Elevated serum levels of soluble tumour necrosis factor receptors (sTNF-R) in patients with HIV infection.

Serum levels of the soluble form of tumour necrosis factor receptor type II (p75) (sTNF-R) were determined in HIV-infected individuals and risk groups and were then correlated with the course of infection and prognosis. sTNF-R levels were determined by an ELISA with MoAbs and polyclonal antibodies to urine-derived sTNF-R proteins. The mean +/- s.e. levels of sTNF-R in the sera of 49 HIV+ male homosexuals, 34 HIV- male homosexuals and 44 matched controls were 6.1 +/- 0.3 ng/ml, 4.4 +/- 0.3 ng/ml and 3.4 +/- 0.2 ng/ml, respectively. All these values were significantly different between each of the groups (P less than 0.001-0.05). Sequential studies of sTNF-R revealed higher levels following seroconversion in 5/8 individuals, remained persistently high during the asymptomatic phase of the infection and became even more elevated in some ARC and AIDS patients. At the same time TNF-alpha was undetectable in sera obtained from HIV+ male homosexuals and from healthy controls. This was independent of stage of HIV infection, serum sTNF-R level and type of ELISA kit used. These findings suggest that TNF-alpha/TNF-R system is turned on before and during HIV infection and raise the possibility that sTNF-R, the natural inhibitor of TNF, may be of importance in determining the course and probably prognosis of the disease.     

Serum and cyst fluid levels of interleukin (IL) -6, IL-8 and tumour necrosis factor-alpha in women with endometriomas and benign and malignant cystic ovarian tumours

BACKGROUND: Altered expression of cytokines has been suggested as a specific event for the maintenance and progression of endometriomas. Few data exist on cytokine expression in endometriomas compared with benign and malignant ovarian tumours. Hence, serum and cyst fluid levels of interleukin (IL)-6, IL-8 and tumour necrosis factor-alpha (TNF-alpha) were evaluated in women with endometriomas and compared with those in women with benign or malignant ovarian tumours. METHODS: Investigations included immunoradiometric determination of serum and cyst fluid concentrations of IL-6, IL-8 and TNF-alpha in 34 women with endometriomas, 30 women with benign and 13 women with malignant cystic ovarian tumours. RESULTS: Serum IL-6 levels were higher in ovarian cancer than in endometriomas (P<0.01) or benign tumours (P<0.01). Serum TNF-alpha levels differed between benign tumours and endometriomas (P<0.01), but not between endometriomas and malignant tumours. Cyst fluid levels of IL-8 were higher in endometriomas than in benign tumours (P<0.001) and lower than in malignant tumours (P=0.03). Cyst fluid levels of TNF-alpha differed between malignant tumours and endometriomas (P<0.01) and benign tumours (P<0.01), but not between endometriomas and benign tumours. In the endometriomas group, a positive correlation was found between serum and cyst fluid levels of IL-6 (P=0.003, rho=0.633), and between serum levels of IL-6 and IL-8 (P=0.03, rho=0.415). CONCLUSIONS: Endometriomas were associated with serum TNF-alpha levels similar to those found in women with ovarian cancer, while serum IL-6 levels and cyst fluid IL-8 levels were intermediate between those observed in benign and malignant ovarian tumours.     

Increased expression and occupancy of receptors for tumour necrosis factor on blood monocytes from tuberculosis patients.

Blood monocytes from tuberculosis patients release high amounts of tumour necrosis factor-alpha (TNF-alpha). Because the biological efficiency of TNF-alpha would depend on the expression of TNF-alpha receptors on target cells, we thought to analyse the capacity of blood monocytes from a group of patients with pulmonary tuberculosis to bind 125I-TNF-alpha. We report a slight but not significant enhancement in specific binding of 125I-TNF-alpha on monocytes of 15 consecutively studied patients compared with 10 controls. Per cent cell surface bound and internalized 125I-TNF-alpha was identical in the two groups. To evaluate the receptor occupancy by endogenously generated TNF-alpha, similar experiments were performed after cell exposure to low-pH glycine buffer. Under these conditions, specific binding of 125I-TNF-alpha was significantly higher on tuberculosis monocytes compared with control monocytes. Moreover, the occupancy of TNF-alpha receptors by endogenously generated TNF-alpha that was found to be significantly higher on tuberculosis monocytes than on control monocytes, was directly related to the enhanced capacity of mononuclear cells to generate TNF-alpha in vitro. It normalized after 3 months of antituberculous therapy. Scatchard analysis of the binding data revealed that tuberculosis infection caused a significant increase in high affinity 125I-TNF-alpha binding to monocytes without any significant change in the dissociation constant. Collectively, these results indicate an up-regulation of TNF-alpha generation and binding to blood monocytes in patients with pulmonary tuberculosis. They provide support to the hypothesis that TNF-alpha is of critical importance in the pathogenesis of this infection.     

