The differential diagnostic values of cytokine levels in pleural effusions

The aim is to examine whether the changes in pleural fluid interleukin (IL)-1beta, IL-2, IL-6, and IL-8 levels were significant in differential diagnosis of childhood pleural effusions. IL-1beta, IL-2, IL-6, and IL-8 levels in pleural fluids of all 36 patients were measured. The levels of IL-1beta, IL-2, IL-6, and IL-8 in pleural fluids were statistically significantly higher in the transudate group compared with those of the exudate group. The levels of IL-1 beta, IL-6, and IL-8 were also found to be statistically significantly higher in the empyema group compared with both the parapneumonic and the tuberculous pleural effusion groups. The levels of IL-2 and IL-6 were detected to be statistically significantly higher in the tuberculous pleural effusion group in comparison with those of the parapneumonic effusion group. The results showed that pleural fluids IL-1beta, IL-2, IL-6, and IL-8 could be used in pleural fluids exudate and transudate distinction.     

Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis

TNF and IFN-gamma are thought to be involved in the immune response to mycobacterial infection because they exhibit antimycobacterial effects in vitro. To investigate the roles of these cytokines in vivo at the site of disease activity in human tuberculosis, we evaluated local cytokine production in patients with tuberculous pleuritis. Both TNF and IFN-gamma were selectively concentrated 5- to 30-fold in pleural fluid, compared to blood of the same patients. Messenger RNA for both cytokines was detected in pleural tissue by in situ hybridization, suggesting that selective cytokine concentration is due to local cytokine production. Two Mycobacterium tuberculosis cell wall components, the protein-peptidoglycan complex and lipoarabinomannan, caused dose-dependent release of TNF by pleural fluid mononuclear cells and may constitute the stimuli for TNF production in the pleural space. In contrast to results obtained for TNF release, the protein-peptidoglycan complex, but not lipoarabinomannan, stimulated IFN-gamma release by pleural fluid mononuclear cells. The clinical manifestations of tuberculous pleuritis, such as fever, exudative pleural effusion, and tissue necrosis, may be due to the effects of elevated local TNF concentrations, produced in response to mycobacterial cell wall components.     

Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta

Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the development of heart failure. There is a direct correlation between myocardial function and myocardial TNF levels in humans. TNF may induce local inflammation to exert tissue injury. On the other hand, suppressors of cytokine signaling (SOCS) proteins have been shown to inhibit proinflammatory signaling. However, it is unknown whether TNF mediates myocardial inflammation via STAT3/SOCS3 signaling in the heart and, if so, whether this effect is through the type 1 55-kDa TNF receptor (TNFR1). We hypothesized that TNFR1 deficiency protects myocardial function and decreases myocardial IL-6 production via the STAT3/SOCS3 pathway in response to TNF. Isolated male mouse hearts (n = 4/group) from wild-type (WT) and TNFR1 knockout (TNFR1KO) were subjected to direct TNF infusion (500 pg.ml(-1).min(-1) x 30 min) while left ventricular developed pressure and maximal positive and negative values of the first derivative of pressure were continuously recorded. Heart tissue was analyzed for active forms of STAT3, p38, SOCS3 and SOCS1 (Western blot analysis), as well as IL-1beta and IL-6 (ELISA). Coronary effluent was analyzed for lactate dehydrogenase (LDH) activity. As a result, TNFR1KO had significantly better myocardial function, less myocardial LDH release, and greater expression of SOCS3 (percentage of SOCS3/GAPDH: 45 +/- 4.5% vs. WT 22 +/- 6.5%) after TNF infusion. TNFR1 deficiency decreased STAT3 activation (percentage of phospho-STAT3/STAT3: 29 +/- 6.4% vs. WT 45 +/- 8.8%). IL-6 was decreased in TNFR1KO (150.2 +/- 3.65 pg/mg protein) versus WT (211.4 +/- 26.08) mice. TNFR1 deficiency did not change expression of p38 and IL-1beta following TNF infusion. These results suggest that deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta.     

