Higher Levels Of IL-1beta Research Articles

Circulating IL-1β levels, polymorphisms of IL-1B, and risk of cervical cancer in Chinese women

Long-term human papillomavirus (HPV) infection is a prerequisite for cervical cancer. IL-1beta and IL-1Ra expression levels play an important role in cervical carcinogenesis. Several functional genetic variants in IL1B and IL-RN have been reported to be associated with IL-1beta expression and cancer susceptibility. In the current study, we hypothesized that plasma IL-1beta levels, IL-1B and IL-RN polymorphisms were candidate biomarkers for cervical cancer. We measured plasma IL-1beta levels and genotyped IL-1B and IL-RN polymorphisms in a case-control study of 404 cervical cancer cases and 404 controls in Chinese women. The mean plasma IL-1beta levels in cervical cancer cases (42.19 +/- 31.55 pg/ml) was significantly higher than those in controls (34.86 +/- 22.68 pg/ml, P = 0.0002), and plasma IL-1beta levels above the 75% quartiles in controls (IL-1beta > or = 46.94 pg/ml) were associated with a 1.74-fold significantly increased risk of cervical cancer [95% confidence interval (CI), 1.28-2.36], compared with those of lowest quartile. Multivariate logistic regression analyses revealed that the variant genotypes, IL-1B T-31C TC/CC and C-511T CT/TT, were associated with a significantly increased risk of cervical cancer [adjusted odds ratio (OR), 1.60; 95% CI, 1.16-2.21 for -31TC/CC, and adjusted OR, 1.52; 95% CI, 1.10-2.09 for -511CT/TT, respectively), especially among subjects having higher levels of IL-1beta. However, IL-RN VNTR polymorphism was not associated with cervical cancer risk in the current study. Furthermore, the significant differences of IL-1beta concentration between cervical cancer cases and controls were observed only among subjects carrying T-31C or C-511T variant genotypes. Functional IL-1B genotypes may modify plasma IL-1beta concentrations to contribute to the etiology of cervical cancer in Chinese women; however, further perspective studies are warranted to test the causal effects of IL-1beta concentration in cervical carcinogenesis.

Vascular Factors and Markers of Inflammation in Offspring With a Parental History of Late-Onset Alzheimer Disease

Alzheimer disease (AD) is a complex disorder with a strong heritable component. Amyloid pathology, vascular factors, and inflammation are postulated to be involved in its pathogenesis, but causality has not been established unequivocally. To identify heritable traits in middle age that contribute to AD. We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. In such a design, the offspring under study are enriched for risk factors of AD but do not yet have the disease. The Netherlands. Two hundred six offspring of 92 families with a parental history of late-onset AD and 200 offspring of 97 families without a parental history of AD. The APOE epsilon4 genotype, vascular factors, production capacity of pro- and anti-inflammatory cytokines upon stimulation with lipopolysaccharide, and circulating markers of inflammation. All outcome measures were assessed in the offspring only and not in the parental generation. More offspring with a parental history of AD carried APOE epsilon4 than those without a parental history of the disease (47% vs 21%, P < .001). Those with a parental history of AD also had higher systolic blood pressures (P = .006), higher diastolic blood pressures (P < .001), and lower ankle brachial indices (P = .005) when compared with offspring without a family history of dementia. Production capacity of pro-inflammatory cytokines in offspring with a parental history of AD was also different, with higher levels of IL-1beta (interleukin 1beta) (P < .001), IL-1beta to IL-1ra ratio (P < .001), tumor necrosis factor alpha (P = .008), IL-6 (P = .04), and interferon gamma (P = .01). All of these positive associations were independent of APOE epsilon4 genotype. Hypertension and the expression of an innate pro-inflammatory cytokine profile in middle age are early risk factors of AD in old age. For the offspring of affected families, it provides clues for screening and preventive strategies, of which blood pressure control can be implemented directly.