Elevated soluble tumor necrosis factor receptor levels in seasonal allergic rhinitis patients

In this study, we examined the symptom scores and tumor necrosis factor-alpha (TNF-alpha), p55 soluble tumor necrosis factor receptor (sTNFR1), and p75 soluble tumor necrosis factor receptor (sTNFR2) levels in the sera and nasal epithelial lining fluids (ELF) of 20 patients with Japanese cedar pollinosis from the pre- to the postseason period, and compared the results with those of 10 nonallergic control subjects. The symptom scores of the allergic subjects were significantly (P<0.01) higher than those of the nonallergic subjects during the early stage and mid-stage of the season. There were no statistical differences between the allergic and nonallergic subjects in the TNF-alpha levels in sera and ELF from the pre- to the postseason. In the allergic subjects, however, the levels of sTNFR1 and sTNFR2 in ELF were significantly elevated during the early stage (P<0.05) and mid-stage (P<0.01) of the season, whereas those in sera did not change from the pre- to the post-season period. The levels of TNF-alpha in ELF were more than 10 times higher than those in sera, whereas the levels of sTNFR1 and sTNFR2 in ELF were less than half of those in sera in the allergic and nonallergic subjects. These results suggest that sTNFR1 and sTNFR2 may play a role in the pathogenesis of nasal allergic reaction.     

类风湿关节炎患者血清sTNF—R、TNF—α的变化

目的为探讨类风湿关节炎 (RA)与可溶性肿瘤坏死因子受体 (s TNF- R)、TNF- α、TNF- α/ s TNF- R比值的关系。方法应用双抗体夹心 EL ISA法检测了活动期 RA(2 8例 ) ,稳定期 RA (12例 )及健康人 (30例 )血清中 s TNF- R 、s TNF- R 、TNF-α的水平。结果活动期 RA患者血清 s TNF- R 、s TNF- R 、TNF-α水平明显高于健康人及稳定期 RA组 ,P均 <0 .0 1。稳定期 RA患者血清 s TNF- R 、s TNF- R 、TNF-α水平亦明显高于健康人 ,P<0 .0 1。在 RA患者中 ,血清 s TNF- R 、s TNF- R 水平与 ESR、CRP、Ritchie index呈显著正相关 ,与类风湿因子 (RF)水平无相关性。RA患者治疗 3个月后 s TNF- R 、s TNF- R 及 TNF- α/ s TNF R比值显著下降。结论 RA患者血清 s TNF- R 、s TNFR- 水平显著增高 ,且与疾病活动度呈正相关。测定血清 s TNF- R 、s TNF- R 、TNF- α/ s TNF- R水平可作为 RA诊断 ,监测疾病活动、治疗及判断预后的一项有意义的实验室指标     

Soluble tumour necrosis factor receptors (sTNF-R) and HIV infection: correlation to CD8+ lymphocytes.

The objective of this study was to determine sTNF-R, type I (p55) and type II (p75) in sera of HIV-infected male homosexuals and correlate them to T lymphocyte subpopulations and course of HIV infection. Serum samples were obtained from 39 HIV-1+ asymptomatic male homosexuals, 10 symptomatic (ARC and AIDS) male homosexuals and 44 HIV- non-homosexual healthy controls. sTNF-R levels were determined by ELISA with specific MoAbs and polyclonal antibodies to the sTNF-R proteins. sTNF-RI and II levels were significantly elevated in 72% and 74% respectively of HIV+ asymptomatic male homosexuals and in all of the symptomatic male homosexuals. In sequential studies a highly significant positive correlation was found between sTNF-RI and sTNF-RII (r = 0.8, P < 0.001) and between both sTNF-R and CD8+ lymphocyte counts (r = 0.6 and 0.92, respectively, P < 0.01-0.001) during the asymptomatic stage of the infection. All these correlations were lost, however, during the symptomatic phase of the disease. These results suggest that: (i) HIV infection is associated with elevation of sTNF-R serum levels; (ii) sTNF-R levels are strongly correlated to CD8+ lymphocytes during the asymptomatic stage of HIV infection.     

