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PubMed1999

Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment.

The effects of systemically administered interleukin-1beta (1.0 microg), interleukin-6 (1.0 microg) and interleukin-2 (1.0 microg) on in vivo variations of monoamines were assessed in the nucleus accumbens. Administration of interleukin-1beta did not affect extracellular accumbal dopamine, provoked a modest rise of homovanillic acid, and prevented the decline of dihydroxyphenylacetic acid ordinarily seen in saline treated rats. Also, interleukin-1 provoked a modest increase of extracellular 5-hydroxyindoleacetic acid from the nucleus accumbens. Following exposure to the stress of a series of air-puffs, a still greater increase of accumbal 5-hydroxyindoleacetic acid was evident. In contrast to interleukin-1, systemic administration of interleukin-6 and interleukin-2 both induced marked reductions of interstitial dopamine levels. The air-puff exposure further enhanced these effects in rats that had received the cytokine treatment. As well, interleukin-6 and interleukin-2 were both found to reduce the homovanillic acid response associated with the stress, and interleukin-2 promoted a decline of homovanillic acid levels. Treatment with interleukin-6, like that of interleukin-1, prevented the decline of dihydroxyphenylacetic acid ordinarily observed over time, while interleukin-2 was without effect in this respect. Finally, interleukin-6 provoked a modest rise of 5-hydroxyindoleacetic acid, which was most apparent following air-puff exposure, while administration of interleukin-2 did not affect accumbal 5-hydroxyindoleacetic acid. It is suggested that the cytokines may influence the release of biogenic amines in the nucleus accumbens, but the profile of changes were cytokine-specific. As well, it appeared that the cytokines, particularly interleukin-1 and interleukin-6, may act synergistically with the stressor in promoting the amine variations. Systemic administration of cytokines clearly influenced monoamine activity at the nucleus accumbens, a region associated with both rewarding and aversive events. Thus, it may be expected that cytokine treatments may affect behavior. Moreover, it seems that the effects of interleukin-1 and interleukin-6 may be influenced by the presence of stressful stimuli. It ought to be underscored that although cytokines share features with the effects of stressors, most notably the variations of hypothalamic-pituitary-adrenal hormones, the pattern of central neurochemical changes elicited by the cytokines could be distinguished from the amine variations ordinarily associated with stressors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2005

Acute CD4+ T lymphocyte-dependent interleukin-1-driven arthritis selectively requires interleukin-2 and interleukin-4, joint macrophages, granulocyte-macrophage colony-stimulating factor, interleukin-6, and leukemia inhibitory factor.

OBJECTIVE: To further investigate the effects of interleukin-1 (IL-1) in immune-mediated joint inflammation, we examined the role of IL-2, Th1 interferon-gamma (IFNgamma), and Th2 (IL-4) cytokines, joint macrophages, and macrophage-derived cytokines (IL-12 p40, IL-6, leukemia inhibitory factor [LIF], oncostatin M [OSM], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in a CD4+ T lymphocyte-dependent model of acute arthritis. METHODS: Methylated bovine serum albumin (mBSA)/IL-1-induced arthritis was elicited in wild-type, gene-knockout, and monoclonal antibody-treated mice. Synovial lining macrophages were selectively depleted by intraarticular injection of clodronate liposomes prior to disease induction. The severity of arthritis was assessed histologically. RESULTS: Mice deficient in IL-2 were almost completely protected from arthritis, and neutralization of IL-4 reduced the severity of disease. In contrast, arthritis severity and resolution appeared to be independent of IFNgamma. Synovial lining macrophage depletion markedly reduced arthritis severity. IL-6 or LIF deficiency was only modestly protective, although as previously reported, GM-CSF deficiency conferred profound disease resistance. IL-12 p40-deficient mice (which lack IL-12 and IL-23) and OSM receptor-deficient mice were susceptible to mBSA/IL-1-induced arthritis. CONCLUSION: Acute mBSA/IL-1-induced arthritis is dependent on IL-2 and IL-4, but not IFNgamma. In vivo, the Th1/Th2 paradigm may be distorted by the presence of macrophage-derived cytokines such as IL-1. Synovial lining macrophages are essential in mBSA/IL-1-induced arthritis. However, the requirement for macrophage-derived cytokines is selective; that is, IL-6, LIF, and especially GM-CSF are necessary, but IL-12, IL-23, and OSM are dispensable. IL-1 may therefore influence both adaptive and innate immune mechanisms in acute inflammatory arthritis.