Essential and synergistic roles of IL1 and IL6 in human Th17 differentiation directed by TLR ligand-activated dendritic cells

Requirements for human Th17 differentiation in the context of activated dendritic cells (DCs) are still emerging. Here, we demonstrate that several Toll-like receptor (TLR) ligands, particularly LPS and a synthetic lipoprotein, activate human DCs to direct increased human Th17 differentiation. Based on neutralization studies, IL1, IL6, and TGFbeta contributed to human Th17 differentiation induced by LPS-activated DCs. Furthermore, TLR ligand-activated DCs produced high levels of IL6 and low levels of IL1beta. In an antigen presenting cell (APC)-free system, the minimum requirements identified for human Th17 differentiation from adult naive CD4(+) T cells, depleted of CD25(+) cells, were TGFbeta and high levels of IL1beta. However, in the presence of the physiologically low levels of IL1 such as those produced by DCs, both TGFbeta and IL6 were also essential. These results help to explain the conflicting reports in the literature on the roles of IL1 and IL6 on human Th17 differentiation.

Modulation of cytokines and transcription factors (T-Bet and GATA3) in CD4 enriched cervical cells of Chlamydia trachomatis infected fertile and infertile women upon stimulation with chlamydial inclusion membrane proteins B and C

BackgroundChlamydial Inclusion membrane proteins (Incs), are involved in biochemical interactions with host cells and infecting Chlamydiae. We have previously reported the role of two Chlamydia trachomatis (CT) Incs, namely IncB and IncC in generating host immunity in CT infected women. Emerging data shows involvement of Inc stimulated CD4 positive T cells in aiding host immunity in infected fertile and infertile women through the secretion of interferon gamma. However the lack of data on the intra-cytokine interplay to these Incs in infected cell milieu prompted us to investigate further.MethodsA total of 14 CT-positive fertile, 18 CT-positive infertile women and 25 uninfected controls were enrolled in this study. CD8 depleted, CD4 enriched cervical cells were isolated and upon stimulation with IncB and IncC, modulation of cytokines (Interleukin (IL)-1 Beta, IL-4, IL-5, IL-6, IL-10, Interferon-gamma, IL-12, IL-23, Tumor Necrosis Factor-alpha and Granulocyte macrophage colony-stimulating factor (GM-CSF) and T cell lineage regulating transcription factors T-Bet and GATA3 was determined by real-time reverse-transcriptase (RT)-PCR and ELISA.ResultsSignificant higher expression (P < 0.05) of Interferon-gamma, IL-12, IL-23 and GM-CSF were found in Inc-stimulated CD4 enriched cervical cells of CT-positive fertile women and contrastingly high IL-1 Beta, IL-4, IL-5, IL-6 and IL-10 levels were found in CT-positive infertile women. Positive correlation (P < 0.05) was found between Interferon-gamma and T-Bet levels in CT-positive fertile women and IL-4 mRNA and GATA3 levels in CT-positive infertile patients upon IncB and IncC stimulation.ConclusionOverall our data shows that CT IncB and IncC are able to upregulate expression of cytokines, namely interferon-gamma, IL-12, IL-23 and GM-CSF in CT-positive fertile women while expression of IL-1 Beta, IL-4, IL-5, IL-6 and IL-10 were upregulated in CT-positive infertile women. Our study also suggests that Incs are able to modulate expression of T cell lineage determinants indicating their involvement in regulation of immune cells.

Traumatic Brain Injury Causes Long-Term Reduction in Serum Growth Hormone and Persistent Astrocytosis in the Cortico-Hypothalamo-Pituitary Axis of Adult Male Rats