Compartmentalization of TNF and IL-6 in meningitis and septic shock

We examined the compartmentalization of bioactive tumour necrosis factor (TNF) and interleukin 6 (IL-6) to the subarachnoid space and systemic circulation in patients with meningococcal meningitis and septic shock/bacteraemia. In patients with meningitis, median levels of TNF in 31 paired samples of cerebrospinal fluid (CSF) and serum were respectively 783 pg/ml and below detection limit (p < 0.001) and median levels of IL-6 were 150 ng/ml and 0.3 ng/ml (p < 0.0001). In patients with septic shock without meningitis, median levels in paired samples of CSF and serum were respectively below detection limit and 65 pg/ml (not significant, (ns)) (TNF, eleven patients) and 1.3 ng/ml-3 ng/ml (ns) (IL-6, nine patients). The data show that TNF and IL-6 are localized to the subarachnoid space in patients with meningitis although the blood-brain barrier is penetrable to serum proteins. On the other hand, patients with septic shock tend to have cytokines in both serum and CSF.     

Relationship between circulating interleukin-10 (IL-10) with interleukin-6 (IL-6) type cytokines (IL-6, interleukin-11 (IL-11), oncostatin M (OSM)) and soluble interleukin-6 (IL-6) receptor (sIL-6R) in patients with multiple myeloma

We investigated the serum concentration of the interleukin-10 (IL-10), along with cytokines of interleukin-6 (IL-6) family (IL-6, IL-11 and oncostatin M - OSM), as well as soluble receptor for IL-6 (sIL-6R), in 121 patients with multiple myeloma (MM) and 28 healthy subjects. We studied the interactions between IL-10 and other cytokines, and the receptor. The correlation between IL-10 and some clinical and laboratory parameters associated with the disease activity were also analysed. The IL-10 was detectable in all patients with multiple myeloma and in all controls. The IL-10 concentration was significantly increased in myeloma patients compared with healthy persons (mean - 7.09 and 2.1 pg/ml, respectively) (p = 0.008). The level of IL-10 correlated positively with the advanced stage of disease estimated according to the Salmon and Durie classification (I versus III stage - p = 0.03). Higher values of IL-10 were found in patients with the light chain disease, hypercalcaemia, and correlated with the elevated concentrations of C-reactive protein (CRP). IL-6 was detected in 117 of the 121 patients and in all controls. The concentration of IL-6 was statistically increased in MM patients compared with control group (mean - 16.06 and 4.49 pg/ml, respectively) (p = 0.01). We found a positive correlation between IL-10 and IL-6 serum levels in MM patients. The relationship, expressed as Spearman's rank sum coefficient (rho = 0.249, p = 0.006) was significant. IL-11 was detected in 26 of the 121 MM patients and in 3 of the 28 healthy subjects at the mean concentration of 1.2 and 0.6 pg/ml respectively (p > 0.05). OSM was at detectable levels in 51 of the 121 patients and in only 4 of the 28 controls (mean - 3.84 and 0.1 pg/ml, p = 0. 002). The correlation between IL-10 and IL-11 levels in MM patients was not significant, but there was a strong statistical correlation between IL-10 and OSM concentrations (rho= 0.327, p = 0.0002). The serum concentration of sIL-6R was measurable in all patients and all controls (mean - 66.00 and 39.57 ng/ml respectively), but the difference between these groups was not significant. We found significant, positive correlation between the levels of IL-10 and sIL-6R (rho= 0.233, p = 0.01). In conclusion, we state that the serum concentrations of IL-10, IL-6, OSM and sIL-6R in MM patients may be a useful markers for the evaluation of the disease activity.     

