Angiographic evaluation of culprit lesions in acute coronary syndrome: relation to the original site on previous coronary angiography

Recent studies suggest that release of cytokines during inflammatory states such as septic shock leads to hypocholesterolemia. To examine whether tumor necrosis factor alpha (TNF), which is the major cytokine in inflammatory disease, causes hypocholesterolemia, we measured serum levels of total (bioactive and receptor-bound) TNF, cholesterol, Apo B, and Apo A1 in seven patients with septic shock over a period of 8 days. Since elevated serum TNF levels are accompanied by the release of soluble TNF receptors, levels of TNF receptors p55 and p75 were also measured. Patients with septic shock had significantly higher serum TNF and TNF receptor levels compared with healthy controls. Increased cytokine levels were accompanied by a significant decline in total serum cholesterol apolipoprotein A1 and B. In vitro studies with cultured human skin fibroblasts, human umbilical vein endothelial cells, and HepG2 hepatoma cells showed that TNF increased the degradation of 125I-labeled low-density lipoprotein in all the cell lines tested. Recombinant soluble TNF receptors inhibited the TNF-induced stimulation of low-density lipoprotein receptor in a concentration-dependent manner. However, the calculated ratio of TNF receptors to total TNF measured in serum of these patients was not able to counteract the stimulatory effect of TNF, possibly due to the higher molar excess of TNF receptors required to achieve this effect in vitro. Our data strengthen the hypothesis that serum values of total TNF determine the extent of hypocholesterolemia during sepsis and septic shock despite the presence of a high concentration of TNF receptors. Studies with recombinant TNF also confirm the role of TNF in hypocholesterolemia in inflammation.     

Measuring the quality of outpatient treatment for schizophrenia

OBJECTIVE: Usually it is not possible to study the initial systemic response in patients with acute pancreatitis in the first hours after onset of the disease. We used postendoscopic retrograde pancreatography (ERP) pancreatitis as a model to study cytokine and anticytokine release in the early phase of human acute pancreatitis. METHODS: Post-ERP pancreatitis was defined as a threefold increase in serum amylase and at least two of the following clinical symptoms: abdominal pain, nausea, vomiting or peritonism 24 h after ERP. Serum levels of pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor alpha (TNF), as well as endogenous antagonistic mediators of the systemic inflammatory response such as soluble tumour necrosis factor alpha receptors p55 (TNFR p55) and p75 (TNFR p75), and IL-1-receptor antagonist (IL-1-RA) and interleukin-2-receptor (IL-2R) as indicators of lymphocyte activation were measured before and 0, 1, 4, 12, 24 and 48 h after ERP. In nine patients with acute post-ERP pancreatitis, these parameters were monitored daily until C-reactive protein (CRP) was within normal ranges and were compared to patients without pancreatitis after ERP. RESULTS: IL-1beta was not detectable in five patients with and four patients without post-ERP pancreatitis. The values of the remaining patients in both groups were lower than 3.9 pg/ml. IL-8 and IL-1-RA serum concentrations peaked 12 h after ERP (132.9 and 3245.0 pg/ml respectively) compared to patients without post-ERP pancreatitis (25.8 and 389.9 pg/ml respectively). The IL-6 concentration increased to 81.6 pg/ml (8.0 pg/ml in control patients) 24 h after ERP, while the peak values for CRP were measured 72 h after ERP (164.0 versus 7.7 mg/l). IL-2R content was maximally elevated 144 h after ERP (688.8 versus 255.9 U/ml), while concentrations of TNF and its receptors showed no significant change over time. CONCLUSION: The initial response of the cytokine network to damage of the human pancreas leading to acute pancreatitis includes the release of IL-8 and the IL-1 antagonist IL-1-RA, while IL-1beta is not found in the systemic circulation. The TNF system does not seem to be involved as indicated by the lack of detectable changes in TNF and the soluble TNFR p55 and p75 serum concentrations. Lymphocyte activation as indicated by elevated IL-2R levels occurred days after the initial trauma. Even mild post-ERP pancreatitis leads to significant systemic release of cytokines and their biological counterparts.     