Acute Disease↗

PubMed1999

Interleukin-4 regulation of human monocyte and macrophage interleukin-10 and interleukin-12 production. Role of a functional interleukin-2 receptor gamma-chain.

Interleukin-4 (IL-4) is the prototypic type 2 immunoregulatory cytokine that can suppress the production of many monocyte and macrophage pro-inflammatory mediators. In this study we investigated the regulation by IL-4 of IL-12 and IL-10 production. While IL-4 suppressed lipopolysaccharide (LPS)-induced IL-12 and IL-10 production by human peripheral blood monocytes, IL-4 suppressed LPS-induced IL-12, but not IL-10, production by synovial fluid mononuclear cells from patients with rheumatoid arthritis. IL-4 also suppressed IL-12, but not IL-10 production, by LPS-stimulated in vitro monocyte-derived macrophages. Similarly, IL-4 cannot suppress LPS-induced tumour necrosis factor-alpha (TNF-alpha) production by synovial fluid cells and monocyte-derived macrophages. The failure of IL-4 to regulate IL-10 production is not due to the failure of IL-4 to suppress TNF-alpha, and vice versa. The data suggest that the IL-4 receptor subunit, gammac, is essential for IL-4 regulation of LPS-induced IL-10 production and that a correlation exists between duration of monocyte culture, reduction in gammac mRNA in cultured cells and hyporesponsiveness of monocyte-derived macrophages to IL-4 for regulation of LPS-induced IL-10 production. This study highlights the importance of investigating responses to IL-4, as a potential therapeutic anti-inflammatory agent, by cells isolated from inflammatory sites and not by the more easily accessible blood monocytes. This study emphasizes the involvement of signalling from gammac in IL-4 regulation of LPS-induced IL-10 production by monocytes and macrophages.

Arthritis, Rheumatoid↗

PubMed1992

Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma.

OBJECTIVE: To determine whether interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-4, interferon-gamma (IFN gamma), IL-6, and tumor necrosis factor alpha (TNF alpha) are detected more frequently in sera from scleroderma patients than in sera from controls. METHODS: Serum concentrations of these cytokines were measured in 78 scleroderma patients and 73 controls, using enzyme-linked immunosorbent assay, radioimmunoassay, and bioassay techniques. RESULTS: IL-2, IL-4, and IL-6 were each detected more frequently in sera from scleroderma patients than in sera from controls. TNF alpha and IL-1 alpha were found with equal frequency in patient and control sera. IL-1 beta and IFN gamma were not detected in any sera. CONCLUSION: IL-2, IL-4, and IL-6 may be among the cytokines that contribute to the disease process in scleroderma patients. To our knowledge, this is the first report of elevated serum IL-4 levels in human disease.

Adolescent↗

PubMed1995

Induction of circulating interleukin 10 by interleukin 1 and interleukin 2, but not interleukin 6 immunotherapy.

The objective of this study was to investigate the in vivo production of interleukin 10 (IL-10) in cancer patients undergoing immunotherapy with IL-1 alpha, IL-2 or IL-6 and to study the effect of the same cytokines on the in vitro synthesis of IL-10 by human monocytes and macrophages. In the IL-1 alpha clinical trial, patients received 0.03 g/kg of IL-1 alpha as a 30 minute infusion daily for 5 consecutive days. In these patients, plasma IL-10 levels rose rapidly and peaked within 1 h (121 +/- 16 pg/mL; n = 4) after the first IL-1 alpha infusion. Thereafter, the levels rapidly declined to baseline within 8 h. The peak plasma IL-10 levels measured on days 3 and 5 of therapy were somewhat less pronounced than those on day 1. IL-2 immunotherapy was also associated with the induction of circulating IL-10. These patients were treated with high-dose (6 x 10(5) IU/kg) IL-2 every 8 h for 5 consecutive days. IL-10 was detectable in these patients within 2-4 h after the first IL-2 infusion (105 +/- 12 pg/mL). In contrast to the transient bursts of IL-10 detected in patients treated with IL-1 alpha, IL-10 levels progressively increased throughout the treatment course in the IL-2-treated patients reaching peak levels on day 5 (240 +/- 22 pg/mL; n = 10). IL-6 immunotherapy with a 5-day continuous infusion was not associated with detectable levels of circulating IL-10. Peripheral blood mononuclear cells and in vitro-derived macrophages synthesized similar amounts of IL-10 after stimulation with IL-1 alpha or IL-2, but were unresponsive to IL-6. These results suggest that the proinflammatory cytokines IL-1 alpha and IL-2 induce the anti-inflammatory cytokine IL-10 in vitro and in vivo, whereas Il-6 is not able to stimulate IL-10 synthesis.