Increased soluble p55 and p75 tumour necrosis factor-alpha receptors in patients with hepatitis C-associated mixed cryoglobulinaemia

To investigate whether tumour necrosis factor alpha (TNFalpha) plays a role in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinaemia (HCV-MC), we measured soluble TNFalpha and its soluble p55 (sTNFR1) and p75 (sTNFR2) receptors in the serum of patients with HCV-MC. TNFalpha, sTNFR1 and sTNFR2 were measured in the serum of 32 patients with HCV-MC, 18 patients with hepatitis C without MC (HCV) and 18 healthy volunteers, using specific immunoassays. Correlations between clinical and biological parameters and the concentrations of TNFalpha and sTNFRs were established by studying detailed clinical records of the 32 HCV-MC patients. Although higher, TNFalpha levels were not significantly different in HCV-MC patients compared with healthy or HCV controls. sTNFR1 and sTNFR2, however, were significantly higher in HCV-MC compared with controls or with HCV patients, and higher concentrations of sTNFR1 and sTNFR2 were observed in patients with severe visceral vasculitis, compared with patients with limited purpura. sTNFR1 concentrations positively correlated with fibrinogen levels but TNFalpha, sTNFR1 and sTNFR2 did not correlate with other biological parameters such as rheumatoid factor concentrations, CH50 or C4 values. These data suggest a role for TNFalpha in the pathogenesis of the immune complex-mediated vasculitis associated with HCV-MC.     

SLE患者血清可溶性肿瘤坏死因子受体水平及意义

目的探讨系统性红斑狼疮 (SLE)与可溶性肿瘤坏死因子受体 (sTNF R)的关系。方法利用双抗体夹心ELISA法检测了活动期SLE患者35例,稳定期患者25例及健康对照40例血清中sTNF RI和sTNF RII的水平。结果患者血清sTNF RI和sTNF RII的水平分别为(2.34±0.76)μg/L和(4.33±1.15)μg/L ;健康对照组分别为(1.09±0.11)μg/L和(2.05±0.29)μg/L ,患者明显高于健康对照组(P<0.01)。活动期SLE患者血清sTNF RI和sTNF RII水平分别为(2.93±0.32)μg/L和(5.19±0.53)μg/L ,明显高于稳定期SLE组分别为(1.46±0.15)μg/L和(3.04±0.28)μg/L(P∨0.01)。稳定期也明显高于健康对照组(P<0.01)。在SLE患者组中 ,血清sTNF RI和sTNF RII的水平与疾病活动积分呈显著的正相关(相关系数分别为0.76和0.69)(P<0.01) ;与抗ds DNA抗体水平亦呈显著的正相关(相关系数分别为0.67和0.58)(P<0.01) ;与补体C3的水平呈显著的负相关(相关系数分别为 -0.62和 -0.84)(P<0.01)。结论SLE患者血清sTNF RI和sTNFRII的水平明显增高 ,且与疾病的活动度呈显著正相关 ,这对于SLE的诊断及监测疾病的活动性 ,以及患者的判断预后可能是一种有用的实验室指标。     

Elevation of serum soluble tumour necrosis factor (TNF) receptor and IL-1 receptor antagonist levels in bronchial asthma

The specific inhibitor for TNF-α activity, soluble form of the 55-kD TNF receptor (sTNF-RI) and soluble form of the 75-kD receptor (sTNF-RII), and the specific inhibitor for IL-1 activity, IL-1 receptor antagonist (IL-1Ra), have been identified. It has been shown that the levels of these inhibitors are elevated in plasma/serum and biological fluids in several diseases, and the protective and inhibitory effect of these inhibitors exist in several inflammatory diseases. In the present study, we measured serum levels of sTNF-RI, STNF-RII and IL-1Ra by ELISA in 36 patients with bronchial asthma (16 atopic and 20 non-atopic) during asthma attacks and in stable conditions in order to assess the state of these inhibitors in allergic inflammation. The levels of sTNF-RI, sTNF-RII and IL-1Ra in sera obtained during bronchial asthma attacks were higher than those in sera obtained in stable conditions. These findings were obtained regardless of atopic status. These results suggest that higher levels of serum sTNF-RI, sTNF-RII and IL-1Ra may reflect up-regulation of TNF-R expression and IL-1Ra production in allergic inflammation, and sTNF-RI, sTNF-RII and IL-1Ra may contribute to regulating TNF-α- and IL-1-mediated production and development of allergic inflammation.     