Imbalances in serum proinflammatory cytokines and their soluble receptors: a putative role in the progression of idiopathic IgA nephropathy (IgAN) and Henoch-Sch?nlein purpura nephritis, and a potential target of immunoglobulin therapy?

Following recent experimental data suggesting an aggravating effect of circulating proinflammatory cytokines on the histological lesions of IgAN, we studied changes in serum proinflammatory cytokines and their soluble receptors and antagonists in patients treated with polyvalent immunoglobulins (15 with severe nephropathy who had indicators of poor prognosis: heavy proteinuria, hypertension, altered renal function and Lee's histological grade III or IV; and 14 with moderate forms of IgAN who had permanent albuminuria > 300 mg/day and < 2000 mg/day, Lee's histological grade II and a glomerular filtration rate > 70 ml/min) in comparison with healthy controls (n = 20) and patients with non-IgA nephritides (n = 50). These were measured by means of specific immunometric assays before and after 9 months of immunoglobulin therapy. Total tumour necrosis factor (TNF) serum and IL-6 levels were elevated in IgAN patients before therapy, relative to controls, and normalized after immunoglobulin therapy. Levels of soluble TNF receptor of type I (sR55) and type II (sR75) increased on immunoglobulin therapy. TNF index alpha-55,75 used to assess biologically available TNF-alpha (ratio of total TNF-alpha divided by levels of soluble TNF receptors sR55 and sR75) was elevated before therapy and was below healthy control values after 9 months of immunoglobulin administration. Levels of serum IL-1 receptor antagonist were low prior to immunoglobulin administration in patients with severe forms of IgAN, and normalized on therapy. Serum interferon-gamma was unmodified. The histological activity index correlated with serum total TNF-alpha, TNF index alpha-55,75 and serum IL-6 levels, whereas proteinuria correlated with serum total TNF-alpha and TNF index alpha-55,75 but not with serum IL-6. These data suggest that the overproduction of proinflammatory cytokine is unbalanced by their natural antagonists in IgAN and Henoch-Sch?nlein syndrome. This process may play a role in the progression of the disease and be one of the targets of immunoglobulin therapy.     

Angiosarcoma of the bladder: a review

BACKGROUND/AIMS: Correlations between serum levels of soluble tumor necrosis factor receptors p55 (TNFsRp55) and Child Pugh index have previously been reported in alcoholic patients with cirrhosis. We have undertaken this study to improve understanding of the role of tumor necrosis factor soluble receptors (TNFsRs) in alcoholic liver disease. METHODS: One hundred and two patients with alcoholic liver disease of various severity (23 pure steatosis, 22 fibrosis, seven acute alcoholic hepatitis without cirrhosis, 12 cirrhosis without acute alcoholic hepatitis, 14 cirrhosis with mild acute alcoholic hepatitis and 24 cirrhosis with severe acute alcoholic hepatitis) were studied. Blood was collected on EDTA and plasma was tested for TNFsR concentrations using ELISA assays. RESULTS: Plasma levels of TNFsRp55 and p75 increased progressively with the severity of liver disease, reaching a maximum in cirrhotic patients with severe acute alcoholic hepatitis. Plasma levels of TNFsRp55 in patients with fibrosis and of TNFsRp75 in patients with acute alcoholic hepatitis without cirrhosis were already higher than in healthy controls. In cirrhotic patients with or without acute alcoholic hepatitis TNFsRp55 and p75 were significantly increased compared with controls. In cirrhotic patients, plasma levels of TNFsRp55 correlated positively with all parameters of liver injury, whereas the TNFsRp75/ TNFsRp55 ratio correlated negatively. In cirrhotic patients with severe acute alcoholic hepatitis, the TNFsRp75/TNFsRp55 ratio was significantly lower than in all other groups. In cirrhotic patients with severe acute alcoholic hepatitis treated by prednisolone, the decrease in TNFsRp55 plasma levels between day 1 and day 15 was significantly more important in patients still alive at 2 months than in patients who died within 2 months. CONCLUSIONS: These results show that the expression of TNF-soluble receptors (TNFsRs) participates in the early phases of the alcoholic liver disease and that the TNFsRp75/TNFsRp55 ratio and plasma levels of TNFsRp55 may help to determine the diagnosis and the prognosis of severe acute alcoholic hepatitis in cirrhotics.     

