Proinflammatory cytokine (IL-1beta, IL-6, IL-12, IL-18 and TNF-alpha) levels in sera of patients with subacute cutaneous lupus erythematosus (SCLE)

Subacute cutaneous lupus erythematosus (SCLE) is a subset of lupus erythematosus that identifies patients with clinically recognized erythematous, nonscarring lesions, photosensitivity and serologic abnormalities. Anti-Ro (SS-A) antibodies are considered to be a typical immunopathologic marker of SCLE. Autoimmune diseases have been also characterized by the disturbances in the cytokine network. The aim of this study was to compare the concentrations of proinflammatory cytokines (IL-1beta, IL-6, IL-12, IL-18 and TNF-alpha) in serum of ANA-positive (antibody against nuclear antigen) and ANA-negative patients with SCLE. Sera samples were collected from 15 patients with SCLE (9 ANA-positive and 6 ANA-negative ones). The preliminary identification of autoantibodies as well as their titers was determined on HEp-2 cells using IIF method. Western blotting (EUROIMMUN) was applied to verify the results of IIF. Proinflammatory cytokine concentrations in the patients' sera samples were determined by enzyme-linked immunosorbent assay (ELISA) (Bender MedSystems). The levels of IL-12 were higher in ANA-positive patients than in ANA-negative subgroups [median (interquartile range), 330 pg/ml (128-708 pg/ml) versus 39.4 pg/ml (31.25-80 pg/ml)]. Similar differences were observed in the level of IL-18 [median (interquartile range), 508.4 pg/ml (180-1222 pg/ml) versus 100.5 pg/ml (78.1-154 pg/ml)]. The differences in TNF-alpha levels between the groups of ANA-positive and ANA-negative patients were at the verge of statistical significance, p<0.05. The sera levels of IL-1beta and IL-6 were low and of no significant difference concerning the ANA-positive and ANA-negative subgroups. Since serum levels of IL-12 and IL-18 were higher in ANA-positive patients than in ANA-negative patients, these cytokines might play an important role in the inflammatory process in SCLE.     

In vitro tumor necrosis factor-alpha secretion by monocytes from patients with cystic fibrosis.

Immunoreactive tumor necrosis factor-alpha (TNF-alpha) concentration is increased in plasma from patients with cystic fibrosis and chronic Pseudomonas aeruginosa pulmonary infection. To determine if circulating monocytes could be the source of plasma TNF-alpha, we determined in vitro basal and endotoxin-stimulated TNF-alpha secretion by monocytes. In 10 adult patients studied at the time of a symptomatic respiratory exacerbation, basal secretion of TNF-alpha was significantly less than that for 10 matched healthy controls (median 265 pg/micrograms DNA, nonparametric 95% confidence interval 193 to 463 pg/micrograms DNA versus 575, 298 to 923 pg/micrograms DNA; P less than 0.006), although both groups responded equally effectively to added Escherichia coli endotoxin at greater than or equal to 25 ng/ml. In six patients and six matched controls, monocyte culture was repeated after completion of 2 wk anti-pseudomonal antibiotic treatment in the patients. The reduced basal TNF-alpha secretion in the patients had reversed and was not significantly different to that of controls. This effect mirrored a significant reduction in plasma immunoreactive TNF-alpha in these patients (mean +/- SD, 258 +/- 59.3 pg/ml pretreatment versus 133 +/- 47.8 pg/ml post-treatment; P less than 0.05). These findings suggest that a reversible downregulation of TNF-alpha secretion occurred at the time of a symptomatic respiratory deterioration in the presence of chronic P. aeruginosa infection. This may represent a physiologic regulatory mechanism to maintain a local inflammatory response to chronic pulmonary infection in cystic fibrosis.     