Enhancement of humoral and cellular immunity with an anti-glucocorticoid-induced tumour necrosis factor receptor monoclonal antibody

Adjuvants, including antibodies to tumour necrosis factor receptor superfamily members, augment immune responses. One member of this family, glucocorticoid‐induced tumour necrosis factor receptor (GITR), is expressed at low levels on naive/resting T cells, B cells and macrophages, but at higher levels on T regulatory cells. The aim of this study was to determine the ability of a rat anti‐mouse GITR monoclonal antibody, 2F8, to stimulate murine humoral and cellular immunity in a prime boost model with particular attention to posology and antigen‐specific effects. 2F8 enhanced the humoral immune response to ovalbumin and haemagglutinin (HA) compared with controls and this enhancement was equal to or greater than that obtained in mice dosed with standard adjuvants. 2F8 F(ab′)₂ fragments were as effective as intact antibody in boosting humoral immunity, indicating that FcR‐mediated cross‐linking of 2F8 is not required for efficacy. Moreover, the enhanced response was durable and antigen specific. Administration of 2F8 shifted the immune response towards a T helper type 1 response with significant enhancement of immunoglobulin G2a‐ and G2b‐specific anti‐HA antibodies, as well as enhanced cellular immunity as measured by ELISPOT. 2F8‐treated mice also generated significantly more neutralizing antibodies to HA than control mice. Our findings show that anti‐GITR is a robust, versatile adjuvant that, unlike commonly used adjuvants that primarily enhance humoral immunity, enhances both humoral and cellular immunity. These results support the continued development of anti‐GITR for such indications as haematological and solid tumours, chronic viral infections, and as a vaccine adjuvant.     

Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2

Tumor necrosis factor (TNF)-alpha is a pleiotropic cytokine involved in a broad spectrum of inflammatory and immune responses including proliferation, differentiation and cell death induction in several cell types. The biological effects of TNF-alpha are mediated via the cell-surface TNF receptors TNFR1 and TNFR2. Soluble forms of these two receptors, which contain the extracellular ectodomains, are proteolytically cleaved from the membrane. High levels of soluble (s) TNFR2 in serum have been documented in multiple inflammatory pathologies. We describe here a new differential spliced isoform of human TNFR2 missing exons 7 and 8, DS-TNFR2(Delta7,8). This novel isoform lacks the transmembrane and cytoplasmic domains. Expression studies with DS-TNFR2(Delta7,8) cDNA transiently transfected COS cells showed that it encodes a sTNFR2 receptor of approximately 42 kDa. Soluble DS-TNFR2(Delta7,8) blocked TNF-alpha-induced apoptosis, which suggests that it regulates TNF-alpha function by antagonizing its biological activity. An ELISA was developed that quantifies sTNFR2 generated by alternative splicing. Our data show that sTNFR2 generated by alternative splicing can be found in sera of healthy individuals, at increased levels in patients with sepsis and at high concentrations in rheumatoid arthritis patients.     

An inhibitor of the toxicity of tumour necrosis factor in the serum of patients with sarcoidosis, tuberculosis and Crohn''s disease.

The activated macrophages present in the T cell-dependent granulomata of sarcoidosis and tuberculosis are primed for enhanced release of cytokines including tumour necrosis factor (TNF or cachectin). Release of this cytokine can induce an acute-phase response, fever, and necrosis in suitably prepared sites of inflammation; if chronic, its presence may contribute to weight loss. These clinical features are characteristic of tuberculosis, but not of sarcoidosis, though alveolar macrophages from both diseases release large quantities of TNF in vitro. We therefore postulated the presence in sarcoidosis patients of an inhibitor of TNF. We have studied levels of TNF inhibitory activity by determining the quantity of TNF required to give 50% kill of L929 cells in the presence of 20% heat-inactivated serum derived from various disease states (37 sarcoidosis, 13 tuberculosis, 13 Crohn's disease, 17 healthy donors). Normal sera used in this way do not inhibit significantly, but inhibition of TNF toxicity is caused by most sera from both sarcoidosis and tuberculosis. Used at 20%, five out of 37 sarcoidosis sera and one out of 13 tuberculosis sera caused complete inhibition of TNF, even when the latter was added at 100 times the concentration required to give 50% kill in control wells. This inhibitor may have an important physiological role.     

