Paraneoplastic thrombocytosis in ovarian cancer

<p>Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.</p> <p>Methods: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.</p> <p>Results: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumorderived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.</p> <p>Conclusions: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. </p&gt

Interleukin-6, age, and corpus callosum integrity.

The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories

Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus.

BackgroundCerebral palsy is a nonprogressive motor impairment syndrome that has no effective cure. The etiology of most cases of cerebral palsy remains unknown; however, recent epidemiologic data have demonstrated an association between fetal neurologic injury and infection/inflammation. Maternal infection/inflammation may be associated with the induction of placental cytokines that could result in increased fetal proinflammatory cytokine exposure, and development of neonatal neurologic injury. Therefore, we sought to explore the mechanism by which maternal infection may produce a placental inflammatory response. We specifically examined rat placental cytokine production and activation of the Toll-like receptor 4 (TLR4) pathway in response to lipopolysaccharide exposure at preterm and near-term gestational ages.MethodsPreterm (e16) or near-term (e20) placental explants from pregnant rats were treated with 0, 1, or 10 μg/mL lipopolysaccharide. Explant integrity was assessed by lactate dehydrogenase assay. Interleukin-6 and tumor necrosis alpha levels were determined using enzyme-linked immunosorbent assay kits. TLR4 and phosphorylated nuclear factor kappa light chain enhancer of activated B cells (NFκB) protein expression levels were determined by Western blot analysis.ResultsAt both e16 and e20, lactate dehydrogenase levels were unchanged by treatment with lipopolysaccharide. After exposure to lipopolysaccharide, the release of interleukin-6 and tumor necrosis alpha from e16 placental explants increased by 4-fold and 8-9-fold, respectively (P < 0.05 versus vehicle). Conversely, interleukin-6 release from e20 explants was not significantly different compared with vehicle, and tumor necrosis alpha release was only 2-fold higher (P < 0.05 versus vehicle) following exposure to lipopolysaccharide. Phosphorylated NFκB protein expression was significantly increased in the nuclear fraction from placental explants exposed to lipopolysaccharide at both e16 and e20, although TLR4 protein expression was unaffected.ConclusionLipopolysaccharide induces higher interleukin-6 and tumor necrosis alpha expression at e16 versus e20, suggesting that preterm placentas may have a greater placental cytokine response to lipopolysaccharide infection. Furthermore, increased phosphorylated NFκB indicates that placental cytokine induction may occur by activation of the TLR4 pathway

Phenotypic features of interleukin-6 gene polymorphism in the context of formation of addictive pathology

Search for biomarkers of addictive disorders including molecular-genetic and immunoregulatory characteristics is of relevance. 114 persons with mental and behavioural disorders caused by use of psychoactive substances and 97 conditionally healthy persons have been examined. The assessment of interleukin-6 gene polymorphism rs1800797 has been carried out with use of real-time PCR detection system. Level of extracellular mitogen-induced production of interleukin-6 has been measured on the Luminex 200 multiplex analyzer (USA). Intracellular contents of interleukin-6 have been estimated in mononuclears of stimulated LPS culture of whole blood on the FACS Calibur flow cytofluorimeter (BD, USA). Narcological patients are characterized by higher mitogen-induced production of interleukin-6. Persons with GG genotype of interleukin-6 gene polymorphism rs1800797 have demonstrated significant increase of production of interleukin-6. The GG genotype of interleukin-6 gene polymorphism rs1800797 makes the maximal contribution to formation of mental and behavioural disorders caused by use of psychoactive substances and can be a marker of addictive pathology

High Interleukin-6, Low Cd4+ and Cd8+ T-lymphocytes Expressions as Risk Factors of Cervical Carsinoma Infected by Human Papilloma Virus Type-52

