Interleukin-1 Ra Research Articles

Sequence of pathogenic events in cynomolgus macaques infected with aerosolized monkeypox virus.

To evaluate new vaccines when human efficacy studies are not possible, the FDA's "Animal Rule" requires well-characterized models of infection. Thus, in the present study, the early pathogenic events of monkeypox infection in nonhuman primates, a surrogate for variola virus infection, were characterized. Cynomolgus macaques were exposed to aerosolized monkeypox virus (10(5) PFU). Clinical observations, viral loads, immune responses, and pathological changes were examined on days 2, 4, 6, 8, 10, and 12 postchallenge. Viral DNA (vDNA) was detected in the lungs on day 2 postchallenge, and viral antigen was detected, by immunostaining, in the epithelium of bronchi, bronchioles, and alveolar walls. Lesions comprised rare foci of dysplastic and sloughed cells in respiratory bronchioles. By day 4, vDNA was detected in the throat, tonsil, and spleen, and monkeypox antigen was detected in the lung, hilar and submandibular lymph nodes, spleen, and colon. Lung lesions comprised focal epithelial necrosis and inflammation. Body temperature peaked on day 6, pox lesions appeared on the skin, and lesions, with positive immunostaining, were present in the lung, tonsil, spleen, lymph nodes, and colon. By day 8, vDNA was present in 9/13 tissues. Blood concentrations of interleukin 1ra (IL-1ra), IL-6, and gamma interferon (IFN-γ) increased markedly. By day 10, circulating IgG antibody concentrations increased, and on day 12, animals showed early signs of recovery. These results define early events occurring in an inhalational macaque monkeypox infection model, supporting its use as a surrogate model for human smallpox. Bioterrorism poses a major threat to public health, as the deliberate release of infectious agents, such smallpox or a related virus, monkeypox, would have catastrophic consequences. The development and testing of new medical countermeasures, e.g., vaccines, are thus priorities; however, tests for efficacy in humans cannot be performed because it would be unethical and field trials are not feasible. To overcome this, the FDA may grant marketing approval of a new product based upon the "Animal Rule," in which interventions are tested for efficacy in well-characterized animal models. Monkeypox virus infection of nonhuman primates (NHPs) presents a potential surrogate disease model for smallpox. Previously, the later stages of monkeypox infection were defined, but the early course of infection remains unstudied. Here, the early pathogenic events of inhalational monkeypox infection in NHPs were characterized, and the results support the use of this surrogate model for testing human smallpox interventions.

Association of interleukin-1beta C + 3953T gene polymorphism with human male infertility

Cytokines are involved in the regulation of spermatogenesis likely mediating the crosstalk among Sertoli and germ cells to facilitate germ cell movement across the seminiferous epithelium during cellular events such as germ cell differentiation. Members of the Interleukin-1 (IL-1) family are pleiotropic cytokines that are involved in inflammation, immunoregulation, and other homeostatic functions. Interleukin-1 alpha (IL-1α), IL-1β, and the IL-1 antagonistic molecule (IL-1 Ra) are present in the testis under normal homeostasis and they further increase upon infection/inflammation. In the present study we have examined the association of C + 3953T polymorphism of the human IL-1B gene with human male infertility. The case control study comprised of two groups: 222 infertile patients and 230 fertile healthy control men. Genotyping for SNP C + 3953T IL-1B was carried out by polymerase chain reaction followed by analysis with specific endonucleases (PCR-RFLP). DNA sequencing was used to validate the PCR-RFLP results. The genotype frequencies of the IL-1B Taq C/T polymorphism were compared between infertile men and controls. The frequency was significantly higher in asthenozoospermic patients compared to fertile control men (odds ratio = 10.4, CI: 2.50- 43.96, p = 0.001). The C + 3953T of the IL-1B gene is associated with male infertility risk in the asthenozoospermic patients from an Indian population.