Increased lipopolysaccharide-induced tumour necrosis factor levels and death in hypercholesterolaemic rabbits.

Nutritional-induced hypercholesterolaemia in New Zealand rabbits causes increased susceptibility to experimental infections. Rabbits fed cholesterol (0.5 g%) for 8 weeks were injected intravenously with varying doses of Escherichia coli 0127: B8 lipopolysaccharide (LPS; 3-100 micrograms/kg). The levels of cholesterol, triglycerides, tumour necrosis factor (TNF), and the survival rates of treated rabbits were then measured. Rabbits fed either normal chow or chow impregnated with sesame oil were used as controls. LPS induced higher serum TNF levels in hypercholesterolaemic rabbits than in normal rabbits or rabbits fed with chow containing sesame oil. TNF levels rose faster in hypercholesterolaemic rabbits than in normal rabbits, reaching maximum levels at 60 min and 120 min, respectively, after LPS injection. The survival rate of hypercholesterolaemic rabbits (1/11) was lower than in normal rabbits (6/7) or rabbits fed with the sesame oil chow (4/4) at the higher LPS doses. No death occurred at lower doses. One possible interpretation of these results, also supported by neutralization experiments, is that increased TNF secretion in hypercholesterolaemic rabbits raises the host's susceptibility to experimental endotoxaemia and possibly to Gram-negative infection.     

Tumour necrosis factor receptors and apoptosis of alveolar macrophages during early infection with attenuated and virulent Mycobacterium bovis

Apoptosis of macrophages has been reported as an effective host strategy to control the growth of intracellular pathogens, including pathogenic mycobacteria. Tumour necrosis factor-α (TNF-α) plays an important role in the modulation of apoptosis of infected macrophages. It exerts its biological activities via two distinct cell surface receptors, TNFR1 and TNFR2, whose extracellular domain can be released by proteolysis forming soluble TNF receptors (sTNFR1 and sTNFR2). The signalling through TNFR1 initiates the majority of the biological functions of TNF-α, leading to either cell death or survival whereas TNFR2 mediates primarily survival signals. Here, the expression of TNF-α receptors and the apoptosis of alveolar macrophages were investigated during the early phase of infection with attenuated and virulent mycobacteria in mice. A significant increase of apoptosis and high expression of TNFR1 were observed in alveolar macrophages at 3 and 7 days after infection with attenuated Mycobacterium bovis but only on day 7 in infection with the virulent M. bovis. Low surface expression of TNFR1 and increased levels of sTNFR1 on day 3 after infection by the virulent strain were associated with reduced rates of apoptotic macrophages. In addition, a significant reduction in apoptosis of alveolar macrophages was observed in TNFR1^−/− mice at day 3 after bacillus Calmette–Guérin infection. These results suggest a potential role for TNFR1 in mycobacteria-induced alveolar macrophage apoptosis in vivo. In this scenario, shedding of TNFR1 seems to contribute to the modulation of macrophage apoptosis in a strain-dependent manner.     

Mutant forms of tumour necrosis factor receptor I that occur in TNF-receptor-associated periodic syndrome retain signalling functions but show abnormal behaviour

Tumour necrosis factor (TNF)-receptor-associated periodic syndrome (TRAPS) is a hereditary autoinflammatory disorder involving autosomal-dominant missense mutations in TNF receptor superfamily 1A (TNFRSF1A) ectodomains. To elucidate the molecular effects of TRAPS-related mutations, we transfected HEK-293 cells to produce lines stably expressing high levels of either wild-type (WT) or single mutant recombinant forms of TNFRSF1A. Mutants with single amino acid substitutions in the first cysteine-rich domain (CRD1) were produced both as full-length receptor proteins and as truncated forms lacking the cytoplasmic signalling domain (deltasig). High-level expression of either WT or mutant full-length TNFRSF1A spontaneously induced apoptosis and interleukin-8 production, indicating that the mutations in CRD1 did not abrogate signalling. Consistent with this, WT and mutant full-length TNFRSF1A formed cytoplasmic aggregates that co-localized with ubiquitin and chaperones, and with the signal transducer TRADD, but not with the inhibitor, silencer of death domain (SODD). Furthermore, as expected, WT and mutant deltasig forms of TNFRSF1A did not induce apoptosis or interleukin-8 production. However, whereas the WT full-length TNFRSF1A was expressed both in the cytoplasm and on the cell surface, the mutant receptors showed strong cytoplasmic expression but reduced cell-surface expression. The WT and mutant deltasig forms of TNFRSF1A were all expressed at the cell surface, but a proportion of the mutant receptors were also retained in the cytoplasm and co-localized with BiP. Furthermore, the mutant forms of surface-expressed deltasig TNFRSF1A were defective in binding TNF-alpha. We conclude that TRAPS-related CRD1 mutants of TNFRSF1A possess signalling properties associated with the cytoplasmic death domain, but other behavioural features of the mutant receptors are abnormal, including intracellular trafficking and TNF binding.     