In humans, traumatic brain injury (TBI) causes pathological changes in the hypothalamus (HT) and the pituitary. One consequence of TBI is hypopituitarism, with deficiency of single or multiple hormones of the anterior pituitary (AP), including growth hormone (GH). At present no animal model of TBI with ensuing hypopituitarism has been demonstrated. The main objective of this study was to investigate whether cortical contusion injury (CCI) could induce long-term reduction of serum GH in rats. We also tested the hypothesis that TBI to the medial frontal cortex (MFC) would induce inflammatory changes in the HT and AP. Nine young adult male rats were given sham surgery (n = 4) or controlled impact contusions (n = 5) of the MFC. Two months post-injury they were killed, trunk blood collected and their brains and AP harvested. GH was measured in serum and AP using ELISA and Western blot respectively. Interleukin-1beta (IL-1beta) and glial fibrillary acidic protein (GFAP) were measured in the cortex (Cx), HT, and AP by Western blot. Lesion rats had significantly (p < 0.05) lower levels of GH in the AP and serum, unaltered serum IGF-1, and significantly (p < 0.05) higher levels of IL-1beta in the Cx and HT and GFAP in the Cx, HT, and AP compared to that of shams. CCI leads to a long-term depletion of serum GH in male rats. This chronic change in GH post-TBI is probably the result of systemic and persistent inflammatory changes observed at the level of HT and AP, the mechanism of which is not yet known.

The host cytokine response to Porphyromonas gingivalis is modified by gingipains

Clinical studies indicate that primary proinflammatory cytokines, such as interleukin-1beta (IL-1beta) are elevated in the gingival crevice around teeth with periodontitis but the secondary cytokines and chemokines, IL-6 and IL-8, are not. The human gingival epithelial cells (HGECs) lining the gingival sulcus respond to perturbation by microbes of dental plaque by releasing a wide range of cytokines. Porphyromonas gingivalis, a putative periodontal pathogen, possesses numerous virulence factors some of which directly impact on the host response. In the present study, we sought to determine how P. gingivalis influences the inflammatory cytokine responses. HGECs were challenged with P. gingivalis and other putative periodontal pathogens, and the resultant production of IL-1beta, IL-6, and IL-8 was assayed by enzyme-linked immunosorbent assay (ELISA). Culture supernatants and recombinant human cytokines were challenged with live P. gingivalis wild-type and gingipain-deficient strains and the resultant cytokine profile was assessed by ELISA and Western blot. We show here that primary HGECs challenged with live P. gingivalis result in high levels of IL-1beta but not the related secondary cytokines IL-6 and IL-8. We further demonstrate that cytokine response differences are the result of the action of P. gingivalis proteases, with lysine gingipain being the most effective. We conclude that P. gingivalis, through lysine gingipain, can subvert the protective host proinflammatory response by direct cytokine degradation. Changes in the crevicular cytokine profile have consequences in periodontal disease pathogenesis that should be considered in the development of diagnostic and therapeutic modalities.

Differential Invasion of Trypanosoma brucei brucei and Lymphocytes into the Brain of C57BL/6 and 129Sv/Ev Mice

Trypanosoma brucei subspecies invade the brain parenchyma at late stages of human and experimental rodent infections. In this study, we compared the outcome of infection with T. b. brucei in MHC-matched (H-2b) C57BL/6 (B6) and 129Sv/Ev (Sv-129). Sv-129 showed higher parasitaemia and lower specific IgM (but not IgG) antibody levels than B6 mice. The number of trypanosomes, CD4+ and CD8+ T cells in the brain parenchyma was higher in B6 mice. B6 mice lost weight and showed higher cumulative mortality when compared with Sv-129 mice. Higher levels of IL-1beta, IL-6, IL-10, TNF-alpha, IFN-gamma, ICAM-1 and E-selectin, but low levels of TGF-beta mRNA were present in brains of B6 when compared with Sv-129-infected mice. Thus, host genetics differentially determine the invasion of T. b. brucei into the brain parenchyma, which is paralleled by the severity of inflammation in the brain and course of the disease, but not by parasitaemia nor by antibody titres.