Association of the IL1RN Gene VNTR Polymorphism with Human Male Infertility

Interleukin-1 (IL-1) is a regulatory cytokine that plays an important role in the maintenance of the immune environment of the testis, regulation of junction dynamics and cell differentiation during spermatogenesis. Members of the IL-1 family are pleiotropic cytokines that are involved in inflammation, immunoregulation and other homeostatic functions in the body. IL-1α, IL-1β, and the IL-1 receptor antagonistic molecule (IL-1 Ra) are expressed in the testis under normal homeostasis and they further increase upon infection/inflammation. In the present study we have examined the association of Variable Number Tandem Repeats (VNTR) polymorphism of the Interleukin-1 receptor antagonist gene (IL1RN) with human male infertility. The case-control study comprised of two groups: 331 idiopathic infertile patients and 358 fertile healthy men. The study indicates risk of IL1RN2 variant with male infertility (OR: 1.43, CI: 1.1546 to 1.7804, P = 0.001). To our best knowledge, this is the first report that links IL1RN VNTR polymorphism with human male infertility.

Opium Addiction Increases Interleukin 1 Receptor Antagonist (IL-1Ra) in the Coronary Artery Disease Patients

BackgroundThere is evidence that opium addiction has immunosuppressant effects. Coronary artery disease (CAD) is a condition resulted from atherosclerosis which is dependent on the immune response.PurposeTo evaluate plasma levels of interleukin-6 and interleukin-1Ra in 30 patients with three-vessel coronary artery disease, ejection fraction of more than 35% and to evaluate their changes after prognostic treadmill test in 15 opium addicted and 15 non-addicted patients.MethodsThe participants underwent prognostic treadmill test and plasma levels of interleukin-6 (IL-6) and interleukin-1Ra (IL-1Ra) were evaluated with ELISA method before, just after and 4 hours after the test.ResultsIL-1Ra (2183 pg/ml) tended to decrease over time in the opium addicted group (1372 pg/ml after prognostic treadmill test and 1034 pg/ml 4 hours after that), although such decrease did not reach the statistical significance. IL-1Ra levels were significantly higher in opium addicted than in non addicted patients. Opium addiction had no significant effect on IL-6 changes.ConclusionConsumption of opium in CAD patients is associated with higher IL-1Ra levels.

Cytokine level in blood serum of patients with osteoarthrosis

The article examines pathogenetic and diagnostic roles of the following cytokines in osteoarthrosis of large joints: interleukin 1 beta (IL-1β), interleukin 1RA (IL-1RA), interleukin 4 (IL-4), interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNF-α). It was revealed that levels of IL-1β and IL-6 increased from osteoarthrosis stages I-II to III-VI. IL-1RA concentration in patients’ blood at stages III-VI was lower versus I-II, IL-4 being higher only at stages III-IV of the disease, while TNF-α remained within normal values. Such changes of interleukin content in blood serum of patients with osteoarthrosis demonstrated severe immunological disturbances in their organism. A correlation between cytokine production levels at different stages of osteoarthrosis is indicative of the development of a natural induction of an acute inflammatory process in joints.

Sex Differences in the Association of Adiponectin and Low-Grade Inflammation With Changes in the Body Mass Index From Youth to Middle Age

There are sex differences in low-grade inflammation markers in obesity-related disorders. Little is known, however, about a possible sex-specific association of relative weight change from youth to adulthood with actual low-grade inflammation. The aim of this study was to identify possible sex differences in adiponectin, interleukin-1β (IL-1β), interleukin-1Ra (IL-1Ra), and high-sensitivity C-reactive protein (hs-CRP) levels with respect to the relative change in body mass index (BMI) from youth to middle age. The study population consisted of 403 men and 500 women from 1 Finnish town. Weight, height, and adiponectin, IL-1β, IL-1Ra, and hs-CRP levels were measured in 2003 at a mean age of 46 years. Self-reported weight at the age of 20 years was recorded. In women, even after adjustment for BMI in adulthood, a statistically significantly negative linear association was observed between the quartiles of relative change in BMI and adiponectin levels (P < 0.001 for linearity). Significantly positive linear associations were also observed between the change in BMI and IL-1Ra (P = 0.032 for linearity) and hs-CRP (P = 0.029 for linearity) levels. In men, there was no statistically significant association among the quartiles of relative change in BMI and measured inflammatory markers after adjustment for BMI in adulthood. A relative increase in weight may be more harmful in women than in men with respect to adiponectin and inflammatory markers.