Circulating levels of sTNFR and discrepancy between cytotoxicity and immunoreactivity of TNF-α in patients with visceral leishmaniasis

Objectives To study the influence of soluble tumour necrosis factor (TNF) receptors (sTNFR) on bioactivity and immunoreactivity of TNF-α in patients with visceral leishmaniasis (Kala-azar) and to examine the association between circulating levels of sTNFR type I and type II with clinical manifestations of the disease.
Methods   Ten patients with Kala-azar were enrolled. Plasma samples for TNF-α and sTNFR were obtained on days 0, 7 and 21–28 of antimonial therapy. Bioactivity of TNF-α was measured by cytotoxicity to L-929 cells and immunoreactivity by enzyme-linked immunosorbent assay (ELISA). sTNFR-I and sTNFR-II were measured by ELISA.
Results   Measured by ELISA, TNF-α was detected at baseline in all patients (range from 22.3 to 163 pg/mL) and showed a linear decline over time on therapy ( r  = −0.49, P  = 0.007). In contrast, when measured by cytotoxicity assay, TNF-α was detected in only one patient at baseline (193 pg/mL) and in four patients at the end of therapy (38.7, 95, 133 and 232 pg/mL) and there was no linear association between TNF-α and duration of therapy ( r  = −0.18, P  = 0.45). sTNFR-I and sTNFR-II were detected in all patients before therapy. There was a strong positive correlation between plasma concentrations of sTNFR-I and sTNFR-II ( r  = 0.8, P  = 0.006). Levels of sTNFR-I and sTNFR-II declined exponentially with time on therapy.
Conclusions   We concluded that sTNFR-I and sTNFR-II are related to disease activity in patients with Kala-azar and that these circulating receptors may interfere with the biological activity of TNF-α in patients with Kala-azar.     

Cytostasis of different tumours by a murine PPD-reactive CD4+ T lymphocyte clone is mediated by interferon-gamma and tumour necrosis factor alone or synergistically.

We have shown that a murine CD4+ PPD-reactive T lymphocyte clone was weakly cytotoxic towards the syngeneic tumour B16 melanoma and MC6A fibrosarcoma which had been coated with PPD using a monoclonal antibody-PPD heteroconjugate. Cell-free supernatants produced by PPD-stimulated T lymphocyte clones were however highly cytostatic for the two tumour targets when assayed over 48-72 h. In this study we have demonstrated good titres of tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma) in the supernatants, which accounted for their observed cytostatic activity on the tumour targets. The high level of cytostasis seen with the B16 melanoma using the supernatants could be attributed to their sensitivity to the cytostatic activity of IFN-gamma; the lower levels of cytostasis seen with the IFN-gamma-resistant MC6A target was the result of IFN-gamma increasing the sensitivity of this target to TNF. Antibodies to IFN-gamma were able to neutralize the majority of the cytostatic activity of the supernatants on both targets, consistent with the role demonstrated for this lymphokine.     