Altered Generation of Interleukin 1 in Chronic Human Schistosomiasis Mansoni

Chronic schistosomiasis mansoni is associated with impaired cell-mediated immune responsiveness (CMI). To assess co-stimulatory factors essential in the induction phase of CMI, interleukin 1 (IL-1) concentration was determined in the sera and cell culture supernatants of Schistosoma mansoni-infected patients, and circulating monocytes were phenotyped, labelling membrane IL-1 and HLA-DP. In addition, adherent cell oxidative-burst capacity was investigated. Since involvement of IL-1 beta in the pathogenesis of severe granulomatous lesions could not be ruled out, 17 patients with intestinal schistosomiasis and 17 patients with hepatosplenic schistosomiasis were matched for intensity of infection and monitored 3-6 months after praziquantel therapy. Seventeen age- and sex-matched uninfected residents of the study area in Alagoas, Brazil, acted as controls. Whereas schistosomiasis patients and controls did not differ in the expression of monocyte surface antigens and the capacity of adherent cells to generate H2O2, IL-1 beta release by monocytes in vitro was significantly reduced in both intestinal and hepatosplenic patients. Low concentrations of circulating IL-1 beta were detected in comparable frequencies in untreated patients and controls. Three months after therapy, IL-1 beta was detectable in serum in an increased proportion of intestinal schistosomiasis patients. IL-1 release in vitro gradually increased in all patients and reached control values 6 months after therapy.     

Serum levels of tumor necrosis factor-alpha, interleukin-1, and interferon-gamma in beta(o)-thalassemia/HbE and their clinical significance.

Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), and interferon-gamma (IFN-gamma) were estimated by conventional ELISA kits in 60, 42, and 58 Thai patients, respectively, with beta(o)-thalassemia HbE and found to be above the normal range in 13%, 21%, and 33% of the patients, respectively. Using high-sensitivity ELISA systems, an additional 10 beta(o)-thal/HbE patients were compared with 9 controls for concentrations of circulating TNF-alpha and IL-1beta, and 9 and 5 patients, respectively, but only 1 and none of the controls, respectively, showed values above the normal ranges. In patients with abnormally high IFN-gamma levels, basal hemoglobin values were significantly lower than in those with normal levels of the cytokine (mean +/- SEM: 6.03+/-0.24 vs. 7.08+/-0.18, p < 0.05), although circulating concentrations of soluble transferrin receptors (sTrF) and absolute reticulocyte counts were similar in the two groups. Patients with raised or normal levels of TNF-alpha, IL-1alpha, or IL-1beta had similar basal hemoglobin values. In a phagocytosis assay, monocytes of patients with raised serum levels of IFN-gamma showed significantly more attached or ingested IgG-coated red cells than those of patients with normal concentrations of the cytokine (mean +/- SEM: 192+/-22 vs. 140+/-14 per 100 monocytes, p < 0.05). Moreover, in 3 of 4 of the former patients, the number of attached or ingested IgG-coated red cells per 100 monocytes was above the 95% reference limit for the latter patients. The results suggest that IFN-gamma aggravates the anemia of beta(o)-thal/HbE by activating mononuclear phagocytes for destruction of red cells but not by inhibiting erythropoiesis. The elevated serum levels of TNF-alpha and IL-1 could contribute to complications of the disease, such as cachexia and thromboembolic phenomena.     

Circulating monocytes in patients with acute coronary syndromes lack sufficient interleukin-10 production after lipopolysaccharide stimulation