Alterations of the CD4+, CD8+ T Cell Subsets, Interleukins-1β, IL-10, IL-17, Tumor Necrosis Factor-α and Soluble Intercellular Adhesion Molecule-1 in Rheumatoid Arthritis and Osteoarthritis: Preliminary Observations

Rheumatoid arthritis is a multisystem disease with underlying immune mechanisms. Osteoarthritis is a debilitating, progressive disease of diarthrodial joints associated with the aging process. Although much is known about the pathogenesis of rheumatoid arthritis and osteoarthritis, our understanding of some immunologic changes remains incomplete. This study tries to examine the numeric changes in the T cell subsets and the alterations in the levels of some cytokines and adhesion molecules in these lesions. To accomplish this goal, peripheral blood and synovial fluid samples were obtained from 24 patients with rheumatoid arthritis, 15 patients with osteoarthritis and six healthy controls. The counts of CD4 (+) and CD8 (+) T lymphocytes were examined using flow cytometry. The levels of some cytokines (TNF-alpha, IL1-beta, IL-10, and IL-17) and a soluble intercellular adhesion molecule-1 (sICAM-1) were measured in the sera and synovial fluids using enzyme linked immunosorbant assay. We found some variations in the counts of T cell subsets, the levels of cytokines and sICAM-1 adhesion molecule between the healthy controls and the patients with arthritis. High levels of IL-1beta, IL-10, IL-17 and TNF-alpha (in the serum and synovial fluid) were observed in arthritis compared to the healthy controls. In rheumatoid arthritis, a high serum level of sICAM-1 was found compared to its level in the synovial fluid. A high CD4(+)/CD8(+) T cell ratio was found in the blood of the patients with rheumatoid arthritis. In rheumatoid arthritis, the cytokine levels correlated positively with some clinicopathologic features. To conclude, the development of rheumatoid arthritis and osteoarthritis is associated with alteration of the levels of some cytokines. The assessment of these immunologic changes may have potential prognostic roles.

Differential expression of pro-inflammatory cytokines and a pro-apoptotic protein in pelvic ileal pouches for ulcerative colitis and familial adenomatous polyposis

Pouchitis after total rectocolectomy is among the most common complications of patients with ulcerative colitis (UC). However, its frequency is quite rare in patients with familial adenomatous polyposis (FAP). We evaluated the inflammatory and pro-apoptotic activity in endoscopically normal mucosa of the ileal pouch in patients with UC and FAP. Twenty patients (10 with UC and 10 with FAP) with "J" pouch after total proctocolectomy were studied as were 10 normal controls. Biopsies were obtained from the mucosa of the pouch of UC and FAP patients and from the normal ileum of controls. The expression levels of TNF-alpha, IL-1beta, IL-6, IL-8 and phospho-BAD were determined by immunoblotting. Activated NFkappaB was evaluated by immuno-precipitation and immunoblotting for IkappaB kinase beta. Patients with UC had higher levels of IL-1beta, IL-6, IL-8 and TNF-alpha than patients with FAP. The level of TNF-alpha was higher in patients with UC than in patients with FAP; both patient groups had TNF-alpha levels higher than controls. Activation of NFkappaB was similar in all three groups. The expression of phospho-BAD was significantly lower in patients with FAP than in patients with UC. As compared with patients with FAP, patients with UC presented increased levels of some pro-inflammatory cytokines, even in the absence of clinical or endoscopic signs of pouchitis. Patients with FAP presented lower levels of pro-inflammatory proteins and of phospho-BAD. These findings may explain the higher rates of progression to pouchitis in UC patients, which could correlate with mucosal atrophy that occurs in inflamed tissue.

Gene polymorphisms in the NALP3 inflammasome are associated with interleukin‐1 production and severe inflammation: Relation to common inflammatory diseases?

NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1beta (IL-1beta) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome. Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1beta production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects. Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL-1beta measured in samples from the patient returned to normal levels after treatment with anakinra. Our results indicate that the patient's symptoms were due to elevated levels of IL-1beta, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1beta levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.

