Mechanistically identified suitable biomarkers of exposure, effect, and susceptibility for silicosis and coal-worker's pneumoconiosis: a comprehensive review

Clinical detection of silicosis is currently dependent on radiological and lung function abnormalities, both late manifestations of disease. Markers of prediction and early detection of pneumoconiosis are imperative for the implementation of timely intervention strategies. Understanding the underlying mechanisms of the etiology of coal workers pneumoconiosis (CWP) and silicosis was essential in proposing numerous biomarkers that have been evaluated to assess effects following exposure to crystalline silica and/or coal mine dust. Human validation studies have substantiated some of these proposed biomarkers and argued in favor of their use as biomarkers for crystalline silica- and CWP-induced pneumoconiosis. A number of "ideal" biological markers of effect were identified, namely, Clara cell protein-16 (CC16) (serum), tumor necrosis factor-alpha (TNF-alpha) (monocyte release), interleukin-8 (IL-8) (monocyte release), reactive oxygen species (ROS) measurement by chemiluminescence (neutrophil release), 8-isoprostanes (serum), total antioxidant levels measured by total equivalent antioxidant capacity (TEAC), glutathione, glutathione peroxidase activity, glutathione S-transferase activity, and platelet-derived growth factor (PDGF) (serum). TNF-alpha polymorphism (blood cellular DNA) was identified as a biomarker of susceptibility. Further studies are planned to test the validity and feasibility of these biomarkers to detect either high exposure to crystalline silica and early silicosis or susceptibility to silicosis in gold miners in South Africa.     

Cytokine production in whole blood ex vivo.

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) have been reported to contribute to the pathogenesis of many inflammatory diseases, e.g., rheumatoid arthritis. As monocytes are believed to be the primary source of these cytokines in peripheral blood, the present study was conducted to establish ranges and patterns of IL-1 beta and TNF-alpha secretion. Using heparinized unseparated whole blood obtained from normal human volunteers, peripheral blood monocytes were stimulated with Sal. minnesota LPS or BSA/anti-BSA immune complex-coated beads (BSA-beads). ELISAs for IL-1 beta and TNF-alpha were employed to quantitate cytokine levels in blood plasma without performing arduous and time-consuming extraction procedures. Over the course of a 6 hr incubation, LPS elicited a dose-dependent increase in TNF-alpha and IL-1 beta production. Preincubation of whole blood with interferon-gamma prior to the addition of a suboptimal dose of LPS or BSA-beads resulted in a synergistic potentiation of IL-1 beta/TNF-alpha production. Dexamethasone, utilized in the treatment of rheumatoid arthritis, proved to be a potent inhibitor of cytokine biosynthesis in whole blood ex vivo. The measurement of cytokine biosynthesis in a relevant physiologic environment not only avoids non-specific monocyte activation, but also may increase our ability to predict clinical outcomes in rheumatoid arthritis and/or other inflammatory diseases.     

Modified arabinoxylan rice bran (MGN3/Biobran) enhances intracellular killing of microbes by human phagocytic cells in vitro

Phagocytic cells, comprised of neutrophils and monocytes/macrophages, play a key role in the innate immune response to infection. Our earlier study demonstrated that arabinoxylan rice bran (MGN-3/Biobran) activates murine peritoneal macrophage and macrophage cell lines. In this study, we investigated whether MGN-3 can upregulate the phagocytic activity of human phagocytes in peripheral blood to phagocytize Escherichia coli (E. coli), trigger the oxidative burst and produce cytokines. Phagocytic cells were pre-labeled with dichlorofluorescin diacetate dye and were incubated with phycoerythrin-labeled E. coli in the presence or absence of MGN-3. Phagocytosis and oxidative burst were assessed by flow cytometry. Results showed that treatment with MGN-3 enhanced the phagocytosis of E. coli by neutrophils and monocytes. This was associated with an increased oxidative burst. In addition, it caused a significant induction of cytokines (TNF-alpha, IL-6, IL-8 and IL-10); the effect was detected at 1 microg/ml and increased in a dose-dependent manner (P 相似文献   

Pro-inflammatory cytokines in stable chronic alcoholics: relationship with fat and lean mass.