Acute coronary syndromes (ACS) are associated with inflammation resulting from monocyte activation. We sought for differences in the production of pro- and anti-inflammatory cytokines by monocytes from patients with ACS. C-reactive protein (CRP) and neopterin were measured in 22 patients with acute coronary syndromes, 50 patients with stable vascular disease and 22 healthy controls. Production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 was determined after, respectively, 6 and 24 h of incubation of full blood with lipopolysaccharide (LPS). Levels of CRP [median, interquartile range (IQR)][1.5 mg/l (0.8-4.5) ACS patient versus 2.1 (0.9-3.6) stable disease versus 0.4 (0.3-1.2) healthy controls] (P < 0.001) and neopterin [7.4 nmol/l (6.0-8.7) ACS patient versus 7.1(6.0-8.9) stable disease versus 6.4 (5.6-7.3) healthy controls] (P = 0.07) were higher in both the patient groups. IL-10 production after LPS stimulation was greatly reduced in patients with acute coronary syndromes (16 175 pg/ml, 7559-28 470 pg/ml) as opposed to patients with stable disease (28 379 pg/ml, 12 601-73 968 pg/ml) and healthy controls (63 830 pg/ml, 22 040-168 000 pg/ml) (P = 0.003). TNF-alpha production was not signi fi cantly different between the groups [7313 pg/ml (4740-12 615) ACS patient versus 11 002 (5913-14 190) stable disease versus 8229 (5225-11 364) healthy controls] (P = 0.24). Circulating monocytes in unstable coronary syndromes produce equal amounts of TNF-alpha but less IL-10 after stimulation with LPS in vitro as compared with healthy controls. We hypothesize that, in acute coronary syndromes, the production proinflammatory cytokines is not counterbalanced by anti-inflammatory cytokines such as IL-10.     

Variations in serum levels of interleukin (IL)-1beta, IL-2, IL-6, and tumor necrosis factor-alpha during specific immunotherapy.

BACKGROUND: Cytokine production by T helper cells is essential for the induction and maintenance of allergic inflammation in the bronchial mucosa. According to recent views, specific immunotherapy (SIT) favors the differentiation of T lymphocytes into cells of the Th1 rather than those of the Th2 subset. OBJECTIVE: To determine whether or not SIT induces a decrease in the inflammatory reaction by studying eventual variations in the serum levels of IL-1beta, IL-2, IL-6, and TNF-alpha in allergic subjects during SIT. METHODS: Serum levels of IL-1beta, IL-2, IL-6, and TNF-alpha were determined before and after 3, 6, and 9 months of SIT by an immunoradiometric assay (IRMA) in 11 adults with perennial allergic asthma and/or rhinitis caused by house dust mites and in 6 nonatopic healthy volunteers. RESULTS: Median serum IL-1beta and TNF-alpha levels of the patients were significantly higher at baseline than those of the controls and decreased during SIT to values similar to or lower (P < .01) after 6 months of SIT for TNF-alpha than those of the controls. Median serum IL-2, significantly lower at baseline than in the controls, increased during SIT to a level similar to that of the controls. Although the median values of IL-1beta and TNF-alpha in the patients tended to decrease and those of IL-2 to increase during SIT, the differences were not significant; the correlation coefficients (r) of the serum levels of IL-1beta IL-6, and TNF-alpha versus duration of SIT were negative, while that of IL-2 was positive. CONCLUSIONS: Decreases in median serum IL-1beta and TNF-alpha levels during SIT, together with the increases in serum IL-2 and IL-6, compared with those of the controls furnish evidence supporting a reduction in the inflammatory response in the course of SIT.     

Membrane molecules which trigger the production of interleukin-1 and tumor necrosis factor-alpha by lipopolysaccharide-stimulated human monocytes.

We have investigated the role of the membrane molecules CD11/CD18 and CD14 which may mediate the binding of lipopolysaccharide (LPS) to human monocytes, in the induction of the production and release of interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha) by LPS-stimulated cells. Blockade of CD11a, CD11b and CD18 with saturating concentrations of specific mAb did not inhibit the release of cytokines from LPS-stimulated monocytes. In contrast, inhibition of the release of IL-1 beta and TNF-alpha occurred in monocytes cultures that had been pretreated with either of two monoclonal antibodies (mAb) recognizing different epitopes on the CD14 molecule. The binding of LPS to CD14 has been previously shown to require serum factors. In the present study, we found that serum had an enhancing effect on the release of IL-1 and TNF-alpha from LPS-stimulated cultures of normal human monocytes. The inhibitory effect of anti-CD14 mAb was, however, observed in cultures performed in the presence or in the absence of serum, suggesting that triggering of IL-1/TNF-alpha release by CD14 is independent of LPS-binding proteins or other serum proteins. IL-1 beta and TNF-alpha were also released from LPS-stimulated cultures of monocytes from patients with paroxysmal nocturnal hemoglobinuria lacking expression of CD14. Thus, CD14 but not CD11/CD18 can trigger serum-dependent and independent cytokine release from endotoxin-stimulated normal human monocytes; CD14 is not, however, the only LPS receptor that is involved in the secretory response of endotoxin-stimulated cells.     