In Indonesia cervical carcinoma is the most common cancer in women and one of the leading cause of mortality. High risk human papillomavirus (HPV) is the major risk factor of cervical cancer. This study aims to know the role of IL-6, CD4+ and CD8+ T-lymphocyte for the risk of cervical carcinoma infected by HPV52. This study was a case control study, specimens of cervical carcinoma patients infected by HPV type-52 as the case group and HPV type-16 or 18 as the control group. HPV genotyping used SPF10 primer and type specific E7 primer by LiPA. Immunohistochemistry method was used to know expression of IL-6, CD4+ and CD8+ T lymphocyte. Pearson's c2 test was applied with statistical significance was set at the 2-sided 0.05 level. The odds ratios (OR) were calculated for the risk, with 95% confidence intervals on SPSS 16.0 for windows. PCR examination was performed in 185 paraffin-embedded tissue. The risk of high IL-6 expression in cervical carcinoma infected by HPV type-52 was statistically significant 6-fold higher compare with cervical carcinoma infected by HPV type 16 (OR = 6.00 ; CI 95% = 1.13-31.99; p = 0.03; p < 0.05) and HPV type 18 (OR = 6.00 ; CI 95% = 1.13-31.99; p = 0.03; p < 0.05). The risk of low CD4+ T lymphocyte expression in cervical carcinoma infected by HPV type 52 was statistically significant 6-fold higher and 7.43-fold higher respectively compare with cervical carcinoma infected by HPV type 16 (OR = 6.00 ; CI 95% = 1.003-35.91; p = 0.04; p < 0.05) and HPV type 18 (OR = 7.43 ; CI 95% = 1.23-45.01; p = 0.02; p < 0.05). The risk of low CD8+ T lymphocyte expression in cervical carcinoma infected by HPV type 52 was statistically significant 13.5-fold higher and 11-fold higher respectively compare with cervical carcinoma infected by HPV type 16 (OR = 13.50 ; CI 95% = 1.42-128.26; p = 0.01; p < 0.05) and HPV type 18 (OR = 11.00 ; CI 95% = 1.16-103.94; p = 0.02; p < 0.05). No significance different between cases and controls group in mean-age, parity and sexual activity (p > 0.05). In conclusion, this study found that high IL-6 expression, low CD4+ and CD8+ T lymphocyte expression were the risk factors of cervical carcinoma infected by HPV type 52

Inflammatory Markers Associated With Subclinical Coronary Artery Disease: The Multicenter AIDS Cohort Study.

BackgroundDespite evidence for higher risk of coronary artery disease among HIV+ individuals, the underlying mechanisms are not well understood. We investigated associations of inflammatory markers with subclinical coronary artery disease in 923 participants of the Multicenter AIDS Cohort Study (575 HIV+ and 348 HIV- men) who underwent noncontrast computed tomography scans for coronary artery calcification, the majority (n=692) also undergoing coronary computed tomography angiography.Methods and resultsOutcomes included presence and extent of coronary artery calcification, plus computed tomography angiography analysis of presence, composition, and extent of coronary plaques and severity of coronary stenosis. HIV+ men had significantly higher levels of interleukin-6 (IL-6), intercellular adhesion molecule-1, C-reactive protein, and soluble-tumor necrosis factor-α receptor (sTNFαR) I and II (all P<0.01) and a higher prevalence of noncalcified plaque (63% versus 54%, P=0.02) on computed tomography angiography. Among HIV+ men, for every SD increase in log-interleukin-6 and log intercellular adhesion molecule-1, there was a 30% and 60% increase, respectively, in the prevalence of coronary stenosis ≥50% (all P<0.05). Similarly, sTNFαR I and II in HIV+ participants were associated with an increase in prevalence of coronary stenosis ≥70% (P<0.05). Higher levels of interleukin-6, sTNFαR I, and sTNFαR II were also associated with greater coronary artery calcification score in HIV+ men (P<0.01).ConclusionsHigher inflammatory marker levels are associated with greater prevalence of coronary stenosis in HIV+ men. Our findings underscore the need for further study to elucidate the relationships of inflammatory pathways with coronary artery disease in HIV+ individuals