Interleukin-1β Regulates CXCL8 Release and Influences Disease Outcome in Response to Streptococcus pneumoniae, Defining Intercellular Cooperation between Pulmonary Epithelial Cells and Macrophages

The success of Streptococcus pneumoniae (the pneumococcus) as a pulmonary pathogen is related to its restriction of innate immune responses by respiratory epithelial cells. The mechanisms used to overcome this restriction are incompletely elucidated. Pulmonary chemokine expression involves complex cellular and molecular networks, involving the pulmonary epithelium, but the specific cellular interactions and the cytokines that control them are incompletely defined. We show that serotype 2 or 4 pneumococci induce only modest levels of CXCL8 expression from epithelial cell lines, even in the absence of a polysaccharide capsule. In contrast, coculture of A549 cells with the macrophage-like THP-1 cell line, differentiated with vitamin D, or monocyte-derived macrophages enhanced CXCL8 release. Supernatants from the THP-1 cell line prime A549 cells to release CXCL8 at levels similar to cocultures. Interleukin-1Ra (IL-1Ra) inhibits CXCL8 release from cocultures and reduces the activity of macrophage-conditioned media, but inhibition of tumor necrosis factor alpha (TNF-α) had only a minimal effect on CXCL8 release. Release of IL-1β but not TNF-α was upregulated in cocultures. IL-1 type 1 receptor knockout C57BL/6 and BALB/c mice confirmed the importance of IL-1 signaling in CXC chemokine expression and neutrophil recruitment in vivo. In fulminant disease, increased IL-1 signaling resulted in increased neutrophils in the airway and more invasive disease. These results demonstrate that IL-1 is an important component of the cellular network involving macrophages and epithelial cells, which facilitates CXC chemokine expression and aids neutrophil recruitment during pneumococcal pneumonia. They also highlight a potential clinical role for anti-IL-1 treatment to limit excessive neutrophilic inflammation in the lung.

Candidate genes for temporal lobe epilepsy: a replication study

The objective of this study is to replicate previously published results regarding the involvement of several susceptibility genes in temporal lobe epilepsy (TLE): interleukin 1beta (IL-1beta), interleukin 1beta (IL-1alpha), interleukin 1RA (IL-1RA), apolipoprotein E (ApoE) and prodynorphin (PDYN). We used a case-control approach comparing several polymorphisms within these candidate genes between unrelated TLE patients and matched controls. We were thus able to confirm the role of ApoE, IL-1alpha and IL-1RA genes in TLE disease, but failed to confirm the involvement of IL-1beta and PDYN. This failure should be interpreted with caution, as this may be due to the small size of our study groups and the resultant lack of statistical power.

Multiplex Immunoassay Analysis of Cytokines in Idiopathic Inflammatory Myopathy

Abstract Context.—Idiopathic inflammatory myopathies (IIMs), including dermatomyositis, polymyositis, and inclusion-body myositis, can be difficult to diagnose. Objective.—To determine if a multiplex immunoassay for markers of inflammation in muscle homogenates correlates with a diagnosis of IIM. Design.—Frozen archived muscle biopsy specimens from 30 patients with IIM and 34 patients without IIM were homogenized and analyzed for cytokine content with a multiplex microbead-based immunoassay system. Analyte concentrations were normalized to total lysate protein concentration prior to comparison. Results.—Two cytokines, interleukin 1ra and monocyte chemoattractant protein 1, and 1 soluble adhesion molecule, intracellular adhesion molecule 1, were found at significantly greater concentrations in muscle samples from patients with IIM. Intracellular adhesion molecule 1 levels alone were 83% sensitive and 91% specific for IIM at a cutoff of 1240 pg/mg muscle protein. Conclusions.—Immunoassays for selected infla...