Production of tumor necrosis factor alpha by monocytes from patients with pulmonary tuberculosis.

We studied the production of tumor necrosis factor alpha (TNF-alpha) by peripheral blood monocytes taken from patients with pulmonary tuberculosis and from healthy controls. It was found that the monocytes from patients with newly diagnosed tuberculosis released significantly greater amounts of TNF-alpha in vitro in response to lipopolysaccharide than did those from healthy controls (P less than 0.05). However, the monocytes from patients with chronic refractory tuberculosis released significantly lower amounts of TNF-alpha than did those from patients with newly diagnosed tuberculosis (P less than 0.005). Even when the cells were primed for 24 h with 500 U of recombinant interferon gamma per ml, the same pattern of results was observed. The depressed TNF-alpha production by the monocytes from patients with chronic refractory tuberculosis was also shown in response to Mycobacterium bovis BCG. This depressed TNF-alpha production did not recover, even when cultured for 1 to 7 days in the sera of healthy individuals. The sera from patients with chronic refractory tuberculosis did not have any suppressive effect on the lipopolysaccharide-induced TNF-alpha production. Thus, it was demonstrated that the levels of TNF-alpha produced by monocytes were related to the disease states of pulmonary tuberculosis and that the depressed TNF-alpha production by monocytes in patients with chronic refractory tuberculosis might not be acquired.     

Serum cytokine responses during acute human granulocytic ehrlichiosis

Human granulocytic ehrlichiosis (HGE) is caused by obligate intracellular bacteria in the Ehrlichia phagocytophila group. The disease ranges from subclinical to fatal. We speculated that cell-mediated immunity would be important for recovery from and potentially in the clinical manifestations of HGE; thus, serum tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), gamma interferon (IFN-gamma), IL-10, and IL-4 concentrations were studied. IFN-gamma (1,035 +/- 235 pg/ml [mean +/- standard error of the mean]) and IL-10 (118 +/- 46 pg/ml) concentrations were elevated in acute-phase sera versus convalescent sera and normal subjects (P 相似文献   

A type 2 response in lipopolysaccharide (LPS)-stimulated whole blood cell cultures from periodontitis patients

It is acknowledged that periodontitis results from the interaction of the host immune response with bacteria accumulating on the tooth surfaces. Although bacteria are essential, they are insufficient to cause the disease. Despite this knowledge it remains unclear why certain individuals are more susceptible to periodontitis than others. Therefore the present study investigated whether differences exist in the actual immune response between periodontitis patients and controls after stimulation of peripheral blood cells. Whole blood cell cultures (WBCC) were stimulated with LPS from Escherichia coli during 18 h and the release of prostaglandin E2 (PGE2), IL-1beta, IL-6, IL-8, IL-10, IL-12p40, IL-12p70 and tumour necrosis factor-alpha (TNF-alpha) was measured. The levels of PGE2 were two-fold higher in the WBCC from periodontitis patients than from controls. In contrast, the levels of IL-12p70 in WBCC from patients were two-fold lower. Furthermore, WBCC from patients secreted lower levels of IL-1beta and higher levels of IL-8 when compared with WBCC from controls. No differences were observed with respect to IL-6, IL-10, IL-12p40 and TNF-alpha production. It is known from the literature that LPS-stimulated WBCC reflect specifically the behaviour of the monocytes and that monocytes are peripheral precursors of antigen-presenting cells (APC). Therefore it is concluded that the monocytes in the present WBCC from periodontitis patients are responsible for the higher levels of PGE2 and lower levels of IL-12p70. Since it is has been shown that APC-derived IL-12p70 induces type (Th1) cells that promote cellular immunity, while APC-derived PGE2 induces type 2-helper (Th2) cells that promote humoral immunity, it is postulated that APC from periodontitis patients may have a bias in directing Th2 responses and thereby promoting the humoral immunity in periodontitis.     