Humans↗

PubMed2006

Evidence for interleukin-1-independent stimulation of interleukin-12 and down-regulation by interleukin-10 in Helicobacter pylori-infected murine dendritic cells deficient in the interleukin-1 receptor.

Helicobacter pylori infection is characterized by infiltration of cells of the immune system, including dendritic cells, into the gastric mucosa. During chronic inflammation with Helicobacter pylori infection, a variety of cytokines are secreted into the mucosa, including interleukin-1beta (IL-1beta). The role of IL-1 in H. pylori infection was investigated using bone-marrow-derived dendritic cells from wild-type and IL-1 receptor-deficient (IL-1R-/-) mice. Dendritic cells were incubated with H. pylori at a multiplicity of infection of 10 and 100, and cytokine production evaluated. Helicobacter pylori SS1, H. pylori SD4, and an isogenic cagE mutant of SD4 stimulated IL-12, IL-6, IL-1beta, IL-10, and tumor necrosis factor-alpha at comparable levels in dendritic cells from both wild-type and IL-1R-/- mice. IL-10 production required the higher inoculum, while IL-12 was decreased at this bacterial load. Pretreatment of dendritic cells with an antibody to IL-10 resulted in an increased production of IL-12, confirming the down-regulation of IL-12 by IL-10. cagE was required for maximum stimulation of IL-12 by H. pylori. We speculate that the down-regulation of IL-12 by IL-10 at the higher multiplicity of infection represents the modulation of the host inflammatory response in vivo by H. pylori when the bacterial load is high, allowing for persistent colonization of the gastric mucosa.

Animals↗

PubMed2000

Human intestinal epithelial cells secrete interleukin-1 receptor antagonist and interleukin-8 but not interleukin-1 or interleukin-6.

BACKGROUND: There is growing evidence that intestinal epithelial cells (IECs) are involved in the mucosal immune system. AIM: To assess the pattern of cytokines secreted by IECs and lamina propria mononuclear cells (LPMNCs). To achieve this, the expression and secretion of interleukin (IL)-1, IL-1 receptor antagonist (IL-1ra), IL-6, and IL-8 in human primary colonic and ileal IECs and LPMNCs from the same patient were studied. METHODS: IECs and LPMNCs were isolated from surgical specimens or endoscopic biopsy samples. mRNA expression was investigated by northern blot analysis. Secretion of IL-1beta, IL-6, IL-8, and IL-1ra was measured by enzyme linked immunosorbent assay. RESULTS: IL-1ra mRNA levels were higher in IECs than in LPMNCs in all probands. IL-8 mRNA was only present in low amounts in the IECs from two controls. In none of the specimens were IL-1beta and IL-6 mRNA present in IECs. Transcripts encoding IL-1beta, IL-1ra, IL-6, and IL-8 were identified in LPMNC preparations of all specimens. IECs from normal mucosa produced no detectable amounts of IL-1beta or IL-6, whereas LPMNCs did. IECs secreted some IL-8 (65 (9) pg/10(5) cells) but significantly more was generated by LPMNCs (408 (43) pg/10(5) cells, p<0.0001). However, IECs secreted more IL-1ra than did LPMNCs (120 (12) v 94 (11) pg/10(5) cells). In acute inflammation, IEC IL-1ra secretion was significantly increased. A correlation between secreted IL-1ra and the macroscopical degree of inflammation was found in Crohn's disease (r = 0.64, p<0.0001, n = 36) and ulcerative colitis (r = 0. 76, p<0.0001, n = 24). CONCLUSIONS: IECs from normal mucosa express and secrete IL-1ra and low amounts of IL-8, but no IL-1 or IL-6. In inflamed mucosa the secretion of IL-1ra by IECs is slightly increased but may be not sufficient to antagonise the greatly increased production of proinflammatory cytokines by LPMNCs and the IECs themselves.