Multiplex Immunoassay Analysis of Cytokines in Idiopathic Inflammatory Myopathy

Idiopathic inflammatory myopathies (IIMs), including dermatomyositis, polymyositis, and inclusion-body myositis, can be difficult to diagnose. To determine if a multiplex immunoassay for markers of inflammation in muscle homogenates correlates with a diagnosis of IIM. Frozen archived muscle biopsy specimens from 30 patients with IIM and 34 patients without IIM were homogenized and analyzed for cytokine content with a multiplex microbead-based immunoassay system. Analyte concentrations were normalized to total lysate protein concentration prior to comparison. Two cytokines, interleukin 1ra and monocyte chemoattractant protein 1, and 1 soluble adhesion molecule, intracellular adhesion molecule 1, were found at significantly greater concentrations in muscle samples from patients with IIM. Intracellular adhesion molecule 1 levels alone were 83% sensitive and 91% specific for IIM at a cutoff of 1240 pg/mg muscle protein. Immunoassays for selected inflammatory markers can serve in conjunction with histopathologic analysis as sensitive and specific tools for the diagnosis of IIM.

Fetal Polymorphisms in Anti-inflammatory Cytokine and β-adrenergic Receptor Genes Associated With Placental Pathological Lesions

Prematurity is the leading cause of infant morbidity and mortality. Altered intra-amniotic levels of anti-inflammatory cytokines, interleukin (IL) 1ra and IL-4, and beta2-adrenergic receptor (beta2AR) production have been associated with preterm labor and delivery. The aim of this study was to evaluate potential associations of polymorphisms in these genes with specific placental pathological findings. Maternal and fetal DNA were analyzed for a length polymorphism in the IL-1ra gene and for single nucleotide polymorphisms in the IL-4 and beta2AR genes. Placentas were evaluated for pathological abnormalities in the following major categories: meconium, malperfusion, acute deciduitis, chorioamnionitis, umbilical cord problems, villitis, and fetal vascular thrombosis. In fetal DNA, homozygosity for the IL-1ra 2 allele (P = 0.029) and carriage of the IL-4 T allele (P < 0.01) were associated with acute deciduitis. In addition, carriage of the beta2AR A allele (P = 0.036) was associated with umbilical cord problems. There were no associations between placental lesions and any maternal gene polymorphisms. Although susceptibility to premature delivery is multifactorial, the present study provides pathological evidence for a connection between specific alleles and placental abnormalities. Carriage of these alleles may render the fetus more susceptible to the adverse consequences of infection and inflammation.

Assessment of 54 Biomarkers for Biopsy-Detectable Prostate Cancer

We analyzed the association of 54 biomarkers from seven classes including adipokines, immune response metalloproteinases, adhesion molecules, and growth factors with prostate cancer risk adjusting for the Prostate Cancer Prevention Trial (PCPT) risk score. A total of 123 incident prostate cancer cases and 127 age-matched controls were selected from subjects in the San Antonio Center for Biomarkers of Risk of Prostate Cancer cohort study. Prediagnostic serum concentrations were measured in the sample collected at baseline using LabMAP technology. The odds ratios (OR) of prostate cancer risk associated with serum concentrations of 54 markers were estimated using univariate conditional logistic regression before and after adjustment for the PCPT risk score. Two-way hierarchical unsupervised clustering techniques were used to evaluate whether the 54-marker panel distinguished cases from controls. Vascular endothelial growth factor, resistin, interleukin 1Ra (IL-1Ra), granulocyte colony-stimulating factor, matrix metalloproteinase-3, plasminogen activator inhibitor, and kallikrein-8 were statistically significantly (P < 0.05) underexpressed in prostate cancer cases, and alpha-fetoprotein was statistically significantly overexpressed in prostate cancer cases, but all had area underneath the receiver-operating characteristic curve <60%; none were statistically significant adjusting for multiple comparisons (P < 0.0008) or after adjustment for the PCPT risk score. Statistical clustering of patients by the marker panel did not distinguish a separate group of cases from controls. This age-matched case-control study did not support findings of increased diagnostic potential from a 54-marker panel when compared with the conventional risk factors incorporated in the PCPT risk calculator. Future discovery of new biomarkers should always be tested and compared against conventional risk factors before applying them in clinical practice.