Cytokines are mediators of the inflammatory response, secreted by many tissues, including adipocytes. Chronic alcoholic liver disease and alcoholic hepatitis are associated with elevated serum cytokine levels which yield prognostic value in this situation. Most studies have been performed in patients with acute alcoholic hepatitis. However, cytokine alterations in stable alcoholics have been less studied, as is also the case for the relationship between cytokines and fat and lean mass in these patients. The aim of the present study was to analyse the relationships between some proinflammatory serum cytokine levels and lean mass, fat mass, nutritional status, and liver function parameters in stable alcoholic patients. We determined serum TNF-alpha, interleukin (IL)-6, IL-8 and TNF receptor 2 (TNFr2) in 77 male alcoholic patients in a stable phase (before hospital discharge). In all patients we performed a total-body composition analysis (Hologic DEXA), nutritional assessment including body mass index, triceps skinfold, brachial perimeter, and assessment of liver function. Forty-two healthy volunteer health workers served as controls. IL-8, TNF-alpha and TNFr2 were significantly higher in patients than in controls. No differences were observed between patients and controls regarding fat mass, but alcoholics showed significantly decreased lean mass than controls. Only IL-6 was significantly related with body fat in patients with elevated IL-6 levels. Poor relationships were observed between lean mass and cytokines; some nutritional parameters showed inverse relationships with serum TNF, whereas TNF and IL-8 were inversely related with albumin and prothrombin activity. Thus, cytokine levels were elevated in stable alcoholic patients, and IL-6 levels showed significant correlation with body fat mass, raising the possibility that adipose tissue contributes to the persistence of high levels of cytokines in stable alcoholics.     

Caffeine suppresses TNF-alpha production via activation of the cyclic AMP/protein kinase A pathway

This study investigated the effect of in vitro exposure to caffeine, and its major metabolite paraxanthine, at concentrations relevant to typical caffeine consumption in humans, on lipopolysaccharide (LPS)-stimulated cytokine production in human whole blood. In addition, a role for the cyclic AMP/protein kinase A (PKA) pathway in the immunomodulatory effect of caffeine was investigated. Diluted whole blood (taken following >/=15 h abstinence from caffeine-containing food and beverages) was preincubated with caffeine or paraxanthine (10-100 microM) and stimulated with LPS (1 proportional, variant g/ml) for 24 h. The proinflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-12, and the antiinflammatory cytokine IL-10 were measured in cell-free supernatants. Whilst caffeine and paraxanthine had little or no effect on IL-10, IL-1beta, or IL-12 production, TNF-alpha production was suppressed in all individuals studied. The effect was statistically significant at 100 microM and consistent across seven experiments performed. Although not statistically significant, a similar effect was observed with paraxanthine. Caffeine (100 microM) also increased intracellular cyclic AMP concentrations in LPS-stimulated monocytes isolated from whole blood. Moreover, the effect of caffeine on TNF-alpha production was abolished by pretreatment with the protein kinase A inhibitor Rp-8-Br-cAMPS (10(-4) and 10(-5)M). To conclude, this study demonstrates that concentrations of caffeine that are relevant to human consumption consistently suppress production of the proinflammatory cytokine TNF-alpha in human blood and that this effect is mediated by the cyclic AMP/protein kinase A pathway.     

Examination of lung toxicity, oxidant/antioxidant status and effect of erdosteine in rats kept in coal mine ambience