Effect of fibrinogen on the secretion of interleukin-1beta and - 8 by polymorphonuclear leukocytes

To investigate the effect of one of the acute-phase proteins, fibrinogen, on the release of IL-1beta and -8 by human peripheral polymorphonuclear leukocytes (PMN) and the possible role of fibrinogen during the destruction of periodontium. Peripheral PMN were isolated by discontinuous density gradient centrifuging technique. The freshly isolated PMN were suspended in Hank's balanced saline solution (1 x 10(9)/L) supplemented with 0.5% BSA and 0.1% glucose. The levels of IL-1beta and -8 in the supernatants produced by cultured cells upon the addition of human fibrinogen at different concentrations were measured by ELISA technique. Incubated with human fibrinogen at 2 g/L or 10 g/L for different time periods, human peripheral PMN released significantly greater amount of IL-1beta [(10.41 +/- 0.37) - (35.86 +/- 0.30) ng/L or (22.81 +/- 0.45) - (57.77 +/- 2.08) ng/L] and IL-8 [(93.90 +/- 13.95) - (2045.66 +/- 53.03) ng/L or (115.02 +/- 10.61) - (3858.69 +/- 25.65) ng/L] than PMN without the stimulation of fibrinogen (IL-1beta, P < 0.001, and IL-8, P < or = 0.016). The higher concentration of fibrinogen or the longer treatment time, the higher levels of IL-1beta and -8 were released by PMN (P < 0.001). Fibrinogen induced the secretion of pro-inflammatory cytokines IL-1beta and -8 by PMN and may be involved in magnification of the inflammatory response of periodontium and bone resorption.

Cerebrospinal fluid cytokines in enterovirus 71 brain stem encephalitis and echovirus meningitis infections of varying severity

Taiwan has experienced several outbreaks of enterovirus 71 (EV71) infections since 1998. This study examined the quantitative relationship between specific cytokines in the cerebrospinal fluid (CSF) and the severity of EV71 brain stem encephalitis (BE), and investigated whether the CSF cytokine response differed from that to uncomplicated echovirus meningitis (EM). The study included 57 children with EV71 BE, of whom 24 had isolated BE, 24 had autonomic nervous system (ANS) dysregulation, and nine had pulmonary oedema (PE), and 15 children with EM. All were confirmed by virus culture. Mean CSF glucose, total protein and lactate levels were increased significantly in association with the severity of EV71 BE. The mean CSF concentration of interleukin (IL)-1beta in children with EV71 PE was significantly higher than in those with isolated BE. IL-6 and interferon (IFN)-gamma levels were significantly higher for EV71 PE and ANS dysregulation than for isolated BE. In contrast, EM was associated with high levels of IL-1beta and low levels of IFN-gamma. Cytokines in the central nervous system, as well as in blood, appear to be involved in the pathogenesis of EV71 BE.

The role of titanium surface topography on J774A.1 macrophage inflammatory cytokines and nitric oxide production

A role for monocyte/macrophage modulation of wound healing at endosseous implants is proposed. The modification of the endosseous implant surface topography can alter cell adhesion and resultant cell behavior. The aim of this study was to define the effect of increased cpTitanium surface topography on adherent J744A.1 macrophage phenotype in culture. The J744A.1 cells were cultured on 20mm diameter cpTitanium disks prepared with smooth and grit-blasted/acid rough surface topographies for 24-72 h. Following culture in growth media with or without lipopolysaccharide (LPS), total RNA was isolated and real-time polymerase chain reaction (PCR) was used to measure the steady-state levels of the pro-inflammatory cytokines interleukin 1-beta (IL-1beta) and interleukin 6 (IL-6) and the anti-inflammatory cytokine interleukin-10 (IL-10). Additional evidence of pro-inflammatory signaling was sought by measurement of cellular nitric oxide (NO) production. In the absence of LPS, IL-1beta levels were increased on grit-blasted/acid rough surfaces during the first 48 h. In contrast, IL-6 levels were reduced on the grit-blasted/acid rough surfaces. When cultures were treated with LPS, high levels of IL-1beta and IL-6 expression were measured, irrespective of surface topography. The responses of J744A.1 cells to surface and superimposed LPS stimulation suggest only modest effects of the modeled endosseous implant surface on adherent cell pro-inflammatory cytokine expression and NO signaling.