Epithelial Cells↗

PubMed2002

Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain.

The biologic activities of interleukin (IL)-13 and IL-4 often overlap, and evidence supports their importance in atopic disease and airways hyperresponsiveness. Here, their capacity to release eosinophil-activating cytokines was examined in cultured human airway smooth muscle. IL-13 and IL-4 induced selective release of eotaxin with no effect on granulocyte-macrophage colony-stimulating factor, regulated upon activation, normal T-cell expressed and secreted (RANTES), or IL-8. A profound synergistic increase in eotaxin release occurred when IL-13 or IL-4 was combined with IL-1beta that was abrogated by a neutralizing antibody to the IL-4 receptor alpha (IL-4Ralpha)-chain but not to the IL-2 receptor gamma (IL-2Rgamma)-chain. Expression of cell surface IL-4 receptors and IL-4Ralpha in lysates was constitutive and unchanged by treatment with IL-13 or IL-4 alone or in combination with IL-1beta. Activation of IL-4Ralpha by IL-13 or IL-4 induced signal transducer and activation of transcription-6 (STAT6), p42/ p44 ERK, p38, and to a lesser extent, SAPK/JNK mitogen-activated protein kinase phosphorylation. STAT6 and MAP kinase activation by IL-13 or IL-4 was not further potentiated after combined stimulation with IL-1beta. However, eotaxin release induced by IL-13 or IL-4 alone, and in combination with IL-1beta, was prevented by the MEK inhibitor U 0126 and by the p38 inhibitor SB 202190. Collectively, the data suggest that selective eotaxin release induced either by IL-13 and IL-4 or when combined with IL-1beta is mediated by a constitutive cell surface IL-4Ralpha and the activation of multiple intracellular pathways.

Adult↗

PubMed1998

Interleukin-5 mRNA stability in human T cells is regulated differently than interleukin-2, interleukin-3, interleukin-4, granulocyte/macrophage colony-stimulating factor, and interferon-gamma.

Interleukin-5 (IL-5) transcriptional activation and mRNA stability were investigated in a human TH0 T-cell clone (SP-B21) and in nonclonal CD4 TH2 cells, differentiated in vitro from peripheral blood T cells. Cells were stimulated with alpha-CD3 monoclonal antibody (mAb) with and without alpha-CD28 mAb. Comparison to other cytokine genes revealed aspects of mRNA regulation unique to IL-5. The half-life (t1/2) of IL-5 mRNA, determined by addition of actinomycin D (ActinoD) or cyclosporin A (CSA) was longer (by >= 2 h) than that of IL-2, IL-3, IL-4, interferon-gamma, or granulocyte/macrophage colony-stimulating factor. With the exception of IL-5, t1/2 values were significantly shorter with CSA as the transcriptional inhibitor than with ActinoD. The t1/2 value of IL-5 mRNA, but not the other cytokine transcripts, determined with either ActinoD or CSA, was longer than predicted from the kinetics of steady-state mRNA decline. Co-stimulation of both cell types with alpha-CD28 mAb increased the stability of cytokine transcripts weakly, and IL-5 remained the most stable transcript. Thus, the degradation pathway that targets IL-5 is distinct from the other cytokine transcripts measured and involves proteins whose transcription is blocked by ActinoD and CSA. From examination of the levels of transcription initiation (nuclear run-on assay) and steady-state mRNA attained in cultures stimulated in the presence of the protein synthesis inhibitor, cycloheximide, only IL-5 transcription initiation had an absolute dependency on new protein synthesis.

Antibodies, Monoclonal↗

PubMed1994

Design of human interleukin-4 antagonists inhibiting interleukin-4-dependent and interleukin-13-dependent responses in T-cells and B-cells with high efficiency.