Occupational exposure to coal dust causes pneumoconiosis and other diseases. Reactive oxygen species (ROS) have been implicated in the pathogenesis of coal dust-induced lung toxicity. In this experimental study, we investigated the oxidant/antioxidant status, nitric oxide (NO) and hydroxyproline (HP) levels in lungs and blood of rats exposed to coal dust in mine ambience. In addition, we also investigated the attenuating effects of erdosteine. At the end of the experiment processes, tissue levels of HP, malondialdehyde (MDA) and NO, as well as the activities of superoxide dismutase, glutathione peroxidase, catalase, xanthine oxidase (XO), myeloperoxidase (MPO) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated in the lung tissues, plasma samples or erythrocytes of rats. Exposure to coal dust resulted in a significant increase in the oxidant parameters (MDA, NO levels, and XO activity) and HP levels, as compared to the controls. A decrease in activities of antioxidant enzymes, and an increase in MPO activity were found in the study group, compared to the controls. Increased NO levels of lung were found in the study groups, that were significantly reduced by erdosteine. Our studies provide evidence that supports the hypothesis for ROS mediated coal workers' pneumoconiosis. Erdosteine may be beneficial in the coal dust-induced lung toxicity via antioxidant and free radical scavenger properties.     

Cytokine production and treatment response in major depressive disorder.

In a controlled study, such immunological parameters as whole blood production of the cytokines interleukin-6 (IL-6) and tumor-necrosis factor-alpha (TNF-alpha) were assessed in 24 inpatients with a major depressive disorder (MDD) both before and again under treatment. After a 6-week treatment period with amitriptyline, patients were classified as responders or nonresponders according to their psychopathological outcome as evaluated by the Hamilton and the Montgomery-Asberg Depression Rating Scales. Pre-treatment levels of c-reactive protein (CRP) were significantly higher in both patient subgroups than in the control subjects. In comparison to the controls, unstimulated pretreatment production of IL-6 was significantly decreased in the responders; whereas it was significantly increased in the nonresponder subgroup. Post-treatment values did not differ significantly among the patient and control groups. Pretreatment levels of TNF-alpha were increased in both patient subgroups, with a significant decrease during treatment only in the responder subgroup. Pretreatment levels of IL-6/10(5) mononuclear cells and the ratio between lymphocytes and monocytes acted as independent variables with regard to the clinical response. Our data indicate that unstimulated secretion of TNF-alpha is related to the psychopathological improvement; whereas, IL-6 levels might dichotomize the patients into subsequent responders and nonresponders already at admission.     

度洛西汀对抑郁症患者血清microRNA和细胞因子水平的影响

目的探讨度洛西汀对抑郁症患者血清microRNA和细胞因子水平的影响。方法选取某院收治的抑郁症患者50例(抑郁症组),同期健康查体人群50例(对照组),采用real-time PCR及ELISA法检测两组人群血清miR-132、miR-182及细胞因子IL-1、IL-6、TNF-α水平。抑郁症患者给予度洛西汀治疗8周,比较治疗前后患者血清miR-132、miR-182及细胞因子水平有无差异。同时评价患者临床疗效,并分析临床疗效与血清miR-132、miR-182及细胞因子的相关性。结果 50例患者完成了8周治疗,其中痊愈22例,显效16例,好转8例,无效4例,显效率(痊愈+显效)为76.0%。抑郁症组患者血清miR-132、miR-182、IL-1、IL-6和TNF-α均显著高于对照组,且差异具有统计学意义(P<0.05);抑郁症组治疗后血清miR-132、miR-182和细胞因子IL-1、IL-6、TNF-α均显著降低(P<0.05)。分别以治疗前血清miR-132、miR-182、 IL-1、IL-6和TNF-α为预测度洛西汀显效的敏感性分别为78.2%、71.6%、75.3%、68.4%和66.9%,特异性分别为69.5%、65.8%、60.7%、66.5%和70.3%。诊断的ROC曲线下面积分别为0.73、0.68、0.66、0.64和0.69。结论抑郁症患者血清miR-132、miR-182、IL-1、IL-6和TNF-α显著高于健康人群。给予度洛西汀治疗后上述指标显著降低,并可作为判断度洛西汀疗效的生物学指标。     

Thalidomide's ability to augment the synthesis of IL-2 in vitro in HIV-infected patients is associated with the percentage of CD4+ cells in their blood