细胞因子IFN-γ,IL-2,TNF-α和ADA对结核性和恶性胸腔积液鉴别诊断的价值

目的：探讨细胞因子γ-干扰素（IFN-γ）、白介素-2（IL-2）、肿瘤坏死因子-α（TNF-α）和腺苷脱氨酶（ADA）对结核性和恶性胸腔积液的鉴别诊断的价值。方法：以2012年9月至2013年3月期间在青岛大学医学院附属医院呼吸科及青岛胸科医院未经治疗的胸腔积液患者为研究对象,其中恶性胸腔积液患者46例,结核性胸腔积液患者42例。采用双抗体夹心酶联免疫吸附测定法（ELISA）分别检测结核性和恶性胸腔积液患者中IFN-γ、IL-2、TNF-α及ADA的表达情况。并应用ROC曲线分析两组患者胸腔积液中IFN-γ、IL-2、TNF-α及ADA的表达差异及意义。结果：结核性胸腔积液组IFN-γ、IL-2、TNF-α及ADA的表达明显高于恶性胸腔积液组,差异有统计学意义（t=8.118、8.126、8.066、7.221;P=0.000、0.000、0.000、0.000,P〈0.001）;ROC曲线分析结果显示胸腔积液中IFN-γ、IL-2、TNF-α及ADA的诊断临界值为201.45 pg/mL、41.91 pg/mL、21.55 pg/mL、33.78 U/L;诊断敏感度分别为91.3%、93.5%、91.2%、89.1%;特异度分别为91.0%、92.1%、89.9%、90.1%。结论：胸腔积液中IFN-γ、IL-2、TNF-α及ADA的表达对结核性和恶性胸腔积液诊断与鉴别诊断具有重要参考价值。     

Modulation of IL-1 inflammatory and immunomodulatory properties by IL-6.

Among the major cytokines present in inflammatory lesions interleukin-1 (IL-1), tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) share many biological activities. Since IL-1 alpha, IL-1 beta and TNF alpha have been previously demonstrated to play an important role in connective tissue destruction by stimulating the production of prostaglandin E2 (PGE2) and collagenase, these functions were investigated in the presence or absence of natural human IL-6 (nhIL-6) or recombinant human IL-6 (rhIL-6). IL-6 was found 1 degree to stimulate immunoglobulin A production by the CESS B cell line up to 19 fold without being affected by the presence of IL-1 beta and 2 degrees to stimulate murine thymocytes proliferation up to 2-4 fold, with an increase up to 60-fold in costimulation with either IL-1 alpha or beta. IL-6 alone, even at very high concentrations (up to 200 U/ml and 50 ng/ml), did not induce PGE2 production by fibroblasts and synovial cells. However, IL-1 alpha or beta induced PGE2 production by human dermal fibroblasts and by human synovial cells was inhibited (in 5/8 experiments) up to 62% by addition of IL-6. On the contrary in 2/4 experiments TNF alpha-induced PGE2 production was increased (approximately 2 fold) by the addition of IL-6. IL-1 and TNF alpha-induced collagenase production in synovial cells remained unchanged in the presence of IL-6.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased plasma macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels in type 1 Gaucher disease

Pancytopenia, hepatosplenomegaly and skeletal complications are hallmarks of Gaucher disease. Monitoring of the outcome of therapy on skeletal status of Gaucher patients is problematic since currently available imaging techniques are expensive and not widely accessible. The availability of a blood test that relates to skeletal manifestations would be very valuable. We here report that macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, both implicated in skeletal complications in multiple myeloma (MM), are significantly elevated in plasma of Gaucher patients. Plasma MIP-1alpha of patients (median 78 pg/ml, range 21-550 pg/ml, n=48) is elevated (normal median 9 pg/ml, range 0-208 pg/ml, n=39). Plasma MIP-1beta of patients (median 201 pg/ml, range 59-647 pg/ml, n=49) is even more pronouncedly increased (normal median 17 pg/ml, range 1-41 pg/ml, n=39; one outlier: 122 pg/ml). The increase in plasma MIP-1beta levels of Gaucher patients is associated with skeletal disease. The plasma levels of both chemokines decrease upon effective therapy. Lack of reduction of plasma MIP-1beta below 85 pg/ml during 5 years of therapy was observed in patients with ongoing skeletal disease. In conclusion, MIP-1alpha and MIP-1beta are elevated in plasma of Gaucher patients and remaining high levels of MIP-1beta during therapy seem associated with ongoing skeletal disease.     