Clusters of Cytokines Determine Malaria Severity inPlasmodium falciparum–Infected Patients from Endemic Areas of Central India

We investigated the role of interferon (IFN)- gamma , interleukin (IL)-1 beta , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)- alpha , and transforming growth factor (TGF)- beta in clinically well-defined groups of Plasmodium falciparum-infected patients manifesting mild malaria (MM), severe noncerebral malaria (SM), or cerebral malaria (CM) and in control subjects from Gondia, a malaria-endemic site in India, as well as in healthy subjects from non-malaria-endemic areas. Two-way coupled cluster analysis revealed 2 clusters of cytokines relevant to clinical subgroups of disease. The first cluster was composed of IFN- gamma , IL-2, IL-5, IL-6, and IL-12, the levels of which were significantly increased during infection but were predominant in patients with MM and allowed us to distinguish them from patients with SM or CM. The second cluster was composed of TGF- beta , TNF- alpha , IL-10, and IL-1 beta , the levels of which were highly correlated with each other in the different clinical groups of patients and significantly increased with disease severity, particularly in CM. Discriminant analyses allowed us to propose a minimal model. Levels of cytokines such as IL-5, IL-1 beta , IL-10, and IL-2 increase with infection. Levels of IL-12, IL-5, and IL-6 discriminate severe forms of malaria from MM. Finally, levels of IL-1 beta , IL-12, and IFN- gamma are relevant for the discrimination of CM from SM: high IL-1 beta levels are associated with CM, and high IL-12 and IFN- gamma levels are associated with SM.

Unconjugated bilirubin activates and damages microglia

Microglia are the resident immune cells of the brain and are the principal source of cytokines produced during central nervous system inflammation. We have previously shown that increased levels of unconjugated bilirubin (UCB), which can be detrimental to the central nervous system during neonatal life, induce the secretion of inflammatory cytokines and glutamate by astrocytes. Nevertheless, the effect of UCB on microglia has never been investigated. Hence, the main goal of the present study was to evaluate whether UCB leads to microglial activation and to the release of the cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. Additionally, we investigated the effects of UCB on glutamate efflux and cell death. The results showed that UCB induces morphological changes characteristic of activated microglia and the release of high levels of TNF-alpha, IL-1beta, and IL-6 in a concentration-dependent manner. In addition, UCB triggered extracellular accumulation of glutamate and an increased cell death by apoptosis and necrosis. These results demonstrate, for the first time, that UCB is toxic to microglial cells and point to microglia as an important target of UCB in the central nervous system. Moreover, they suggest that UCB-induced cytokine production, by mediating cell injury, can further contribute to exacerbate neurototoxicity. Interestingly, microglia cells are much more responsive to UCB than astrocytes. Collectively, these data indicate that microglia may play an important role in the pathogenesis of encephalopathy during severe hyperbilirubinemia.

Spontaneous Inflammatory Cytokine Gene Expression in Normal Human Peripheral Blood Mononuclear Cells

Cytokines regulate cellular immune activity and are produced by a variety of cells, especially lymphocytes, monocytes, and macrophages. Measurement of cytokine levels has yielded useful information on the pathological process of different diseases such as AIDS, endotoxic shock, sepsis, asthma, and cancer. It may also be of use in the monitoring of disease progression and/or inflammation. To determine spontaneous cytokine gene expression in whole blood and PBMCs, whole blood was obtained from healthy volunteers and total mRNA was isolated from PBMCs. The kinetics of response were determined by sequential testing of cytokine gene expression by RT-PCR analysis. Our results demonstrated that isolated and incubated PBMCs expressed TNF-alpha and high levels of IL-1beta, IL-6, IL-8, and IL-10. In contrast, WB only expressed the mRNA cytokines of TNF-alpha and IL-8 (p < 0.05). These results suggest that spontaneous myriad mRNA cytokine expression can be avoided with the use of WB incubation and the rapid collection of PBMCs. Furthermore, this method should be employed in all cases where the levels of cytokine gene expression can be evaluated.