Thalidomide is used for treating erythema nodosum leprosum. It is also used to treat aphthous ulcers in HIV-infected patients. The mechanism of action of this drug is yet to be fully understood, but modulation of inflammatory cytokines like IL-2 and TNF-alpha may play a role. We investigated the effect of thalidomide on the production of IL-2 and TNF-alpha by staphylococcal enterotoxin A (SEA) stimulated peripheral blood mononuclear cells (PBMC) from HIV-infected patients. The PBMC from 20 patients was incubated in the presence of 4.0 microg/ml of thalidomide and 50 ng/ml of SEA. After 18 h, the culture supernatant was assayed for IL-2 and TNF-alpha. The PBMC incubated with thalidomide and SEA produced significantly more IL-2 than those incubated with SEA alone. The TNF-alpha secreted by the same cells incubated with thalidomide and SEA was not significantly different from that secreted by the cells incubated with SEA alone. The amount of IL-2 produced in the thalidomide and SEA treated cultures was directly correlated with the percentage of CD4+ cells in blood, and inversely correlated with the percentage of CD8+ cells in blood. No statistically significant correlations were found when comparing the amount of TNF-alpha produced in the thalidomide and SEA treated cultures with the percentage of CD4+ or CD8+ cells in the blood. Thalidomide can act, in vitro, as an additional stimulant to augment the synthesis of IL-2 in HIV-infected patients. Increased production of IL-2 by activated T-cells may be a mechanism through which it exerts its immunomodulatory effects.     

Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages.

Curcumin, a dietary pigment responsible for the yellow colour of curry, has been used for the treatment of inflammatory diseases and exhibits a variety of pharmacological effects such as anti-inflammatory activity. The mechanism in anti-inflammatory activity of curcumin has been investigated; however, little is known about the effect of curcumin on cytokine production by human peripheral blood monocytes and alveolar macrophages. In the present study, we shed light on the effect of curcumin on inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. To this end, we determined the concentrations of interleukin-8 (IL-8), monocyte inflammatory protein-1 (MIP-1alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-1beta (IL-1beta), and tumour necrosis factor-alpha (TNF-alpha) in the culture supernatants from phorbor ester, 4beta phorbor 12beta-myristate-13alpha acetate (PMA)- or lipo-polysaccharide (LPS)-stimulated monocytes and alveolar macrophages in the presence or absence of curcumin. Curcumin inhibited the production of IL-8, MIP-1alpha, MCP-1, IL-1beta, and TNF-alpha by PMA- or LPS-stimulated monocytes and alveolar macrophages in a concentration- and a time-dependent manner. These results show that curcumin exhibits an inhibitory effect on the production of IL-8, MIP-1alpha, MCP-1, IL-1beta, and TNF-alpha by PMA- or LPS-stimulated monocytes and alveolar macrophages.     

Effect of lead on the levels of some immunoregulatory cytokines in occupationally exposed workers

Lead (Pb) may affect humoral and cellular immunity, acting on lymphocytes as well as on granulocytes and monocytes. Cytokines and nitric oxide (NO) play a central role in the immune balance. In this study, plasma levels of nitrites and nitrates (NOx), IL2, IL4, IL6, IL10, TNF-alpha and INF-gamma, were measured in healthy workers with very low (Pb-B=3.2-18.0 microg/dL) and low (Pb-B=9.1-46.0 microg/dL) Pb-exposure compared to non-exposed workers. Low Pb-exposed workers (Pb-B=9.1 -46.0 microg/ dL) were found to have significantly higher plasma IL-10 levels, and tendentially higher plasma TNF-alpha levels compared to non-exposed workers. This is the first report of a significant increase of plasma IL-10 levels in Pb-exposed workers. Plasma IL-10 increase was influenced by blood Pb levels even after correction for main confounding factors. No difference was found in plasma NOx levels between Pb-exposed and non-exposed workers, which is in agreement with previous findings exclusively regarding groups in the general population. Low Pb-exposure can induce an increase of pro-inflammatory cytokines, such as TNF-alpha, with a consequent increase of other cytokines, such as IL-10, considered a T cell cross-regulatory factor, suggesting possible interference of Pb in the system of immunophlogosis.     

Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages

BACKGROUND AND PURPOSE: Macrophages release cytokines that may contribute to pulmonary inflammation in conditions such as chronic obstructive pulmonary disease. Thus, inhibition of macrophage cytokine production may have therapeutic benefit. p38 MAPK may regulate cytokine production, therefore, the effect of two p38 MAPK inhibitors, SB239063 and SD-282, on the release of TNF-alpha, GM-CSF and IL-8 from human macrophages was investigated. EXPERIMENTAL APPROACH: Cytokine release was measured by ELISA. Immunoblots and mRNA expression studies were performed to confirm p38 MAPK isoform expression and activity. Macrophages were isolated from lung tissue of current smokers, ex-smokers and emphysema patients and exposed to lipopolysaccharide. These cells then released cytokines in a concentration-dependent manner. KEY RESULTS: SB239063 only inhibited TNF-alpha release (EC50 0.3 +/- 0.1 microM). Disease status had no effect on the efficacy of SB239063. SD-282 inhibited both TNF-alpha and GM-CSF release from macrophages (EC50 6.1 +/- 1.4 nM and 1.8 +/- 0.6 microM respectively) but had no effect on IL-8 release. In contrast, both inhibitors suppressed cytokine production in monocytes. CONCLUSIONS AND IMPLICATIONS: The differential effects of p38 MAPK inhibitors between macrophages and monocytes could not be explained by differences in p38 MAPK isoform expression or activity. However, the stability of TNF-alpha mRNA was significantly increased in macrophages compared to monocytes. These data suggest a differential involvement for p38 MAPK in macrophage cytokine production compared with monocytes. These effects are not due to lack of p38 activation or p38alpha expression in macrophages but may reflect differential effects on the stability of cytokine mRNA.     

HEPC-based liposomes trigger cytokine release from peripheral blood cells: effects of liposomal size, dose and lipid composition

The immune response caused by liposome stimulation was studied by assessing the level of several cytokines released from human peripheral blood cells. Liposome stimulation resulted in the release of IL-6, IL-10, IL-1beta, TNF-alpha and IFN-gamma. The size of the liposomes affected the degree of the cytokine releases with larger sized liposomes causing higher levels of cytokine induction. In addition, it appears that the lipid composition of liposomes had no effect on the degree of cytokine release. The release of cytokines occurred even in the absence of serum, suggesting that serum proteins did not contribute to liposome stimulation in peripheral blood cells. The release of cytokines induced by liposome stimulation was inhibited by the presence of either protein kinase-C (PKC) or protein tyrosine kinase (PTK) inhibitor, but not by the presence of an endocytosis inhibitor. This indicates that signal transduction via PKC or PTK is necessary, in order for human peripheral blood cells to release cytokines (IL-6, IL-10, IL-1beta, TNF-alpha and IFN-gamma) as the result of liposome stimulation. These quantitative data on the release of cytokines by liposomal stimulation provide useful information for the development of rational drug delivery systems and the safety of cytokine induction via the use of liposomes.     

Effects of angiotensin II receptor blockade with valsartan on pro-inflammatory cytokines in patients with essential hypertension

Chronic inflammation is common in hypertension and acts as an independent determinant of arterial blood pressure. Hypertensive patients are reported to have high circulating levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). Recently, angiotensin II receptor blockers (ARBs) have been shown to possess benefits in addition to their ability to lower blood pressure, including anti-inflammatory and antioxidative properties within the vasculature. We evaluated the effects of the angiotensin II receptor blocker, valsartan, on these inflammatory cytokines. Thirty-nine patients with essential hypertension participated. These subjects received valsartan, 40 to 80 mg/day. Serum TNF-alpha, IL-6, CRP, and serum amyloid A (SAA) were measured before and after 3 months of treatment with valsartan. Valsartan significantly decreased systolic and diastolic blood pressure (160 +/- 16/92 +/- 11 mm Hg to 147 +/- 21/84 +/- 11 mm Hg, P = 0.001/P = 0.001, respectively). Serum TNF-alpha (9.1 +/- 8.6 pg/mL to 6.1 +/- 1.0 pg/mL, P = 0.006) and IL-6 (9.3 +/- 1.7 pg/mL to 8.9 +/- 1.4 pg/mL, P = 0.005) were significantly reduced after treatment with valsartan. However, C-reactive protein and serum amyloid A did not change. The angiotensin II receptor blocker, valsartan, may inhibit the development of atherosclerosis by lowering serum pro-inflammatory cytokines.     