Enhancement of IL-6 receptor beta chain (gp130) expression by IL-6, IL-1 and TNF in human epithelial cells.

Analysis of the IL-6 Receptor beta chain (gp130) mRNA expression on the two human epithelial cell lines UAC and Hep3B reveals that it is enhanced by IL-6, IL-1 and TNF treatment. In the case of UAC cells, TNF action might be mediated by IL-6. For Hep3B cells, TNF seems to exert a direct effect on gp130, as no IL-6 expression is detected after stimulation by this cytokine. On the same cells, increase of the binding of an anti-gp130 monoclonal antibody was observed after treatment by TNF, which denotes the effective appearance of new gp130 molecules on the cell surface. All this cytokines seem to act selectively on the beta chain of the IL-6 receptor. This probably reflects the importance for some cells to have gp130 represented on their membrane in inflammatory contexts.     

Levels of soluble VCAM-1, soluble ICAM-1, and soluble E-selectin in patients with tuberculous pleuritis

Tuberculosis is characterized by the presence of activated mononuclear cells both in the peripheral circulation and in pleural fluid. Expression and up-regulation of adhesion molecules is the basis of cell-cell adhesion in granuloma formation and in leukocyte migration to the inflammatory site. Soluble isoforms of adhesion molecules have been described, and their expression at high levels indicated an activated state. The purpose of this study was to evaluate levels of soluble adhesion molecules in serum and pleural fluid from patients with tuberculous pleural effusions, compared with non-tuberculous pleural effusions. We analysed levels of soluble vascular cell adhesion molecule-1 (s.VCAM-1), soluble intercellular adhesion molecule-1 (s.ICAM-1), and soluble E-selectin (sE-selectin) in serum and pleural fluid from patients with tuberculous pleuritis, by sandwich ELISA. Serum levels of s.ICAM-1 and s.VCAM-1 in patients with tuberculosis were higher than those in healthy controls (p < 0.001). Levels of sE-selectin levels were in the normal range compared with control groups. In pleural fluid, levels of s.VCAM-1 and s.ICAM-1 were increased in pleural effusions. Patients with tuberculous pleural effusion exhibited high levels of s.ICAM-1 compared with patients with neoplastic pleural involvement. Up-regulation of s.VCAM-1 and s.ICAM-1 in serum, along with increased levels of sE-selectin in pleural effusions from tuberculous patients, may result in transmigration of activated inflammatory cells inducing pleural damage, which may contribute to the pathological processes involved.     

Plasma levels of interleukin-12 (IL-12), interleukin-18 (IL-18) and transforming growth factor beta (TGF-beta) in Plasmodium falciparum malaria