Plasma patterns of tumor necrosis factor-alpha (TNF) and TNF soluble receptors during acute meningococcal infections and the effect of plasma exchange

In 39 patients with acute meningococcal infections, the plasma concentrations of tumor necrosis factor-alpha (TNF) and its soluble receptors (sRs) TNFsR-p55 and TNFsR-p75 were measured from admission till recovery. At admission, patients with shock had significantly higher TNF, TNFsR-p55, and TNFsR-p75 values than patients without shock. In addition, during the first 24 hours, patients with shock had higher TNFsR-p75 to TNFsR-p55 ratios, indicating that in shock the increase of TNFsR-p75 exceeds that of TNFsR-p55. TNF measured more than 12 hours after admission failed to differentiate between shock and nonshock because TNF concentrations normalized within 12-24 hours. However, because concentrations of TNFsRs remained elevated for 5-6 days, at that time plasma TNFsRs still differentiated between shock and nonshock. Plasma exchange or whole blood exchange (PEBE), performed in 20 patients with shock, accelerated the decrease of plasma TNFsRs. However, because of a rebound after each PEBE session, the overall half-lives of both TNFsRs were not affected by PEBE.     

TNF receptor p55 plays a major role in centrally mediated increases of serum IL-6 and corticosterone after intracerebroventricular injection of TNF

The aim of this work was to study the relative role of the two TNF receptors (p55 and p75) in the central actions of TNF, studying the elevation of serum corticosterone (CS) and IL-6 levels after injection of recombinant murine (rm)TNF (intracerebroventricularly (i.c.v.)) in normal or p55-deficient (p55 -/-) mice. rmTNF induced high serum IL-6 levels and doubled serum CS in normal mice, whereas no elevation of serum IL-6 or CS was induced in p55 -/- mice. However, a normal CS response was observed in p55 -/- mice after LPS (2.5 microg, i.c.v.). p55 -/- mice also responded, although to a lesser extent than p55 +/+, in terms of LPS-induced IL-6 production. We also injected two agonist Abs specific for the two receptors, alpha p55 and alpha p75. While alpha p55 injected i.c.v. induced a marked elevation in CS and IL-6, alpha p75 induced CS (although less than alpha p55) but no IL-6. rmTNF, which binds both receptors, was more potent in inducing IL-6 and CS than injection of rhTNF, which in mice binds only p55. Finally, we investigated the role of p55 and p75 in IL-6 induction by TNF in a murine brain endothelioma. The results resembled closely those obtained in vivo: rmTNF was more potent than rhTNF and only alpha p55, and not alpha p75, induced IL-6 production. These data indicate that p55 plays a major role in TNF activation of the hypothalamus-pituitary-adrenal axis and in the centrally mediated induction of peripheral IL-6 by TNF, but p75, despite having little IL-6 inductive properties by itself, seems to potentiate p55 induction of IL-6.     

Early prediction of outcome in score-identified, postcardiac surgical patients at high risk for sepsis, using soluble tumor necrosis factor receptor-p55 concentrations