Multiple mechanisms involved in the inhibition of proinflammatory cytokine production from human monocytes by N-(p-coumaroyl)serotonin and its derivatives

We have reported that N-(p-coumaroyl)serotonin(CS) isolated from safflower oil cake (Carthamus tinctorius L.) inhibits the production of proinflammatory cytokines by endotoxin (LPS)- stimulated human monocytes. In this study, the effects of CS and its three derivatives, N-(trans-cinnamoyl)serotonin (Cin.S), N-(trans-cinnamoyl)tryptamine (Cin.T), and N-(p-coumaroyl)tryptamine (CT) on the production of proinflammatory cytokines were compared. Cin.S possessed radical scavenging activity at a comparable level to CS, while CT and Cin.T exhibited lower activity, suggesting that hydroxyl group in serotonin is essential for the antioxidative activity. CS and CT strongly inhibited the production of proinflammatory cytokines (IL-1alpha, IL-1beta, IL-6, IL-8, and TNF-alpha) from LPS-stimulated human monocytes. However, Cin.S inhibited the production of only IL-1alpha and IL-1beta, and Cin.T inhibited none of these cytokines production. CS and CT markedly inhibited the protein synthesis in monocytes, the inhibitory effect of Cin.S was moderate, and that of Cin.T was quite weak. These results indicate that CS and its derivatives inhibit the production of proinflammatory cytokines through multiple mechanisms.     

强直性脊柱炎患者Th淋巴细胞功能的研究

目的:探讨辅助性T细胞(Th)Th1/Th2比例失衡及Th1/Th2细胞因子网络的异常在强直性脊柱炎(AS)发病机制中的作用。方法:利用酶联免疫吸附试验(ELISA)测定30例AS伴膝关节积液患者、20例正常对照血清及AS患者关节液中Th1/Th2型细胞因子肿瘤坏死因子-α(TNF-α)和白细胞介素(IL)-10;应用三色流式细胞分析法(FCM)检测外周血Th细胞(CD3+CD4+)比例及其胞浆内Th1/Th2细胞因子干扰素-γ(IFN-γ)和IL-4的表达;AS患者同时检测红细胞沉降率(ESR)及C-反应蛋白(CRP)。结果:(1)AS患者血清TNF-α和IL-10水平均明显高于正常对照组(P<0.01),AS患者关节液TNF-α水平高于血清水平(P<0.01),IL-10水平与血清中水平差异无统计学意义(P>0.05)。(2)AS患者外周血Th、Th2细胞(CD3+CD4+IL-4+)百分率与对照组差异无统计学意义(P>0.05),而Th1细胞(CD3+CD4+IFN-γ+)百分率及Th1/Th2比值高于对照组(P<0.01)。(3)AS患者血清中TNF-α的水平与ESR、CRP呈正相关(P<0.01或P<0.05);而IL-10水平、外周血Th1和Th2细胞百分率、Th1/Th2比值与ESR、CRP均无明显相关性(P>0.05)。结论:AS患者外周血存在Th1/Th2比例失衡,为Th1优势状态。Th1型细胞因子TNF-α在AS患者外周血及关节液中均呈现高水平表达。     