The interaction between pro- and anti-inflammatory cytokines such as interleukin 12 (IL-12), interleukin 18 (IL-18) and transforming growth factor beta (TGF-beta) may play an important role in malaria pathogenesis and outcome. IL-18 cooperates with IL-12 in the IFN-gamma production by T, B, and NK cells, and synergizes with IL-12 for IFN-gamma production by Th1 cells. Recently it has been demonstrated that these cytokines modulate the immunoresponse in Plasmodium falciparum malaria. The aim of this study was to measure the plasma levels of IL-12, IL-18 and TGF-beta in 105 African children with various degrees of malaria, and correlate the production of these cytokines with the severity of the disease. IL-12, IL-18 and TGF-beta levels were determined using enzyme-linked immunosorbent assay. The severity of malaria was established by parasitemia, clinical symptoms and haematological parameters. The levels of IL-12, IL-18 and TGF-beta were found to be significantly elevated (15.6 + / - 12.3, 22.7 + / - 13.8 pg/ml and 25.14 + / - 13.22 pg/ml respectively) in all of the children. IL-12 and IL-18 levels were significantly lower (13.2 + / - 5.53 and 21.5 + / - 10 pg/ml pg/ml) in children with severe disease, whereas the level of TGF-beta was higher (28.09 + / - 12.39 pg/ml). In contrast, IL-12 and IL-18 levels were found to be higher (17.32 + / - 7.8 pg/ml and 25.7 + / - 7.6 pg/ml) in patients with mild disease, whereas the level of TGF-beta was lower (20.92 + / - 12.76 pg/ml) compared to the severe malaria group. The correlation between IL-12 and IL-18 demonstrated a progressive relationship up to a value of IL-12 < 25 pg/ml, while IL-18 remained stable at higher levels of IL-12. An inverse correlation was found between IL-12 and TGF-beta up to a value of IL-12 < 30, after which the level of TGF-beta remained stable. This finding suggests that fine mechanisms regulate the interaction between IL-12, IL-18 and TGF-beta in the immune response to Plasmodium falciparum.     

Cytokine regulation of IL-1 beta gene expression in the human polymorphonuclear leukocyte

Although recently polymorphonuclear leukocytes (PMN) have been identified as producers of IL-1 beta in response to LPS and granulocyte/monocyte colony stimulating factor, little is known regarding the ability of other cytokines to induce the production of IL-1 beta in the PMN. Inasmuch as IL-1 and TNF have been shown to be important priming agents, as well as agents that induce migration of PMN, we investigated their effect on IL-1 beta gene expression in human peripheral blood PMN. In the present study, we demonstrate that human peripheral blood PMN produce IL-1 beta in response to IL-1 alpha, IL-1 beta, and TNF-alpha. Control (unstimulated) human PMN had virtually undetectable levels of IL-1 beta mRNA. Either IL-1 beta or TNF, induced PMN to transiently express IL-1 beta mRNA with peak expression at 1 h, returning to untreated levels by 2 h. A dose response indicated that as little as 0.05 ng/ml of IL-1 beta or TNF resulted in IL-1 beta induction, with maximal effects at 1 ng/ml of IL-1 beta and 5 ng/ml of TNF. IL-1 alpha or IL-1 beta exhibited similar dose responses in IL-1 beta mRNA induction. Inasmuch as cytokines have been shown to have synergistic effects in cell function studies, we induced PMN with a combination of maximally effective doses of TNF plus IL-1 beta. They demonstrated a cooperative effect on IL-1 beta gene expression, in that mRNA levels were sustained for three hours. IL-1 beta Ag expression, as measured by ELISA, paralleled IL-1 beta mRNA expression with cell associated peak levels at 2 to 4 h. IL-1 beta Ag levels in PMN lysates and supernatants correlated with IL-1 beta mRNA levels, i.e., TNF + IL-1 greater than TNF greater than IL-1. Thus, these studies represent the first demonstration of IL-1 and TNF induction of IL-1 beta gene expression in the PMN. Furthermore, the time course of induction is unique to the PMN, with peak induction of mRNA at 1 h, which is consistent with the short lived nature of these cells in inflammatory lesions.     