Levels of IL-1 beta control stimulatory/inhibitory growth of cancer cells

Different cellular signaling pathways operate in response to varying levels of IL-1 beta leading to genotoxic damage, cell apoptosis or cell growth. At high levels of IL-1 beta, cells receiving genotoxic insults engage apoptotic pathways. The IL-1 beta over expressing stable MCF7 cell secreting high level of IL-1 beta peptides undergo cell apoptosis. Cotreatment with an inhibitor of IL-1 beta and TNF-alpha synthesis prevented stilbene estrogen-induced lesions. In addition to direct effect of 17 beta-estradiol (E2) on mitochondria and redox cycling of catechol estrogens, E2-induced overexpression of IL-1 beta can produce an increase in the level of ROS. Our recent data showed that MCF7 cell growth and cyclin D1 expression are suppressed by antioxidants and mitochondrial blockers. Stably IL-1 beta transfected cells secreting moderate level of IL-1 beta peptides stimulated the clonal expansion of MCF7 cells. These studies support that in addition to ovarian estrogens, mitogenic signals may also come from TNF-alpha and IL-1 beta-generated O2*- and hydrogen peroxide. Further validation of this concept that the concentrations of the peptide interleukin-1 beta within the cells determine its stimulatory or inhibitory signals regulating the growth of estrogen-dependent tumors might result in novel preventive strategies.

Mycobacterium tuberculosisUpregulates Coreceptors CCR5 and CXCR4 While HIV Modulates CD14 Favoring Concurrent Infection

Tuberculosis is the most frequent coinfection in humans infected with HIV-1, but little is known about mechanisms that favors coinfection. The aim of this work is to understand tuberculosis and HIV infections. We determined the pattern of expression of CD11c, CD14, CD40, CCR5, and CXCR4 and quantified IL-1beta, IL-6, IL-8, TNF-alpha, and RANTES in tuberculosis patients and HIV patients. Monocytes from healthy PPD+ volunteers (HP(+)V) stimulated with intracellular proteins (IP), lipids, and polysaccharides (PLS) from Mycobacterium tuberculosis down regulate CD11c expression (p < 0.05). On the contrary, CD14 expression was elevated in tuberculosis patients (p < 0.05) and HIV-infected patients (p > 0.05). CD14 expression was elevated on monocytes from HP(+)V stimulated with PLS and lipids (p < 0.05). CD40 low expression was found in tuberculosis patients and on monocytes from HP(+)V stimulated with lipids, but it was elevated in HIV-infected patients (p < 0.05). CXCR4 and CCR5 expression was high in pulmonary tuberculosis patients and low in HIV-infected patients (p < 0.05). Finally, CCR5+ monocytes from HP(+)V after stimulation with PLS and CXCR4+ lymphocytes were elevated after stimulation with IP (p < 0.05). In general, high levels of IL-1beta, IL-6, and TNF-alpha were found in all groups, but low levels of RANTES were found in pulmonary tuberculosis patients. In conclusion, the pulmonary tuberculosis patients have a microenvironment that facilitates the HIV infection through three possible mechanisms: (1) increasing the coreceptor for HIV entrance, (2) increasing proinflammatory cytokines, and (3) down-regulating RANTES. At the same time, HIV patients have a microenvironment that facilitates entry of M. tuberculosis into macrophages through CD14.

In Smoldering/Indolent (SMM/IMM) Myeloma Patients Treated with Interleukin-1 Receptor Antagonist (IL-1Ra), Responders Demonstrate a Significantly Increased Time to Progression (TTP) and a Decreased C-Reactive Protein (CRP) Compared with Nonresponders.