The accuracy of serum interleukin-6 and tumour necrosis factor as markers for ovarian torsion

BACKGROUND: The aim of this study was to investigate a possible role for interleukin-6 (IL-6) and tumour necrosis factor (TNF-alpha) as pre-operative markers for the diagnosis of ovarian torsion. METHODS: Twenty consecutive patients admitted to the gynaecological emergency room with suspected clinical diagnosis of ovarian torsion were prospectively assigned to the study. Blood samples were drawn pre-operatively and examined for serum concentrations of IL-6 and TNF-alpha. Surgeons were blinded to laboratory results prior to laparoscopy. RESULTS: The pre-operative diagnosis of ovarian torsion was confirmed during an urgent diagnostic laparoscopy in 8 (40%) patients. The surgical diagnosis among the remaining 12 patients was a large ovarian cyst not in torsion. In six out of eight (75.0%) patients with ovarian torsion serum IL-6 concentrations were elevated. None of the 12 patients without torsion had elevated serum IL-6 concentrations. This difference was statistically significant (P < 0.001). There was no significant difference in the proportion of women with elevated serum TNF-alpha concentrations, two of eight (25.0%) patients with torsion and four of 12 (33.3%) control cases. CONCLUSIONS: Elevated serum IL-6 concentrations, but not serum TNF-alpha concentrations, were significantly associated with the occurrence of ovarian torsion. In patients with vague clinical signs of ovarian torsion, serum IL-6 might help to distinguish which patients should undergo diagnostic laparoscopy.     

Serum levels of the soluble receptor for tumor necrosis factor in patients with renal disease

Tumor necrosis factor- (TNF-) has been found to be elevated in patients during hemodialysis and is thought to mediate some of the immune and metabolic dysfunctions in these patients. It has been speculated that infusions of soluble TNF receptor (sTNF-R) may prevent some of the cytotoxic effects of TNF. However, little is still known about preexisting serum TNF-R levels in patients with chronic renal failure, with or without hemodialysis. Therefore we analyzed serum samples of sTNF-R in 26 patients with chronic renal failure (group I), 6I hemodialysis patients (group II), 9 renal transplant recipients with acute renal failure requiring posttransplant dialysis (group III), 13 renal transplant patients with rejection and moderate kidney dysfunction (group IV), and 21 renal transplant recipients with borderline kidney dysfunction and diverse infectious complications (group V). Control groups consisted of 34 blood donors and diseased controls (11 renal transplant recipients with normal kidney function without complications). All patient groups showed significantly higher sTNF-R levels compared to the control groups. In groups I, IV, and V comparable levels were observed. In group I there was a clear correlation between sTNF-R levels and serum creatinine. The highest sTNF-R serum levels were seen in groups II and III, but there was no correlation with creatinine. In the posttransplant cases (group III and diseased controls) there was a decrease in sTNF-R with improvement of kidney function. These data strongly suggest that sTNF-R serum levels are dependent on kidney function.Abbreviations TNF tumor necrosis factor - TNF-R tumor necrosis factor receptor - sTNF-R soluble tumor necrosis factor receptor - RTX renal transplantation - ELISA enzyme-linked immunosorbent assay Correspondence to: G. Halwachs     

Kinetics of serum soluble tumour necrosis factor receptor (TNF-R) type-I and type-II after a single interferon-alpha (IFN-alpha) injection in chronic hepatitis C.

Circulating soluble TNF receptors, which act as TNF inhibitors, increase following the administration of IFN-alpha. Whether this is due to a direct IFN action or to indirect mechanisms involving the release of other cytokines is unclear. The kinetics of serum IFN, TNF, IL-6, IL-10, soluble TNF receptor type-I (sTNF-RI) and sTNF-RII were evaluated by enzyme immunoassays in 11 patients with chronic hepatitis C, following the first dose of recombinant human IFN-alpha2b (3 MU given subcutaneously). sTNF-RI concentrations paralleled IFN concentrations, rising from a mean +/- s.e.m. value of 3.5 +/- 0.3 ng/ml at baseline to a peak value of 5.5 +/- 0.5 ng/ml after 9 h, followed by a return to 4.1 +/- 0.4 ng/ml after 24 h (P = 0.0001). sTNF-RII concentrations, which were 7.6 +/- 0.5 ng/ml at baseline, fell initially to 6.9 +/- 0.5 ng/ml, to reach a peak at 24 h of 9.0 +/- 0.7 ng/ml (P < 0.0001). In contrast, the concentrations of TNF, IL-6 and IL-10 fluctuated with no significant changes at any time point. The area under the curve (AUC) of incremental IFN values had a strong positive correlation with the AUC of incremental sTNF-RI values (r = 0.75, P < 0.01). In patients with hepatitis C, IFN concentrations reached after a single dose of IFN were paralleled by correlationally increased concentrations of sTNF-RI, which are a much better marker of administered IFN than sTNF-RII, IL-6 or IL-10.