A newly established murine immature dendritic cell line can be differentiated into a mature state, but exerts tolerogenic function upon maturation in the presence of glucocorticoid

AbstractThe phenotype and function of murine dendritic cells (DCs) are primarily studied using bone-marrow–derived DCs (BM-DCs), but may be hampered by the heterogenous phenotype of BM-DCs due to their differential state of maturation. Here we characterize a newly established murine DC line (SP37A3) of myeloid origin. During maintainance in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and M-CSF, SP37A3 cells resemble immature DCs characterized by low expression of major histocompatibility complex (MHC) II and costimulatory molecules and low T-cell stimulatory capacity. Upon stimulation, SP37A3 cells acquire a mature phenotype and activate naive T cells as potently as BM-DCs. Similar to BM-DCs, SP37A3 cells activated in the presence of dexamethasone-induced regulatory T cells, which were anergic upon restimulation and suppressed proliferation of naive T cells. This tolerogenic state was reflected by lower expression levels of costimulatory molecules and proinflammatory cytokines compared with mature cells, as well as up-regulated expression of FcγRIIB and interleukin-1RA (IL-1RA). SP37A3 cells were responsive to dexamethasone even when applied at later time points during activation, suggesting functional plasticity. Thus, DC line SP37A3 represents a suitable model to study functions of immature and mature as well as tolerogenic myeloid DCs, circumventing restrictions associated with the use of primary DCs and BM-DCs.

RANKL-stimulated osteoclast-like cell formation in vitro is partially dependent on endogenous interleukin-1 production

Receptor activator of NF-κB ligand (RANKL) and interleukin-1 (IL-1) individually plays a critical role in the differentiation and activation of osteoclasts in bone. In addition, both RANKL and IL-1 activate similar signal transduction pathways including p38 MAP kinase and c-Jun NH 2 terminal kinase (JNK). We examined if endogenously produced IL-1 influenced osteoclast-like cell (OCL) formation in murine bone marrow and bone marrow monocyte (BMM) cultures that were stimulated with M-CSF and RANKL. RANKL stimulated OCL formation in a dose-dependent manner in bone marrow cultures, and this response was significantly inhibited by IL-1 RA (100 ng/ml), a specific IL-1 antagonist. Interleukin-1 further increased OCL formation in BMM cultures that were treated with M-CSF (30 ng/ml) and RANKL (1, 3, 10 and 30 ng/ml). In addition, BMM cultures from IL-1 type I receptor-deficient mice, which do not respond to IL-1, demonstrated significantly less OCL formation compared to wild-type BMM cultures. We examined the time course and dose response of IL-1alpha protein expression by ELISA in BMM cultures that were treated with or without M-CSF and RANKL. RANKL dose dependently stimulated IL-1α protein significantly (up to 46%) in 6-day cultures. The interaction of RANKL and IL-1 on osteoclastogenesis did not appear significantly dependent on prostaglandin synthesis since PGE 2 expression in the conditioned medium of BMM cultures was nearly undetectable and the PGHS-2 specific inhibitor, NS-398, was without effect. We also investigated the effect of IL-1 on p38 MAP kinase and JNK in BMM cultures. The combination of RANKL and IL-1 had additive effects on JNK but not p38 MAP kinase compared to results in cultures treated with RANKL or IL-1 alone. In addition, SP600125, a specific JNK inhibitor, markedly reduced OCL formation in BMM cultures that were treated with RANKL or the combination of RANKL and IL-1. These findings demonstrate that endogenously produced IL-1 augments the response of bone marrow cells to RANKL, and this effect appears mediated by mechanisms that are associated with enhancement of JNK activity.