OBJECTIVE: To investigate the prognostic value of increased serum concentrations of soluble tumor necrosis factor (TNF) receptors in patients at high risk for sepsis. DESIGN: Prospective study. SETTING: Cardiac surgical intensive care unit in a University Hospital. PATIENTS: Those 27 of 870 consecutive postcardiac surgical patients who met a previously validated high-risk criterion for imminent sepsis (Acute Physiology and Chronic Health Evaluation II [APACHE II] score of > or = 24 on the first postoperative day [day 1]). In this population, systemic inflammatory response syndrome was present in 96% of the patients and the in-hospital mortality rate was 30%. In addition, ten postcardiac surgical patients with an uncomplicated course (mortality rate 0%) were studied for comparison. INTERVENTIONS: Blood sampling for measurements of serum concentrations of TNF and soluble TNF receptors 55 kilodalton (TNF receptor-p55) and 75 kilodalton (TNF receptor-p75) on days 1, 2, 3, and 5. MEASUREMENTS AND MAIN RESULTS: Compared with the ten patients with an uncomplicated course (group A), the high-risk patients had significantly higher baseline (day 1) serum concentrations of soluble TNF receptor-p55 (9.2 vs. 4.2 ng/mL) and soluble TNF receptor-p75 (9.2 vs. 5.5 ng/mL). These high-risk patients could be further differentiated into two subgroups: one (B) with a prompt decrease in APACHE II score and a good prognosis (mortality rate 0%) and another (C) with a persisting high risk of sepsis and mortality rate (40%, p < .05). Although baseline APACHE II score was similar in both high-risk subgroups, soluble TNF receptor-p55 concentrations were significantly higher in subgroup C compared with subgroup B already at baseline (10.7 vs. 4.7 ng/mL). The receiver operating characteristic curve for subgroup classification by soluble TNF receptor-p55 was in a discriminating position with an area (0.773 +/- 0.096), confirming soluble TNF receptor-p55 as a predictor of mortality. TNF and soluble TNF receptor-p75 concentrations were less predictive at baseline. CONCLUSIONS: This study suggest that increased soluble TNF receptor-p55 concentrations in the serum of postcardiac surgical patients allow earlier prognostication of subsequent hospital course than APACHE II scores alone. This study further suggests that the combination of physiologic scores and cytokine receptor measurements could improve the predictive power of early postoperative risk stratification.     

Serum levels and in situ expression of TNF-alpha and TNF-alpha binding proteins in inflammatory liver diseases

Cells respond to tumour necrosis factor-alpha (TNF-alpha) via binding to 75-kDa (type A) and 55-kDa (type B) receptors which have different intracellular signalling pathways and can also circulate as soluble molecules. Both receptors are co-expressed in many tissues, but their relative contributions to cellular TNF responses is for most situations unknown. In patients with viral and non-viral inflammatory liver diseases serum TNF-alpha was determined by an immunoenzymetric assay and soluble type A and B TNF receptors (TNF-alpha r) by enzyme-linked immunological and biological assays (ELIBA). In addition, cellular expression of TNF and its binding proteins were studied in liver biopsies by an indirect immunoperoxidase technique. Secretion of TNF-alpha and upregulation of TNF-alpha r-A were particularly prominent in viral hepatitis. Strong TNF-alpha in-situ production by mononuclear cells could be demonstrated in liver biopsies from patients with acute viral hepatitis. However, TNF-alpha r-A was detected only on hepatocytes. Serum TNF-alpha r-A was elevated two-fold in relative abundance over TNF-alpha r-B and was correlated to serum TNF-alpha (r = 0.6464, P < 0.0001). Soluble TNF-alpha r levels normalized, when the viral hepatitis was cleared, and successful therapy of hepatitis B was associated with a temporary rise of TNF-alpha r-A during the initial flare of aminotransferase. Patients with alcoholic hepatitis had also evidence of TNF-alpha activation but clearly differed from patients with viral induced liver diseases: Soluble TNF-alpha r-A and TNF-alpha r-B were highly elevated in equal proportions. In situ analysis in liver biopsies revealed a distinctive pattern of TNF-alpha r expression with strong cytoplasmic staining for both TNF-alpha r-A and B on scattered hepatocytes in addition to infiltrating mononuclear cells. The data propose that TNF release during antiviral immune responses is predominantly associated with TNF-alpha r-A upregulation and shedding, whereas upregulation and shedding of TNF-alpha r-B is more prominent in alcoholic hepatitis. As cytotoxicity and apoptosis by TNF are mediated mainly via TNF-alpha r-B, our results are consistent with more severe TNF-alpha induced liver damage in alcoholic hepatitis as compared to viral hepatitis.     