Serum IL-1beta, IL-2, and IL-6 in insulin-dependent diabetic children

Insulin-dependent diabetes mellitus (IDDM) is a chronic disease characterized by T-cell-dependent autoimmune destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans, resulting in an absolute lack of insulin. T cells are activated in response to islet-dominant autoantigens, the result being the development of IDDM. Insulin is one of the islet autoantigens responsible for the activation of T-lymphocyte functions, inflammatory cytokine production, and development of IDDM. The aim of this study was to investigate serum concentrations of interleukin (IL)-1beta, IL-2, IL-6, and tumor necrosis factor (TNF)-alpha in children IDDM. The study population consisted of 27 children with IDDM and 25 healthy controls. Children with IDDM were divided into three subgroups: (1) previously diagnosed patients (long standing IDDM) (n : 15), (2) newly diagnosed patients with diabetic ketoacidosis (before treatment) (n : 12), and (3) newly diagnosed patients with diabetic ketoacidosis (after treatment for two weeks) (n : 12). In all stages of diabetes higher levels of IL-1beta and TNF-alpha and lower levels of IL-2 and IL-6 were detected. Our data about elevated serum IL-1beta, TNF-alpha and decreased IL-2, IL-6 levels in newly diagnosed IDDM patients in comparison with longer standing cases supports an activation of systemic inflammatory process during early phases of IDDM which may be indicative of an ongoing beta-cell destruction. Persistence of significant difference between the cases with IDDM monitored for a long time and controls in terms of IL-1beta, IL-2, IL-6, and TNF-alpha supports continuous activation during the late stages of diabetes.     

Cell origins and diagnostic accuracy of interleukin 27 in pleural effusions

The objective of the present study was to investigate the presence of interleukin (IL)-27 in pleural effusions and to evaluate the diagnostic significance of pleural IL-27. The concentrations of IL-27 were determined in pleural fluids and sera from 68 patients with tuberculous pleural effusion, 63 malignant pleural effusion, 22 infectious pleural effusion, and 21 transudative pleural effusion. Flow cytometry was used to identify which pleural cell types expressed IL-27. It was found that the concentrations of pleural IL-27 in tuberculous group were significantly higher than those in malignant, infectious, and transudative groups, respectively. Pleural CD4(+) T cells, CD8(+) T cells, NK cells, NKT cells, B cells, monocytes, macrophages, and mesothelial cells might be the cell sources for IL-27. IL-27 levels could be used for diagnostic purpose for tuberculous pleural effusion, with the cut off value of 1,007 ng/L, IL-27 had a sensitivity of 92.7% and specificity of 99.1% for differential diagnosing tuberculous pleural effusion from non-tuberculous pleural effusions. Therefore, compared to non-tuberculous pleural effusions, IL-27 appeared to be increased in tuberculous pleural effusion. IL-27 in pleural fluid is a sensitive and specific biomarker for the differential diagnosing tuberculous pleural effusion from pleural effusions with the other causes.     

Mechanisms of dimethyl sulfoxide augmentation of IL-1 beta production

Expression of the inflammatory cytokine IL-1beta occurs in various inflammatory diseases, and IL-1beta production is regulated at multiple levels. There are conflicting reports about the effects of antioxidants on IL-1beta production. In this study, we investigated the regulatory role of the antioxidant DMSO on LPS-stimulated IL-1beta gene expression in human PBMC and in vivo. This study demonstrated that 1% DMSO increased LPS-stimulated (50 ng/ml) IL-1beta secretion in a dose- and time-dependent manner without altering TNF or IL-6. DMSO also elevated IL-1beta secretion by PBMC in response to exogenous superoxide anions. Despite the increase in IL-1beta, there was no augmentation of NF-kappaB with the addition of DMSO. The steady state mRNA coding for IL-1beta following LPS stimulation was also increased. Cycloheximide studies demonstrated that the DMSO augmentation of IL-1beta mRNA did not require de novo protein synthesis, and studies with actinomycin D showed that DMSO did not alter the half-life of IL-1beta mRNA, suggesting that DMSO did not change the stability of IL-1beta mRNA. Experiments using a reporter vector containing the 5'-flanking region of the human IL-1beta gene revealed that DMSO augmented LPS-induced IL-1beta reporter activity. In vivo, treatment of mice with DMSO significantly increased plasma levels of IL-1beta after endotoxin challenge. These data indicate that DMSO directly increases LPS-stimulated IL-1beta protein production through the mechanisms of augmenting promoter activity and increasing mRNA levels.     