Altered Cell-mediated Immunity and Increased Postoperative Infection Rate in Long-term Alcoholic Patients

Preoperative alteration of T cell-mediated immunity as well as an altered immune response to surgical stress were found in long-term alcoholic patients. The aim of this study was to evaluate perioperative T cell-mediated immune parameters as well as cytokine release from whole blood cells after lipopolysaccharide stimulation and its association with postoperative infections. Fifty-four patients undergoing elective surgery of the aerodigestive tract were included in this prospective observational study. Long-term alcoholic patients (n = 31) were defined as having a daily ethanol consumption of at least 60 g and fulfilling the Diagnostic and Statistical Manual of Mental Disorders for either alcohol abuse or alcohol dependence. The nonalcoholic patients (n = 23) were defined as drinking less than 60 g ethanol/day. Blood samples to analyze the immune status were obtained on morning before surgery and on the morning of days 1, 3, and 5 after surgery. Basic patient characteristics did not differ between groups. Before surgery, the T helper 1:T helper 2 ratio (Th1: Th2) was significantly lower (P < 0.01), whereas plasma interleukin 1beta and lipopolysaccharide-stimulated interleukin 1ra from whole blood cells were increased in long-term alcoholic patients. After surgery, a significant suppression of the cytotoxic lymphocyte ratio (Tc1:Tc2), the interferon gamma:interleukin 10 ratio from lipopolysaccharide-stimulated whole blood cells, and a significant increase of plasma interleukin 10 was observed. Long-term alcoholics had more frequent postoperative infections compared with nonalcoholic patients (54%vs. 26%; P = 0.03). T helper cell-mediated immunity was significantly suppressed before surgery and possibly led to inadequate cytotoxic lymphocyte and whole blood cell response in long-term alcoholic patients after surgery. This altered cell-mediated immunity might have accounted for the increased infection rate in long-term alcoholic patients after surgery.

Kindling stimuli delivered at different times in the sleep-wake cycle.

Clinical and experimental observations argue that sleep disturbances are common and coexist in patients with epilepsy. Our previous observations have suggested that neural-immune interactions between corticotropin-releasing hormone (CRH) and interleukin-1 (IL-1) are involved in the regulation of physiological sleep-wake behavior. In the present study, we determined the involvement of CRH and IL-1 in the alteration of sleep-wake activities in rats when amygdala kindling was given either at the beginning of the light period (light-onset kindling) or at the beginning of the dark period (dark-onset kindling). The analysis of sleep-wake activities was performed before and after full-blown kindling, and the actions of CRH and IL-1 were tested by pharmacological blockade. Neuroscience Laboratory at China Medical University Hospital. PARTICIPANT AND INTERVENTIONS: Male Sprague-Dawley rats were implanted with electroencephalogram (EEG) electrodes and an intracerebroventricular (ICV) guide cannula. Kindling stimuli delivered via a bipolar electrode placing in the right central nucleus of the amygdala. Amygdala kindling induced diverse effects on sleep. Slow-wave sleep (SWS) and rapid eye movement (REM) sleep decreased during the first 12-hour light period when rats were kindled at light onset. When dark-onset kindling was given, SWS increased but REM sleep was not altered during the first 12-hour dark period. After light-onset kindling, the circulating corticosterone concentrations increased and were blocked by ICV administration of the CRH receptor antagonist, astressin or alpha-hCRH. The ICV administration of the CRH antagonist blocked the light-onset kindling-induced decrease of SWS in a dose-dependent manner. After dark-onset kindling, IL-1 mRNA expression in the hippocampus and cortex increased. The dark-onset kindling-induced SWS was blocked in a dose-dependent manner by ICV administration of IL-1 receptor antagonist (IL-1 ra). The slow-wave activity during SWS was enhanced regardless of when kindling occurred, but both CRH antagonists and IL-1 ra had little effect on the alteration of slow-wave activity. These observations argue that amygdala-kindling-induced sleep-wake alterations are modulated by central increases in CRH or IL-1.

Cytokine gene polymorphisms in idiopathic pulmonary fibrosis.

Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of idiopathic pulmonary fibrosis (IPF). The aims of the present case-control study were to examine polymorphisms in the IL-6, transforming growth factor (TGF)-beta 1, tumour necrosis factor (TNF)-alpha and interleukin-1 (IL-1)Ra genes in patients with IPF (n = 22) -compared to healthy controls (n = 140). Genotyping was performed on DNA extracted from peripheral blood lymphocytes, using polymerase chain reaction - restriction fragment length polymorphism with gene polymorphisms determined according to -published techniques. The following sites were examined: (i) IL-1Ra*1-5 (86 bp variable tandem repeat intron 2), (ii) IL-6 (-174G > C), (iii) TNF-alpha (-308G > A) and (iv) TGF-beta 1 (Arg25Pro). The TNF-alpha (-308 A) allele was over-represented in the IPF (p(corr) = 0.004) group compared to controls. Risk of IPF was significant for heterozygotes for: (i) the TNF-alpha (-308 A) allele (A/G) (odds ratio (OR) 2.9; 95% confidence interval (CI) 1.2-7.2; P = 0.02), (ii) homozygotes (A/A) (OR 13.9; 95%CI 1.2-160; P = 0.04) and (iii) carriage of the allele (A/A + A/G) (OR 4; 95%CI 1.6-10.2; P = 0.003). The distribution of alleles and genotypes for IL-6, TGF-beta 1 and IL-1Ra between the two groups was not significantly different. This is the third study to independently confirm that there is a significant association of the TNF-alpha (-308 A) allele with IPF. Further research is needed to assess the utility of cytokine gene polymorphisms as markers of disease -susceptibility.

Interleukin-1 receptor antagonist gene polymorphism is associated with increased risk of epithelial ovarian cancer

BackgroundDifferent studies indicate that immunological components play a key role in the development of cancer. Interleukin-1 (IL-1) is known to be critically involved in ovarian carcinogenesis and in other solid tumors. Therefore, we investigated the possible influence of the polymorphism of the IL-1 receptor antagonist (IL-1 RA) genes on the development of ovarian cancer. Patients and methodsIn a prospective study we analyzed the polymorphism of the IL-1 RA gene in 108 women with ovarian cancer compared with 112 patients with benign gynecological diseases. Genomic DNA fragments were amplified by PCR. ResultsThe distribution of genotype frequencies was significantly different between the study and control group with respect to allele 1/2 heterozygotes (32.4% versus 15.2%; P = 0.004). Patients who were heterozygous at allele 2 for IL-1 RA (IL-RA 1/2) had a significantly higher risk of ovarian cancer with a calculated odds ratio of 2.7 (95% confidence interval 1.4–5.2). There were no differences between IL-1 RA 1/2 polymorphism and all other alleles in tumor stage (International Federation of Gynecology and Obstetrics), histological type, grading, postoperative tumor volume, volume of ascites, recurrence status or age. ConclusionsThe allele 2 polymorphism of the IL-1 RA gene seems to play a role in the occurrence of ovarian cancer and should be investigated for screening and risk evaluation.

The relationship between interleukin-1 and its receptor antagonist gene polymorphism and bone mineral density in postmenopausal Korean women