Shedding kinetics of soluble tumor necrosis factor (TNF) receptors after systemic TNF leaking during isolated limb perfusion. Relevance to the pathophysiology of septic shock

We examined the kinetics of shedding of the soluble TNF receptors (TNF-Rs) in response to TNF leakage during isolated limb perfusion procedures and correlated them to the resulting hemodynamic effects. Shedding of the TNF-Rs started 7 min after TNF leakage into the systemic circulation. Three waves of shedding were observed peaking at 1, 8-12, and 48-72 h both in vivo and in cell cultures. The soluble receptors prolonged the half-life of TNF in the systemic circulation to 2.5-6 h. Excess shedding of the p75 compared with p55 TNF-Rs was noted during the first wave. The amount and speed of shedding of the p75 TNF-Rs were proportional to the serum TNF levels (P < 0.001). A maximal shedding capacity was attained only during the first wave of shedding, at TNF concentrations of approximately 1.5 ng/ml. Above this level, the linearity between TNF and its soluble receptors was lost. TNF-induced hypotension coincided with the initial imbalance between the concentrations of TNF and its soluble receptors. Despite the spontaneous correction of this imbalance at 8-12 h, the hemodynamic and biochemical alterations persisted and were further aggravated at 18 h, suggesting that other factors induced earlier by TNF are responsible for the perpetuation of the hemodynamic instability. This study may provide the basis for a more physiological therapeutic approach to TNF neutralization in septic shock patients.     

Calcium induces a conformational change in the ligand binding domain of the low density lipoprotein receptor

TNF-alpha may play a role in mediating insulin resistance associated with obesity. This concept is based on studies of obese rodents and humans, and cell culture models. TNF elicits cellular responses via two receptors called p55 and p75. Our purpose was to test the involvement of TNF in glucose homeostasis using mice lacking one or both TNF receptors. C57BL/6 mice lacking p55 (p55(-)/-), p75, (p75(-)/-), or both receptors (p55(-)/-p75(-)/-) were fed a high-fat diet to induce obesity. Marked fasting hyperinsulinemia was seen for p55(-)/-p75(-)/- males between 12 and 16 wk of feeding the high-fat diet. Insulin levels were four times greater than wild-type mice. In contrast, p55(-)/- and p75(-)/- mice exhibited insulin levels that were similar or reduced, respectively, as compared with wild-type mice. In addition, high-fat diet-fed p75(-)/- mice had the lowest body weights and leptin levels, and improved insulin sensitivity. Obese (db/db) mice, which are not responsive to leptin, were used to study the role of p55 in severe obesity. Male p55(-)/-db/db mice exhibited threefold higher insulin levels and twofold lower glucose levels at 20 wk of age than control db/db expressing p55. All db/db mice remained severely insulin resistant based on fasting plasma glucose and insulin levels, and glucose and insulin tolerance tests. Our data do not support the concept that TNF, acting via its receptors, is a major contributor to obesity-associated insulin resistance. In fact, data suggest that the two TNF receptors work in concert to protect against diabetes.     

Soluble tumor necrosis factor receptors are present in human vitreous and shed by retinal pigment epithelial cells

Tumor necrosis factor-alpha (TNF) has been implicated in the pathogenesis of several retinal diseases. Soluble forms of the TNF receptors, p55 (55 kDa) and p75 (75 kDa), have recently been identified in biological fluids and may regulate TNF activity. The potential biological significance of these receptors for the human retina was examined by determining their presence in human vitreous and their release from eye cup explants in which the retina has been removed leaving an intact retinal pigment epithelium (HRPE). Normal human vitreous and conditioned medium from eye-cup HRPE explants demonstrated the presence of soluble p55 and p75. Soluble p55 was significantly more abundant than p75 in all vitreous samples (P < 0.03). Conditioned medium from eye-cup HRPE explants contained significantly more soluble p55 than p75 (P < 0.00002). Enzyme-linked immunosorbent assay showed the presence of soluble p55, and not p75, in conditioned medium from primary cultured HRPE cells. Activation of the protein kinase C pathway in these cells with the phorbol ester PMA significantly increased the release of soluble p55 (P < or = 0.001); whereas, pharmacological inhibition of protein kinase C with calphostin-C significantly decreased the shedding of p55 (P < or = 0.001). The results indicate that primary cultured HRPE cells shed p55 and regulate this shedding in part through the protein kinase C pathway. The presence of soluble TNF receptors within normal human vitreous and within conditioned medium from the eye-cup HRPE explant model suggests that these soluble receptors may have a biological function in the eye.     