Mycobacterium avium infection in HIV-1-infected subjects increases monokine secretion and is associated with enhanced viral load and diminished immune response to viral antigens.

The complex interaction between HIV-1 infection and Mycobacterium avium was studied. Viral burden was assessed, as well as immune response to HIV-1 in the context of Myco. avium infections. We also examined serum cytokine levels and cytokine release by blood mononuclear cells in HIV-1-infected subjects, infected or not with Myco. avium. Undetectable serum levels of IL-1, tumour necrosis factor-alpha (TNF-alpha) and IL-6 were found in normal controls and in groups I, II and III of HIV-1-infected subjects. Moderate levels of TNF-alpha, IL-1 and IL-6 were found in the sera of group IV patients. When group IV was subdivided into subjects with and without Myco. avium infections, subjects with Myco, avium infections were shown to have higher serum levels of TNF-alpha, IL-1 beta and IL-6 than those with other infections. Blood mononuclear cells from controls and HIV subjects were stimulated with bacterial lipopolysaccharide, and cytokine levels assessed. Cells from group II patients were shown to secrete normal levels of TNF-alpha and IL-6, and lower levels of IL-1 beta; group III subjects released higher levels of IL-6. Patients in group IV had blood cells that released elevated levels of IL-6 and TNF-alpha, and lower levels of IL-1 beta. Group IV subjects with Myco. avium infections had blood cells that released higher levels of TNF-alpha, IL-6 and IL-1 than group IV subjects with other infections. Assessment of viral burden in cells of HIV-1-infected subjects revealed that Myco. avium-infected subjects had a higher level of virus burden and a lower level of lymphoproliferative response to an inactivated gp120-depleted HIV-1 antigen than AIDS subjects with other infections. These data suggest that Myco. avium infections in HIV-1-infected subjects hasten the progression of viral disease, enhance cytokine release and contribute to the anergy to viral antigens.     

Ability of Ni-containing biomedical alloys to activate monocytes and endothelial cells in vitro.

Nickel-containing alloys commonly are used in medical and dental applications that place them into long-term contact with soft tissues. The release of Ni ions from these alloys is disturbing because of the toxic, immunologic, and carcinogenic effects that have been documented for some Ni compounds. In particular, Ni ions in solution recently have been shown to cause expression of inflammatory mediators, such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and intercellular adhesion molecules (ICAMs) from keratinocytes, monocytes, and endothelial cells. However, the ability of the solid alloys themselves to induce these inflammatory effects has not been demonstrated. An in vitro system was used to determine if Ni-containing biomedical alloys could cause secretion of either IL-1beta or TNF-alpha from monocytes or expression of ICAMs on endothelial cells. Pure nickel, titanium, and three biomedical alloys-18-8 stainless steel, NiTi, and Rexillium III-were evaluated. First, it was determined whether or not the alloys or pure metals could cause cytotoxicity to THP-1 human monocytes or human microvascular endothelial cells (HMVECs) by measuring the succinic dehydrogenase (SDH) activity of the cells. Then, using identical conditions of exposure, the secretion of IL-1beta or TNF-alpha from monocytes or ICAM-1 expression on the HMVECs was determined. Only pure nickel suppressed (by 48% compared to Teflon controls) the SDH activity of the HMVECs or THP-1 monocytes. No alloy or metal caused the HMVECs to express ICAM-1, but the NiTi alloy caused a significant (ANOVA/Tukey) secretion of IL-1beta from the THP-1 monocytes. Secretion of TNF-alpha induced by NiTi was detectable but not statistically significant. The levels of IL-1beta secretion from monocytes were sufficient to induce ICAM-1 expression on HMVECs. The release of Ni from the NiTi was a logical suspect in causing the IL-1beta secretion by monocytes, but its role was not confirmed since other alloys, such as Rexillium III, released the same quantities of Ni yet did not activate the THP-1 monocytes. Within the limitations of in vitro conditions, our results indicate that NiTi alloys pose a risk of promoting an inflammatory response in soft tissues by activating monocytes. Further study is needed to substantiate this finding in vivo.     