Human interleukin-4 possesses two distinct sites for receptor activation. A signalling site, comprising residues near the C-terminus on helix D, determines the efficacy of interleukin-4 signal transduction without affecting the binding to the interleukin-4 receptor alpha subunit. A complete antagonist and a series of low-efficacy agonist variants of human interleukin-4 could be generated by introducing combinations of two or three negatively charged aspartic acid residues in this site at positions 121, 124, and 125. One of the double variants, designated [R121D,Y124D]interleukin-4, with replacements of both Arg121 and Tyr124 by aspartic acid residues was completely inactive in all analysed cellular responses. The loss of efficacy in [R121D,Y124D]interleukin-4 is estimated to be larger than 2000-fold. Variant [R121D,Y124D]interleukin-4 was also a perfect antagonist for inhibition of interleukin-13-dependent responses in B-cells and the TF-1 cell line with a Ki value of approximately 100 pM. In addition, inhibition of both interleukin-4-induced and interleukin-13-induced responses could be obtained by monoclonal antibody X2/45 raised against interleukin-4Rex, the extracellular domain of the interleukin-4 receptor alpha subunit. These results indicate that efficient interleukin-4 antagonists can be designed on the basis of a sequential two-step activation model. In addition, the experiments indicate the functional participation of the interleukin-4 receptor alpha subunit in the interleukin-13 receptor system.

Antibodies, Monoclonal↗

PubMed1999

Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: relationship to occurrence and severity of rheumatoid arthritis.

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.

Arthritis, Rheumatoid↗

PubMed1990

Accessory cell-derived helper signals in human T-cell activation with phytohemagglutinin: induction of interleukin 2-responsiveness by interleukin 6, and production of interleukin 2 by interleukin 1 [corrected].

Interleukins (IL-) 1 and 6 have been shown to represent accessory signals for T-cell activation. In the present study, we further examined the effects of both cytokines on accessory cell-depleted human T cells stimulated with phytohemagglutinin (PHA). The addition of IL-6 to the cultures resulted in T-cell proliferation; however, IL-1 was unable to support PHA-induced T-cell growth. The addition of IL-1 consistently induced a low level of IL-2 production and strongly enhanced T-cell proliferation in the presence of IL-6. Thus, the effect of IL-1 on T-cell growth becomes apparent only in the presence of IL-6. Blocking the IL-2-receptor (IL-2R) with the monoclonal antibodies anti-Tac and MikBêta 1 (directed to the alpha and bêta chains of the IL-2R, respectively) had no effect on PHA/IL-6-supported proliferation, but completely eliminated the growth-enhancing effect of IL-1. On the other hand, a neutralizing anti-IL-4-antiserum did not affect PHA/IL-6- or PHA/IL-6/IL-1-induced proliferation. Further experiments showed that IL-6 enhances T-cell responsiveness to IL-2, as evidenced by enhanced IL-2-induced proliferation. However, we could not find an effect of IL-6 on the expression of IL-2R as measured by staining with anti-Tac and with MikBêta 1 or by binding of (125I)-IL-2 to T cells. It can be concluded from these studies that IL-1 and IL-6 have different helper effects on PHA-induced T-cell activation. In the presence of PHA, IL-6 induces limited IL-2/IL-4-independent growth, and more importantly it renders T cells responsive to IL-2. IL-1 provides a signal leading to IL-2 production. The combination of IL-1 and IL-6 represents a synergistic helper signal, leading to an IL-2-dependent pathway of proliferation.

Antigen-Presenting Cells↗

PubMed2002

Interleukin-6 promotes the production of interleukin-4 and interleukin-5 by interleukin-2-dependent and -independent mechanisms in freshly isolated human T cells.

T helper 2 (Th2) cytokines [interleukin (IL)-4 and IL-5] play a central role in the development of allergic immune responses. After allergen provocation, the expression of Th2 cytokines is rapidly up-regulated in atopy and asthma. IL-6 is a multifunctional cytokine that is able to direct Th2 immune responses and is secreted by multiple tissue cell types. This study shows that IL-6 induces up-regulation of IL-4 and IL-5 after short (5 min) preincubation periods in freshly isolated, alpha-CD3/alpha-CD28-stimulated T cells. After longer preincubation periods with IL-6 (12 and 24 hr), the priming effect on IL-4 production gradually disappears, whereas the effect on IL-5 becomes more pronounced. In contrast, a small but significant inhibitory effect is found on the production of the Th1 cytokine interferon-gamma. Additional experiments indicate that the long-term priming effect of IL-6 on IL-5 production is dependent on IL-2 signalling. This is not the case for the short-term IL-6 effect on IL-5 secretion, where the p38 mitogen-activated protein kinase-dependent induction of activator protein-1 DNA-binding activity is involved, independent of signal transducer and activator of transcription 3 phosphorylation. In summary, these data demonstrate that the short-term and long-term priming effects of IL-6 on Th2 cytokine production are regulated by different mechanisms.