银屑病诱发药物对HaCaT角质形成细胞的影响

为了探讨锂盐、普萘洛尔和氯喹是否通过影响银屑病的细胞因子网络从而诱发或加重银屑病，以不同浓度的碳酸锂、盐酸普萘洛尔或二磷酸氯喹处理HaCaT角质形成细胞后加以TNF-α刺激，应用人类细胞因子抗体分析膜技术测定细胞培养液中多种细胞因子和生长因子的分泌情况；采用实时定量PCR法检测IL-8和IL-6 mRNA的表达。人类细胞因子抗体分析膜技术结果显示，碳酸锂明显促进IL-6和TNF-α的产生；盐酸普萘洛尔明显促进IL-6等多种细胞因子和生长因子的产生；二磷酸氯喹也明显促进IL-6的产生。实时定量PCR结果表明，TNF-α能刺激HaCaT角质形成细胞呈剂量依赖性增加IL-8和IL-6 mRNA的表达(P<0.01)；并对IL-8的调节作用更强(P<0.01)；1×10^-6 mol·L^-1盐酸普萘洛尔能显著上调IL-6 mRNA的表达(P<0.05)。碳酸锂、盐酸普萘洛和二磷酸氯喹对HaCaT角质形成细胞表达以及产生某些细胞因子和生长因子具有调节功能。     

Effect of luteinizing hormone-releasing hormone (LHRH) analogue treatment on a cytokine profile in prostate cancer patients

The aim of the study was to test serum concentrations of the chosen cytokines in patients with prostate cancer (PCa) treated with an luteinizing hormone-releasing hormone (LHRH) analogue. We tested interleukin (IL)-2, IL-10, tumor necrosis factor (TNF)-alpha, interferon (INF)-gamma in blood at three time points; I - before the injection, II - 10 days and III - 20 days after the injection in 14 men with PCa. Patients had one depot injection of the LHRH analogue monthly. The cytokine concentrations in serum samples were determined by ELISA method. Prostate specific antigen (PSA) level was examined before and after six months of the LHRH analogue treatment. After six months of the therapy, we observed normalization of serum PSA value from 16.48 ng/ml to 1.45 ng/ml. LHRH analogue injection resulted in a significant drop of the IL-2 concentration, and the value gradually returned to normal in the next 20 days. IL-10 concentration transiently increased and then was down-regulated. Serum TNF-alpha and INF-gamma concentrations in PCa patients were significantly lower compared to controls and were not affected by the treatment. LHRH analogue treatment in PCa patients modulates concentrations of the chosen cytokines which may result both in antitumor and a transient immunosuppressive effect.     

Nicotine could augment adhesion molecule expression in human endothelial cells through macrophages secreting TNF-alpha, IL-1beta

Nicotine, the major immunomodulatory components of cigarette smoking, is among the leading risk factors in atherosclerosis and various other diseases. The subject of this study is to observe how nicotine affects the function of macrophages and vascular endothelial cells. The changes of nicotine on releasing of cytokines from Ana-1 were detected by radio-immunoassay (RIA) or enzyme-link immunosorbent assay (ELISA). The adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) with Ana-1 supernatant-activated was evaluated through adhesion experiments. ELISA and RT-PCR methods examined expression of soluble adhesion molecular protein and their mRNA. Which cytokines in Ana-1 supernatant affecting HUVECs ability to express adhesion molecular were tested by adhesion blockade analysis and ELISA. The results showed TNF-alpha, IL-1beta could reach the peak with 0.06mM nicotine treated for 24 and 12 h on Ana-1, respectively, but IL-8 and IFN-gamma had no significant alter. Adhesion experiments proved treatment of HUVECs with supernatant of Ana-1 for 24 h obviously augmented the adhesion of monocytes to HUVECs. ELISA and PCR demonstrated expression of soluble intracellular adhesion molecule-1 protein (sICAM-1) increased sharply at 24 h, while soluble vascular cell adhesion molecule-1 protein (sVCAM-1) and soluble endothelial selectin protein (sE-selectin) rose at 9 h; ICAM-1, VCAM-1 and E-selectin mRNA had a similar tendency. Treatment of HUVECs with anti-TNF-alpha, anti-IL-1beta antibodies pre-neutralized supernatant of Ana-1 could block monocytes adhesion. In conclusion, our findings suggest that nicotine could augment macrophages releasing TNF-alpha and IL-1beta, furthermore TNF-alpha and IL-1beta could up-regulate the expression of adhesion molecule and increase adhesion of monocytes to HUVECs. These might be one of the reasons that leaded to endothelial dysfunction.