Differences in cytokine secretion by intestinal mononuclear cells, peripheral blood monocytes and alveolar macrophages from HIV-infected patients.

Mononuclear cells of the lamina propria (LpMNC), isolated from endoscopically taken biopsies of the large bowel from AIDS patients, were analysed for their ability to secrete tumour necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-6. Stimulation of LpMNC from normal controls with pokeweed mitogen (PWM) led to a time- and dose-dependent enhancement of TNF-alpha, IL-1 beta and IL-6 secretion. In contrast, PWM stimulation of LpMNC from AIDS patients resulted in only a small increase in TNF-alpha release. Constitutive secretion of IL-1 beta and IL-6 in these patients was already increased to the concentration range of stimulated cells from normal controls and could not be further increased, probably due to maximal in vivo stimulation. Secretion of TNF-alpha, IL-1 beta and IL-6 by peripheral blood monocytes (PBM) and alveolar macrophages from AIDS patients was elevated with or without stimulation compared with normal controls. Obviously, the regulation of TNF-alpha secretion is dependent on the microenvironment. Since it is known that interferon-gamma (IFN-gamma) may induce the production of TNF-alpha, the secretion of this cytokine was examined. Release of IFN-gamma was constitutively and under stimulation lowered in LpMNC from AIDS patients compared with normal controls. Addition of IFN-gamma to LpMNC did not result in enhanced TNF-alpha secretion. Our data indicate a defective function of intestinal mononuclear cells in AIDS patients as shown by the diminished TNF-alpha secretion.     

Activation of human monocytes by Streptococcus mutans serotype f polysaccharide: immunoglobulin G Fc receptor expression and tumor necrosis factor and interleukin-1 production.

Streptococcus mutans serotype f polysaccharide (poly f) was prepared from S. mutans whole cells by autoclaving. The poly f was purified by chromatography on DEAE Trisacryl M and Bio-Gel P100, treated with insoluble pronase, and resubjected to chromatography on DEAE Trisacryl M. Normal human blood monocytes, stimulated in vitro with purified poly f, produced extracellular tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in a dose-dependent fashion as determined by a heterologous two-site sandwich enzyme-linked immunosorbent assay. Poly f also increased the expression of monocyte cell surface receptors for the Fc part of human immunoglobulin G, activity which is correlated with an increase of the phagocytic activity of the stimulated monocytes. Polymyxin B had no effect on TNF-alpha and IL-1 beta release. Neutralization assays with anti-recombinant human TNF-alpha and anti-recombinant human IL-1 beta immunoglobulin G confirmed the fact that the cytotoxic and mitogenic mediators released by the poly f-stimulated monocytes were mainly TNF-alpha and IL-1 beta.     

Release of cytokines induced by Salmonella typhimurium porins.

Salmonella typhimurium SH5014 porins induce the release of tumor necrosis factor alpha (TNF-alpha), interleukin 1 alpha (IL-1 alpha), and IL-6 by human monocytes and of gamma interferon (IFN-gamma) and IL-4 by human lymphocytes. Porins at 1 microgram/ml induce the greatest release of TNF-alpha, IL-1 alpha, and IL-6 by monocytes and of IL-4 by lymphocytes, while porins at 5 micrograms/ml induce the greatest release of IFN-gamma by lymphocytes. The R form of lipopolysaccharide (LPS-R) induces the greatest release of TNF-alpha and IL-1 alpha by monocytes when used at a low concentration (1 microgram/ml). At higher concentrations (5 and 10 micrograms/ml, respectively), LPS-R induces the maximal release of IL-6 from monocytes and the maximal release of IL-4 from lymphocytes. The S form of LPS (LPS-S) induces the greatest release of TNF-alpha, IL-1 alpha, and IL-6 by monocytes and that of IL-4 by lymphocytes when used at a concentration of 1 microgram/ml. After stimulation with LPS-S, the largest quantity of TNF-alpha and IL-1 alpha released was less than that obtained after stimulation with LPS-R at the same concentration, while the quantity of IL-6 released was found to be slightly higher than that obtained after stimulation with porins or LPS-R. LPS-S (1 microgram/ml) induces IFN-gamma release from lymphocytes in notably smaller quantities than that obtained with LPS-R and slightly larger quantities than that obtained with porins. The preparation of porins used was found to be contaminated with 10 pg of LPS per 10 micrograms of porins, a quantity which was found to have no biological effect; furthermore, porin preparations with the addition of polymyxin B gave the same results.     