Cell Culture Techniques↗

PubMed2006

Role of interleukin-17 and interleukin-17-induced cytokines interleukin-6 and interleukin-8 in unstable coronary artery disease.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease and interleukins are considered to play a key role in the chronic vascular inflammatory response that is typical of atherosclerosis. The serum levels of several of these cytokines have been found to positively correlate with coronary arterial disease and its sequelae. AIM: The aim of our study was to evaluate the levels of a comparatively new cytokine IL-17, in patients with stable and unstable coronary artery disease in order to assess whether unstable coronary artery disease patients had higher IL-17 levels. MATERIALS AND METHODS: We analyzed the concentrations of IL-17, IL-6, IL-8 and IL-10 using enzyme-linked immunosorbent assay and heat-sensitive C-reactive protein using latex particle-enhanced immunoturbidimetry in 58 consecutive unselected patients divided into three groups: stable angina (n=14), unstable angina (n=24) and acute myocardial infarction (n=20). We further compared them with 20 healthy controls. These 58 patients were also angiographically studied and divided into two groups: simple lesion (n=22) and complex lesion (n=36), on the basis of the coronary plaque morphology. RESULTS: Our results show increased concentrations of the proinflammatory cytokines IL-17, IL-6, IL-8 and heat-sensitive C-reactive protein, and decreased concentration of IL-10 in plasma of unstable angina and acute myocardial infarction patients. Plasma concentration of IL-17 was also positively correlated with plasma concentrations of IL-6 and heat-sensitive C-reactive protein. Our findings further showed that IL-17 values were higher in patients having angiographically visible complex types of lesions but no difference was observed between complex and simple lesion morphology patients. CONCLUSION: In conclusion, these findings point towards a role of inflammation in the form of increased activity of IL-17, IL-6 and IL-8 in patients of unstable angina and acute myocardial infarction and thus suggest that IL-17-driven inflammation may play a role in the promotion of clinical instability in patients with coronary artery disease.

Angina, Unstable↗

PubMed2005

Lack of association of genetic polymorphisms in the interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 genes with risk of rheumatic heart disease in Taiwan Chinese.

Inflammation and genetics may play a role in the pathogenesis of rheumatic heart disease (RHD). The aim of this study was to test whether interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1Ra), IL-4, or IL-10 gene polymorphisms could be used as markers of susceptibility to or severity of RHD among the Chinese population in Taiwan. A group of 115 patients with RHD diagnosed by echocardiography, and 163 age- and sex-matched normal control subjects were studied. IL-1beta promoter, IL-1beta exon 5, IL-1Ra, IL-4 promoter, IL-4 intron 3, and IL-10 gene polymorphisms were identified by polymerase chain reaction-based restriction analysis. There was no significant difference in the distribution of genotypes and allelic frequencies between RHD cases and controls for IL-1beta promoter, IL-1beta exon 5, IL-1Ra, IL-4 promoter, IL-4 intron 3, and IL-10 gene polymorphisms. Further categorization of the RHD patients into mitral valve disease and combined valve disease subgroups also revealed no statistical difference in these gene polymorphisms when compared with controls. These findings suggest that the IL-1beta, IL-1Ra, IL-4, or IL-10 gene polymorphisms are not suitable genetic markers for RHD in Taiwan Chinese.

Adult↗

PubMed2003

Lack of association of genetic polymorphisms in the interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4 and interleukin-10 genes with mitral valve prolapse in Taiwan Chinese.