Serum levels of p55 and p75 soluble TNF receptors in adult acute leukaemia at diagnosis: correlation with clinical and biological features and outcome

The tumour necrosis factor (TNF)/TNF-receptor (TNFR) complex plays a role in the growth of leukaemic cells. We retrospectively investigated the relationship between pretreatment serum concentration of soluble TNFR (p55- and p75-sTNFRs) and outcome in adult acute myeloid (AML 82 cases) and lymphoid (ALL 44 cases) leukaemia. Both sTNFRs were significantly higher in AML (p55-sTNFR 4.53 +/- 3.7, median 3.75; p75-sTNFR 6.51 +/- 5.25 ng/ml, median 4.72) and ALL sera (3.31 +/- 1.5, median 2.95; 5.30 +/- 2.3 ng/ml, median 4.56, respectively) than in controls (1.89 +/- 0.5, median 1.98; 2.22 +/- 0.8 ng/ml, median 2.37) (P < 0.01 for both sTNFRs). Fresh leukaemic cells expressed p55- and p75-sTNFRs, which were modulated and released into the supernatant (SN) following short-term in vitro culture, suggesting that in vivo sTNFRs were also leukaemia-derived. Whereas no correlation was observed between sTNFRs and outcome in ALL, in AML higher p55-sTNFR levels (> 3.75 ng/ml) were associated with shorter disease-free survival (DFS) (P = 0.006) and overall survival (OS) (P = 0.0004). At multivariate analysis p55-sTNFR was the most significant predictor of DFS (P = 0.006) and OS (P < 0.001). Our data suggest that the prognostic significance of p55-sTNFR in AML could be related to relevant biological features of AML blasts.     

The onset of CML in blastic crisis: molecular features

The cytokine tumor necrosis factor alpha (TNF alpha) was proposed to mediate obesity related insulin resistance upon production in fat cells and to participate in tissue remodelling leading to vascular complications upon being released by macrophages. To assess its putative role in diabetes we determined plasma levels of TNF alpha in 105 adult humans. Male nondiabetic subjects had significantly lower TNF alpha levels than female controls (4.4 +/- 0.3, n = 17 vs. 6.6 +/- 1.0 pg/ml, n = 13; p = 0.049). Men with NIDDM had elevated TNF alpha (6.7 +/- 0.6 pg/ml, n = 34) compared to nondiabetic subjects (4.4 +/- 0.3 pg/ml, n = 17; p = 0.012). Such a difference was not apparent in women. Levels of TNF alpha were correlated with serum triglyceride levels in male controls (r2 = 0.64; p = 0.007) but not in NIDDM. Neither body mass index nor glycosylated hemoglobin correlated with TNF alpha in any of the groups. The presence of retinopathy (p = 0.046) but not of neuropathy or nephropathy or macroangiopathy was associated with significantly elevated plasma TNF alpha. We conclude that plasma levels of TNF alpha are sex-dependent and that increased TNF alpha occurs in male but not female NIDDM and may participate in the development of diabetic complications.     

Soluble tumour necrosis factor receptor release after anti-CD3 monoclonal antibody treatment in mice is independent of tumour necrosis factor-alpha release

The involvement of TNF-alpha in the release of soluble TNF receptors was assessed in mice, treated with anti-CD3 monoclonal antibodies. After treatment with three different anti-CD3 mAb, we simultaneously studied serum levels of TNF-alpha, soluble TNF receptor P55 and P75. All three anti-CD3 mAb triggered the release of both of the soluble TNF receptors, whereas only one of the anti-CD3 mAb triggered TNF-alpha release. These data demonstrate that in our model soluble TNF receptor release is independent of TNF-alpha release.     

A metalloproteinase inhibitor blocks the shedding of soluble cytokine receptors and processing of transmembrane cytokine precursors in human monocytic cells