Gonadotropin treatment restores in vitro interleukin-1beta and tumour necrosis factor-alpha production by stimulated peripheral blood mononuclear cells from patients with idiopathic hypogonadotropic hypogonadism

In the present study, we aimed to investigate the effects of testosterone deficiency and gonadotropin therapy on the in vitro production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) by peripheral blood mononuclear cells (PBMCs) from patients with idiopathic hypogonadotropic hypogonadism (IHH) in order to elucidate the modulatory role of androgen in cytokine production. Fifteen male patients with untreated IHH and 15 age-matched healthy male subjects were enrolled in the study. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone (FT), sex hormone binding globulin (SHBG), prolactin, and IL-2 and IL-4 levels were also measured. In unstimulated cultures, IL-1beta and TNF-alpha secretion were not significantly different between patient and control groups. However, after stimulation with lipopolysaccharide (LPS), secretion of IL-1beta and TNF-alpha was significantly higher in cultures from untreated patients with IHH than in control subjects. Mean FSH, LH and FT levels were significantly lower, whereas SHBG, IL-2 and IL-4 levels were significantly higher in patients with IHH compared than in controls. In patients with IHH, FT negatively affected the serum levels of IL-4 and in vitro secretion of IL-1beta and TNF-alpha. In addition, IL-2 and IL-4 affected the in vitro secretion of IL-1beta in a positive manner. Gonadotropin therapy decreased both TNF-alpha and IL-1beta in PBMCs from patients with IHH. The levels of serum IL-2 and IL-4 were also decreased by therapy. In conclusion, in the present study, gonadotropin treatment restored the in vitro production of IL-1beta and TNF-alpha by PBMCs from patients with IHH, suggesting that androgen modulates proinflammatory cytokine production, at least directly through its effects on PBMCs. It seems probable that this effect plays an important role in the immunosuppressive action of androgens.     

Serum of patients with septic shock stimulates the expression of Trem-1 on U937 monocytes

Objectives:  To describe the concentrations of sTREM-1 in patients with sepsis and to explore the effects of their serum on the expression of TREM-1 on U937 monocytes. Methods:  Blood was sampled at regular time intervals in 56 patients with sepsis. Concentrations of tumour necrosis factor-alpha (TNFα), interleukin-1beta (IL-1α), IL-6, IL-8, IL-10 and IL-12p70 and sTREM-1 were measured. U937 monocytes were incubated in the presence of serum at sepsis onset. Results:  Median sTREM-1 concentration on day 1 for patients with septic shock was 915 pg/ml and 228.5 pg/ml for those without shock (p = 0.002). TNFα, IL-1α, IL-6, IL-8 and IL-10 did not differ between them. A positive correlation was found between changes of sTREM-1 and SOFA scores from day 1 to 7. Sera of patients with septic shock evoked a significant increase of the expression of TREM-1. The concentrations of TNFα and IL-8 in supernatants increased only after stimulating with sera of patients without shock, but not after stimulating with sera of patients with shock. Conclusions:  Levels of sTREM-1 correlated with sepsis severity. sTREM-1 is considerably higher in patients with shock compared to patients without shock. The serum of shocked patients could stimulate the expression of TREM-1 on U937 monocytes. Received 5 March 2007; returned for revision 4 June 2007; received from final revision 26 February 2008; accepted by K. Visvanathan 21 May 2008