BACKGROUND AND AIMS OF THE STUDY: Inflammation and genetics may play a role in the pathogenesis of mitral valve prolapse (MVP). The study aim was to test whether 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 MVP among the Chinese population in Taiwan. METHODS: A group of 100 patients with MVP diagnosed echocardiographically, and 103 age- and sex-matched normal control subjects was studied. IL-1beta promoter, IL-1beta exon 5, IL-1Ra, IL-4 promoter, IL-4 intron 3 and IL-10 gene polymorphisms were identified by polymerase chain reaction-based restriction analysis. RESULTS: There was no significant difference in the distribution of genotypes and allelic frequencies between MVP cases and controls for IL-1beta promoter, IL-1beta exon 5, IL-1Ra, IL-4 promoter, IL-4 intron 3 and IL-10 gene polymorphisms. Further categorization of MVP patients into mild and severe subgroups also revealed no statistical difference in these gene polymorphisms when compared with controls. CONCLUSION: These findings suggest that the IL-1beta, IL-1Ra, IL-4 or IL-10 gene polymorphisms are not suitable genetic markers of MVP in Taiwan Chinese.

Adolescent↗

PubMed1995

Interleukin-10 downregulates proliferation and expression of interleukin-2 receptor p55 chain and interferon-gamma, but not interleukin-2 or interleukin-4, by parasite-specific helper T cell clones obtained from cattle chronically infected with Babesia bovis or Fasciola hepatica.

Human recombinant interleukin-10 (IL-10) was previously shown to inhibit accessory cell (AC)-dependent proliferation of bovine parasite-specific T helper 1 (Th1), Th2, and Th0 cells in an IL-2-reversible manner (Brown, W.C., Woods, V.M., Chitko-McKown, C.G., Hash, S.M., and Rice-Ficht, A.C., 1994. Infect. Immun. 62, 4697-4708). The present study was therefore designed to determine whether the effect of IL-10 on T cell proliferation corresponded with downregulated expression of cytokines, or their receptors, important for T cell growth. The effects of IL-10 on cellular proliferation and expression of IL-2, IL-4, IL-2 receptor (IL-2R; p55), and IFN-gamma by Babesia bovis- or Fasciola hepatica-specific Th cell clones were simultaneously evaluated. As shown previously, IL-10 strongly inhibited proliferation of all types of Th cell clones, although this did not correspond with reduced expression of IL-2 or IL-4 mRNA or their products. In contrast, expression of IL-2R mRNA was consistently reduced in the IL-10-treated clones. These results indicate that IL-10 does not inhibit AC-dependent proliferation of bovine Th cells by downregulating T cell cytokines; rather, IL-10 may act by downregulating IL-2R p55 expression and subsequent signal transduction leading to decreased cellular proliferation. IFN-gamma production was also consistently downregulated in the presence of IL-10.

Animals↗

PubMed1993

Regulation of interleukin-1ra, interleukin-1 alpha, and interleukin-1 beta production by human alveolar macrophages with phorbol myristate acetate, lipopolysaccharide, and interleukin-4.

Human alveolar macrophages (AM) are antigen-presenting cells that have an important immune effector function in the lung. We have previously shown that AM produce a specific interleukin-1 (IL-1) inhibitor of 20 to 25 kD that blocks biologic activities of IL-1 alpha and IL-1 beta such as prostaglandin E2 production by fibroblasts. This inhibitor acts as a receptor antagonist (IL-1ra) by binding to the IL-1 receptor. We are now presenting evidence that the natural AM-derived IL-1ra is immunologically identical to IL-1ra cloned from human peripheral blood monocytes and shows a band at 20 kD compatible with the natural glycosylated IL-1ra. No constitutive expression of IL-1 mRNA was detected when analyzed by Northern blot immediately after bronchoalveolar lavage from six control patients. Comparison of in vitro kinetics of IL-1ra, IL-1 alpha, and IL-1 beta analyzed during culture in the presence or absence of phorbol myristate acetate revealed that their mRNA expression was asynchronous. IL-1 alpha and IL-1 beta mRNA were expressed after as little as 15 min, whereas IL-1ra mRNA was detectable only after 3 h in culture. The production of IL-1ra was measured by enzyme-linked immunosorbent assay and compared with that of IL-1 alpha and IL-1 beta. In freshly isolated AM (10(6)/ml), cell-associated IL-1ra was present in an average amount of 2.0 +/- 0.5 ng/ml, i.e., 25 and 100 times more than IL-1 alpha and IL-1 beta, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Western↗