Fetal and early neonatal interleukin-6 response

In 1998, a systemic fetal cytokine response, defined as a plasma interleukin-6 (IL-6) value above 11 pg/mL, was reported to be a major independent risk factor for the subsequent development of neonatal morbid events even after adjustments for gestational age and other confounders. Since then, the body of literature investigating the use of blood concentrations of IL-6 as a hallmark of the fetal inflammatory response syndrome (FIRS), a diagnostic marker of early-onset neonatal sepsis (EONS) and a risk predictor of white matter injury (WMI), has grown rapidly. In this article, we critically review: IL-6 biological functions; current evidence on the association between IL-6, preterm birth, FIRS and EONS; IL-6 reference intervals and dynamics in the early neonatal period; IL-6 response during the immediate postnatal period and perinatal confounders; accuracy and completeness of IL-6 diagnostic studies for EONS (according to the Standards for Reporting of Diagnostic Accuracy statement); and recent breakthroughs in the association between fetal blood IL-6, EONS, and WMI

Increased levels of interleukin-6 exacerbate the dystrophic phenotype in mdx mice

Duchenne muscular dystrophy (DMD) is characterized by progressive lethal muscle degeneration and chronic inflammatory response. The mdx mouse strain has served as the animal model for human DMD. However, while DMD patients undergo extensive necrosis, the affected muscles of adult mdx mice rapidly regenerates and regains structural and functional integrity. The basis for the mild effects observed in mice compared with the lethal consequences in humans remains unknown. In this study, we provide evidence that interleukin-6 (IL-6) is causally linked to the pathogenesis of muscular dystrophy. We report that forced expression of IL-6, in the adult mdx mice, recapitulates the severe phenotypic characteristics of DMD in humans. Increased levels of IL-6 exacerbate the dystrophic muscle phenotype, sustaining inflammatory response and repeated cycles of muscle degeneration and regeneration, leading to exhaustion of satellite cells. The mdx/IL6 mouse closely approximates the human disease and more faithfully recapitulates the disease progression in humans. This study promises to significantly advance our understanding of the pathogenic mechanisms that lead to DMD

Interrelationship of interleukin 6, C-reactive protein and Chlamydia pneumoniae IgG antibodies in patients with acute coronary syndromes

Background/Aim. Inflammation due to infection could be associated with the development of acute coronary syndromes, clinical manifestations of ongoing atherosclerosis in vessel walls. Our aim was determine whether interleukin 6, C-reactive protein and Chlamydia pneumoniae IgG antibodies are connected with the development of acute coronary syndromes, to evaluate their interrelationship and to examine whether they are predictive of new events and mortality. Methods. This prospective study included 211 subjects, of whom 111 were patients with acute coronary syndromes (60% male, mean age 59.42 years) and 100 were healthy controls (58% male, mean age 59.03 yuears). Blood samples were taken for analysis on admission, before the application of the therapy. Interleukin 6, high sensitivity C-reactive protein and Chlamydia pneumoniae IgG antibodies were measured, in a follow-up period of 30 days. Results. Levels of interleukin 6 (p < 0.001) and C-reactive protein (p < 0.001) were significantly higher among the patients with acute coronary syndromes than among controls. Chronic infection caused by Chlamydia pneumoniae was present in 72% of patients and in 22% of healthy controls (p < 0.001). There was a correlation between interleukin 6 and C-reactive protein, C-reactive protein and Chlamydia pneumoniae but not between Chlamydia pneumoniae and interleukin 6. Higher levels of interleukin 6 and C-reactive protein were seen with increasing body mass index, smoking exposure, presence of hypertension and diabetes, and decreasing ejection fraction. The patients with ST-segment elevation had higher examined markers than the patients without ST-segment elevation. Interleukin 6 and C-reactive protein were independently related to the clinical outcome. Conclusion. Interleukin 6, C-reactive protein and Chlamydia pneumoniae infection are connected with the development of acute coronary syndromes and may reflect a clinical outcome of the disease