Background: Patients with SMM/IMM are at high risk for progression to active MM and are appropriate candidates for chemoprevention trials. High IL-1beta levels are a useful surrogate marker for progression from SMM/IMM to active myeloma.Methods: We carried out a Phase II clinical trial of IL-1Ra (Anakinra) in patients with SMM/IMM to determine the biologic activity, progression-free rate, and toxicity of IL-1Ra. Since IL-1beta induces paracrine IL-6, we hypothesized that IL-1Ra would inhibit IL-6 production and myeloma cell growth. Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. Patients received 100 mg of Anakinra (IL-1Ra) SQ qd for a total duration of 6 months. Non-progressors were allowed to continue on therapy with IL-1Ra until they converted to active myeloma. IL-1beta levels were measured in a bioassay with a read out of IL-1 inducible IL-6 production. CRP levels served as a surrogate for IL-6 production.Results: Thirty-six patients are included for analysis based on intent to treat at diagnosis. At baseline, twenty-nine patients had elevated functional IL-1beta levels consistent with progressive disease and 12 patients had radiologic evidence of disease on bone survey. The median TTP for the entire group was 1 year and 2 patients exhibited a minor response based on M-protein reduction. A proportional hazards analysis was performed and the variables examined were: % bone marrow plasma cells, plasma cell labeling index (PCLI), circulating plasma cells, albumin, M-protein level, IgA subtype, CRP, CRP % reduction ≥ one-third, beta-2 microglobulin, creatinine, calcium, hemoglobin, urine total protein, presence of lytic bone disease, and IL-1 level. Univariate Cox model results showed that % BMPC, PCLI, circulating plasma cells, CRP % reduction, presence of lytic disease, and IL-1 level were all statistically significant (p < .05) variables. However, only the CRP % reduction from baseline remained significant in the multivariate analysis (p < 0.01). The median TTP for patients without (n=18) and with (n=18) a decrease in CRP was 6 months and > 2 years, respectively (p < .0001). Toxicities included injection site reactions during the first month of therapy and asymptomatic neutropenia necessitating a reduction in therapy to every other day. Five patients in whom the CRP decreased and the baseline PCLI was > 0 also demonstrated a parallel decrease in the PCLI. Several of the patients with progressive disease on IL-1Ra alone could later be rescued with the addition of low dose dexamethasone (20 mg once a week) suggesting that the endogenous IL-1beta levels were too high to inhibit with IL-1Ra alone. Conclusion: In summary, IL-1Ra can prolong the TTP to active myeloma in responsive SMM/IMM patients through inhibition of IL-6 production (decrease in CRP) and myeloma cell growth. [Display omitted]

Synovial proinflammatory cytokines and their correlation with matrix metalloproteinase-3 expression in Behçet’s disease. Does interleukin-1β play a major role in Behçet’s synovitis?

The objective of this study has been the well established fact that proinflammatory cytokines and metalloproteinases play a crucial role in the pathogenesis of chronic arthritis as well as the development of pannus, with the eventual erosive changes. Among the proinflammatory cytokines, interleukin-18 (IL-18) has been shown to contribute to the pathogenesis of chronic synovitis by increasing the secretion of interleukin-1beta (IL-1beta) and the tumor necrosis factor-alpha (TNF-alpha) and also stimulating angiogenesis. The aim of this study is to investigate the synovial IL-18, IL-1beta, TNF-alpha and matrix metalloproteinase-3 (MMP-3) levels in patients with Behçet's disease (BD), and compare them with the levels of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). 30 patients with BD, 20 with RA, and 20 with OA were included in the study. The synovial levels of IL-18, IL-1beta, TNF-alpha and MMP-3 were detected using the two-step sandwich ELISA method. The synovial IL-18, TNF-alpha and MMP-3 levels were significantly higher in RA patients than patients with BD (P=0.004, 0.019, 0.025, respectively) and with OA (P=0.004, 0.045, 0.032, respectively). There were no differences, with respect to the cytokine levels, when patients with BD were compared with those with OA. Patients with RA and BD had higher IL-1beta levels than patients with OA (P=0.017, 0.013, respectively). However, no such difference was found for IL-1beta between BD and RA patients. Among patients with RA, positive correlations were found between TNF-alpha and MMP-3 (r=0.683, P=0.001). Our results showed that MMP-3 and proinflammatory cytokines, except IL-1beta, were expressed in relatively small quantities in Behçet's synovitis. Detection of the lower levels of these cytokines and metalloproteinases might explain the non-erosive character of Behçet's arthritis. We suggest that IL-1beta may be involved in the pathogenesis of Behçet's synovitis.