A number of membrane-anchored cytokines and cytokine receptors are susceptible to yield soluble counterparts. Recently, peptide-hydroxamate metalloproteinase inhibitors have been reported to block the proteolytic processing of tumour necrosis factor (TNF)-alpha 55- and 75-kDa TNF receptors (TNF-R55 and TNF-R75), and interleukin (IL)-6R. In this report the authors studied the effect of an hydroxamate metalloproteinase inhibitor on the secretion of cytokines and the generation of cytokine soluble receptors by human myelomonoycytic cell lines and purified monocytes. Whereas secretion of cytokines lacking a transmembrane domain precursor (IL-1 alpha, IL-1 beta, IL-6 or IL-10) is either unaffected or augmented, shedding/secretion of transmembrane domain-containing cytokines and cytokine receptors [TNF-alpha, macrophage colony-stimulating factor (M-CSF), transforming growth factor (TGF)-alpha, stem cell factor (SCF), TNF-R55, TNF-R75, and IL-6R] was dramatically decreased in the presence of the metalloproteinase inhibitor. The diversity of sequences in the cleavage site of these proteins and differences found in the inhibitory concentration values suggest the existence of a metalloproteinase family displaying different substrate specificity. These results emphasize the important role of metalloproteinases as regulators of membrane expression and secretion of cytokines and cytokine receptors.     

TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation

The pleiotropic activities of the potent proinflammatory cytokine TNF are mediated by two structurally related, but functionally distinct, receptors, p55 and p75, that are coexpressed on most cell types. The majority of biologic responses classically attributed to TNF are mediated by p55. In contrast, p75 has been proposed to function as both a TNF antagonist by neutralizing TNF and as a TNF agonist by facilitating the interaction between TNF and p55 at the cell surface. We have examined the roles of p55 and p75 in mediating and modulating the activity of TNF in vivo by generating and examining mice genetically deficient in these receptors. Selective deficits in several host defense and inflammatory responses are observed in mice lacking p55 or both p55 and p75, but not in mice lacking p75. In these models, the activity of p55 is not impaired by the absence of p75, arguing against a physiologic role for p75 as an essential element of p55-mediated signaling. In contrast, exacerbated pulmonary inflammation and dramatically increased endotoxin induced serum TNF levels in mice lacking p75 suggest a dominant role for p75 in suppressing TNF-mediated inflammatory responses. In summary, these data help clarify the biologic roles of p55 and p75 in mediating and modulating the biologic activity of TNF and provide genetic evidence for an antagonistic role of p75 in vivo.     

Soluble cytokine receptors and receptor antagonists are sequentially released after trauma

Cytokine receptors and receptor antagonists (RAs) have been identified in trauma patients. We hypothesized that after traumatic injury, a sequential release of soluble cytokine receptors and RAs may exist that mirrors the release of the primary cytokines themselves. Twenty-two patients were included in the study: 14 males and 8 females. The mean age was 30.1 +/- 12.5 (range, 19 to 71), and the mean Injury Severity Score was 28.7 +/- 12.6 (range, 4 to 57). There were 15 survivors and 7 nonsurvivors. Samples were collected on arrival to the emergency department and at serial intervals for up to 7 days. Monoclonal antibody enzyme-linked immunosorbent assay kits to tumor necrosis factor (TNF), soluble TNF-receptor (sTNF-R) 55 kd and 75 kd, interleukin (IL)-1 and IL-1 RA, and IL-2 and IL-2r were used. Sera from 22 healthy individuals were used as normal controls. No TNF, IL-1, or IL-2 could be detected in any patient sera after injury. Control levels for the soluble cytokine receptors and RAs were as follows: sTNF-R 55 kd, 607 +/- 89 pg/mL; sTNF-R 75 kd, 2,141 +/- 169 pg/mL; IL-1 RA, 291 +/- 35 pg/mL; and IL-2r, 426 +/- 53 U/mL. In trauma patients, both 55 kd and 75 kd sTNF-R were significantly elevated on arrival to the emergency department, with values of 2,441 +/- 506 pg/mL (p < 0.001) and 4,736 +/- 537 pg/mL (p < 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans

The expression of leptin, an adipocyte-derived protein whose circulating levels reflect energy stores, can be induced by tumor necrosis factor (TNF)alpha in rodents, but an association between the TNF alpha system and leptin levels has not been reported in humans. To evaluate the potential association between serum leptin and the TNF alpha system, we measured the levels of soluble TNF alpha-receptor (sTNF alpha-R55), which has been validated as a sensitive indicator of activation of the TNF alpha system. We studied two groups: 1) 82 young healthy normal controls and 2) 48 patients with noninsulin dependent diabetes mellitus (NIDDM) and 24 appropriately matched controls. By simple regression analysis in controls, there was a strong positive association between leptin and 3 parameters: body mass index, sTNF alpha-R55, and insulin levels. In a multiple regression analysis model, leptin remained significantly and strongly associated with body mass index, and the association of leptin with both insulin and sTNF alpha-R55, although weakened, remained significant. Patients with NIDDM had leptin concentrations similar to controls of similar weight. Importantly, serum levels of sTNF alpha-R55 were also positively and independently associated with leptin in this group of diabetic subjects and matched controls. These data are consistent with the hypothesis that the TNF alpha system plays a role in regulating leptin levels in humans. Further elucidation of a possible role of the TNF alpha system in leptin expression and circulating levels may have important implications for our understanding of obesity and cachexia in humans.     

Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity

Excessive daytime sleepiness (EDS) and fatigue are frequent symptoms in the general population and the chief complaint of the majority of patients at Sleep Disorders Centers. There is evidence that the inflammatory cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and IL-6 are involved in physiological sleep regulation and that their administration to humans is associated with sleepiness and fatigue. To explore whether plasma levels of TNF alpha, IL-1beta, and IL-6 are elevated in patients with EDS, we measured morning plasma levels of TNF alpha, IL-1beta, and IL-6 in 12 sleep apneics, 11 narcoleptics, 8 idiopathic hypersomniacs, and 10 normal controls. TNF alpha was significantly elevated in sleep apneics and narcoleptics compared to that in normal controls (P < 0.001 and P = 0.001, respectively). Plasma IL-1beta concentrations were not different between sleep disorder patients and controls, whereas IL-6 was markedly and significantly elevated in sleep apneics compared to that in normal controls (P = 0.028). The primary factor influencing TNF alpha values was the degree of nocturnal sleep disturbance, whereas the primary determinant for IL-6 levels was the body mass index. Our findings suggest that TNF alpha and IL-6 might play a significant role in mediating sleepiness and fatigue in disorders of EDS in humans.     

Soluble adhesive molecules and cytokines in patients with myasthenia gravis treated with plasmapheresis

BACKGROUND: Plasma exchange (PE) is effective therapeutic method used in patients with myasthenia gravis (MG) refractory to common therapy and/or with life-threatening respiratory complications. Except from acetylcholine receptor antibodies (AChRAb) some other inflammatory mediators possibly activated in MG may be also removed during PE. METHODS AND RESULTS: Serum levels of soluble adhesion molecules (sICAM-1 and sVCAM-1), IL-6 and soluble receptors for IL-2 (sIL-2R), IL6 (sIL-6R) and TNF alpha (sTNF-R II) were measured in 20 patients (pts) with MG indicated to the treatment with PE. Pts were subdivided on the basis of the serum levels of AChRAb into 2 groups (8 pts with low AChRAb, 12 pts with high AChRAb). Soluble adhesion molecules and cytokines were measured before the 1st and last PE, at the end of the 1st PE and in the samples of plasma filtrate obtained during the 1st PE. Pts with MG had before the 1st PE higher serum levels of sICAM-1, sVCAM-1, sIL-2R and sTNF-R II than controls. Both the first PE and the course of PE led to the substantial decrease of serum levels of AChRAb, sICAM-1 and sVCAN-1, serum levels of sIL-2R and sTNF-R II were not, however, significantly influenced by both the single and the course of PE. There were high levels of AChRAb, soluble adhesion molecules and soluble cytokine receptors in plasma filtrate, too. Pts with high circulating AChRAb had higher serum levels of sICAM-1 and sVCAM-1 than pts with low AChRAb. CONCLUSIONS: Increased serum levels of soluble adhesion molecules and soluble cytokine receptors in pts with MG indicated to the treatment by PE suggest some systemic activation of immune response which is more pronounced in pts with high circulating AChRAb. PE led to the decrease of serum AChRAb and soluble adhesion molecules due to their effective filtration, but, on the other hand, serum levels of soluble cytokine receptors were not influenced by PE, in spite of their effective filtration which is probably counteracted by their increased production, possibly stimulated by the contact of the blood with synthetic membrane.