Adenosine deaminase activity is a sensitive marker for the diagnosis of tuberculous pleuritis in patients with very low CD4 counts

Background

Adenosine Deaminase Activity (ADA) is a commonly used marker for the diagnosis of tuberculous pleural effusion. There has been concern about its usefulness in immunocompromised patients, especially HIV positive patients with very low CD4 counts. The objective of this study was to evaluate the sensitivity of ADA in pleural fluid in patients with low CD4 counts.

Materials and Methods

This was a retrospective case control study. Medical files of patients with tuberculous pleuritis and non-tuberculous pleuritis were reviewed. Clinical characteristics, CD4 cell counts in blood and biochemical markers in pleural fluid, including ADA were recorded.

Results

One ninety seven tuberculous pleuritis and 40 non- tuberculous pleuritis patients were evaluated. Using the cut-off value of 30 U/L, the overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ADA was 94%, 95%, 19, and 0.06 respectively. The mean CD4 cell counts among TB pleuritis patients was 29 and 153 cells/microL in patients with CD4 <50 cells/microL and >50 cells/microL, (p<0.05) respectively. The corresponding mean ADA values for these patients were 76 U/L and 72 U/L respectively (p>0.5). There was no correlation between ADA values and CD4 cell counts (r = −0.120, p = 0.369).

Conclusion

ADA analysis is a sensitive marker of tuberculous pleuritis even in HIV patients with very low CD4 counts in a high TB endemic region. The ADA assay is inexpensive, rapid, and simple to perform and is of great value for the immediate diagnosis of tuberculous pleuritis while waiting for culture result and this has a positive impact on patient outcome.     

IL-1beta and IL-6 modulate apolipoprotein E gene expression in rat hepatocyte primary culture

Incubation of rat hepatocytes in primary culture with IL-1beta at a concentration of 2.5 units/ml resulted in an increase (+80%) in the amount of apoE mRNA without any effect upon apoE synthesis. IL-6 at a low concentration (10 units/ml) induced a decrease (-35%) in the amount of apoE mRNA, but increased apoE synthesis (+28%). No effect was observed with higher concentrations of IL-1beta (10 units/ml) or IL-6 (100 units/ml). These results suggest that inflammatory cytokines IL-1beta and IL-6 modulate the expression of apoE gene in cultured rat hepatocytes, at a concentration that does not induce the acute phase response.     

Differential effects of copper and zinc on human peripheral blood monocyte cytokine secretion

The addition of copper and zinc salts to human peripheral blood leukocytes cultured in complete medium containing endotoxin and fetal calf serum stimulated tumor necrosis factor (TNF) secretion in a concentration-dependent manner. The secretion of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) was inhibited by copper under the same culture conditions, while zinc stimulated IL-1 beta secretion in a concentration-dependent manner and had no effect on leukocyte IL-6 release. Both copper and zinc induced increases in TNF mRNA (54 and 14%, respectively) when compared to cells cultured in complete medium alone. In serum-free, low endotoxin medium (less than 6 pg/ml), both copper and zinc failed to stimulate either TNF or IL-1 beta secretion. Under the same conditions the addition of lipopolysaccharide (LPS), at concentrations above 0.01 micrograms/ml, induced a concentration-dependent release of both cytokines. When either copper or zinc were combined with 0.01 micrograms/ml LPS, a synergistic stimulation of TNF secretion resulted. IL-1 beta secretion, unlike TNF, was not synergistically stimulated by combining metals and LPS in serum-free medium. Combining copper and zinc with inhibitors of TNF secretion, transforming growth factor beta, prostaglandin E2, and plasma alpha-globulins, resulted in a reduction of the suppressive effects of each of these agents. This study suggests that the trace metals copper and zinc may play important and possibly distinct roles in regulating leukocyte secretion of TNF, IL-1 beta, and IL-6.