer, including IL-1β, on risk of aspirin ulcer. Methods  232 patients taking 100 mg of aspirin for cardiovascular diseases, of whom 40 had peptic ulcer, were enrolled. IL1β, interleukin-1 receptor antagonist (IL-1RN), tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-1, cytochrome p450 2C9 (CYP2C9), UDP-glucuronosyltransferase (UGT1A6) genotypes were determined, and serum pepsinogen levels were measured. Results  The polymorphisms of IL-1β-511/-31 were significantly associated with peptic ulcer, but other genotypes were not. Serum pepsinogen I and II levels and I/II ratio were significantly higher in the ulcer group than in the non-ulcer group. Taking PPI [adjusted odds ratio (OR), 0.09; 95% confidence interval (CI), 0.02–0.39], pepsinogen I of less than 50 ng/ml (OR, 0.24; 95% CI, 0.10–0.56) and IL-1β-511 T carrier (OR, 0.42; 95% CI, 0.18–0.93) were significantly associated with peptic ulcer. Conclusions  Hypoacidity related to corpus atrophy as well as taking PPI seems to be preventively associated with development of peptic ulcer among low dose aspirin users.     

Vascular endothelial growth factor is upregulated by interleukin-1β in human vascular smooth muscle cells via the P38 mitogen-activated protein kinase pathway

Small tumor vessels are composed of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). These cells have been shown to communicate with each other via cytokine signaling during neovascularization. We previously demonstrated that interleukin-1β (IL-1β) leads to induction of vascular endothelial growth factor (VEGF) in human colon carcinoma cells. As pericytes play a role in regulating EC function, we hypothesized that IL-1β may mediate EC survival by induction of VEGF in a paracrine manner. We investigated the effects of IL-1β on VEGF expression in human VSMCs (hVSMCs) and the signal transduction pathways that may be involved. Treatment of hVSMCs with IL-1β induced VEGF expression in a time- and concentration-dependent manner and increased both the VEGF promoter activity and the mRNA half-life. Treatment with IL-1β induced the expression of P38 mitogen-activated protein kinase (MAPK) within 5 min but did not activate extracellular signal-regulated kinases (Erk)-1/2, c-jun amino terminal kinase (JNK), or Akt. SB203580, a specific P38 MAPK inhibitor, blocked the ability of IL-1β to induce VEGF mRNA and promoter activity. Conditioned media from hVSMCs pretreated with IL-1β prevented apoptosis of ECs, an effect that was partially abrogated by VEGF-neutralizing antibodies. These data demonstrate that IL-1β may induce VEGF in hVSMCs, and suggest that this paracrine signaling pathway, may prevent, in part, apoptosis of ECs. This revised version was published online in June 2006 with corrections to the Cover Date.