Objective: The objectives were to investigate the relationship between polymorphisms in interleukin-1 (IL-1) and IL-1 receptor antagonist (IL-1ra) gene, and bone mineral density (BMD) in postmenopausal Korean women and to evaluate whether these polymorphisms affect the production of cytokines from whole blood cells.Design: Prospective study.Materials and Methods: IL-1 C511T polymorphism was analyzed by restriction fragment length polymorphism using AvaI after polymerase chain reaction (PCR) and the 86-base pair repeat polymorphism in the IL-1ra gene was examined by PCR and electrophoresis in 202 postmenopausal Korean women. Serum osteocalcin, and CrossLaps (CTX) were measured by immunoassay, and IL-1β and IL-1ra produced by whole blood cells that were cultured for 3 days was measured using enzyme-linked immunosorbent assay. BMD at the lumbar spine and proximal femur were determined by dual energy X-ray absorptiometry.Results: There were no significant differences in BMD of the lumbar spine and proximal femur or serum levels of bone turnover markers across the IL-1 genotypes. Four alleles in IL-1ra gene were identified: A1 (4 repeats), A2 (2 repeats), A3 (5 repeats), and A4 (3 repeats). BMD at the lumbar spine, and proximal femur in women carrying A2 allele, was significantly lower, compared with noncarriage of that allele. Serum osteocalcin levels in the former group were higher than the latter group, but no difference in serum CTX levels between two groups was observed. There were no differences in the distribution of IL-1 genotypes and IL-1ra A2 allele among normal, osteopenic, and osteoporotic postmenopausal women. The production of IL-1β and IL-1ra from whole blood cells was not different according to the IL-1 or IL-1 ra genotypes and the status of BMD.Conclusion: BMD of lumbar spine and proximal femur is associated with a polymorphism in IL-1ra gene in Korean women. Polymorphism of IL-1 and IL-1ra gene does not affect the production of cytokines from whole blood cells. Objective: The objectives were to investigate the relationship between polymorphisms in interleukin-1 (IL-1) and IL-1 receptor antagonist (IL-1ra) gene, and bone mineral density (BMD) in postmenopausal Korean women and to evaluate whether these polymorphisms affect the production of cytokines from whole blood cells. Design: Prospective study. Materials and Methods: IL-1 C511T polymorphism was analyzed by restriction fragment length polymorphism using AvaI after polymerase chain reaction (PCR) and the 86-base pair repeat polymorphism in the IL-1ra gene was examined by PCR and electrophoresis in 202 postmenopausal Korean women. Serum osteocalcin, and CrossLaps (CTX) were measured by immunoassay, and IL-1β and IL-1ra produced by whole blood cells that were cultured for 3 days was measured using enzyme-linked immunosorbent assay. BMD at the lumbar spine and proximal femur were determined by dual energy X-ray absorptiometry. Results: There were no significant differences in BMD of the lumbar spine and proximal femur or serum levels of bone turnover markers across the IL-1 genotypes. Four alleles in IL-1ra gene were identified: A1 (4 repeats), A2 (2 repeats), A3 (5 repeats), and A4 (3 repeats). BMD at the lumbar spine, and proximal femur in women carrying A2 allele, was significantly lower, compared with noncarriage of that allele. Serum osteocalcin levels in the former group were higher than the latter group, but no difference in serum CTX levels between two groups was observed. There were no differences in the distribution of IL-1 genotypes and IL-1ra A2 allele among normal, osteopenic, and osteoporotic postmenopausal women. The production of IL-1β and IL-1ra from whole blood cells was not different according to the IL-1 or IL-1 ra genotypes and the status of BMD. Conclusion: BMD of lumbar spine and proximal femur is associated with a polymorphism in IL-1ra gene in Korean women. Polymorphism of IL-1 and IL-1ra gene does not affect the production of cytokines from whole blood cells.

Polymorphisms of the Interleukin-1 Gene Cluster and Ovarian Cancer

Interleukin-1 (IL-1) is known to be critically involved in ovarian carcinogenesis. We investigated a panel of polymorphisms of the IL-1 and the IL-1 receptor antagonist (IL-1 RA) genes in patients with ovarian cancer. One hundred thirty-four patients with surgically staged ovarian cancer, 27 patients with borderline ovarian cancer, and 134 healthy controls were genotyped for three polymorphisms of the IL-1 gene (-889 C/T polymorphism of the IL-1alpha gene [IL1A], -511 C/T polymorphism of the IL-1beta promoter [IL1B promoter], a polymorphism of IL-1beta exon 5 [IL1B exon 5]), and an 86-base pair repeat in intron 2 of the IL-1 RA gene [IL1RN]) using polymerase chain reaction and pyrosequencing. Allelic frequencies did not differ between patients with ovarian cancer and controls. In the ovarian cancer group, polymorphism did not correlate with any of the investigated clinicopathologic variables, including tumor stage, lymph node, and histologic grade. In univariate and multivariate models, there was no correlation between any polymorphism and patients' overall and disease-free survival. We investigated interleukin polymorphisms in ovarian cancer but did not find any association between common polymorphisms of IL1A, IL1B, and IL1RN and the occurrence of ovarian cancer. Allelic variation within the IL-1 gene clusters does not seem to play a role in ovarian carcinogenesis and does not appear to be a useful tool for possible screening and risk evaluation.