Soluble Tumor Necrosis Factor receptor-I Research Articles

Effect of Inhibition of Colony-Stimulating Factor 1 Receptor on Choroidal Neovascularization in Mice

Neovascular age-related macular degeneration is one of the leading causes of blindness. Microglia and macrophages play a critical role in choroidal neovascularization (CNV) and may, therefore, be potential targets to modulate the disease course. This study evaluated the effect of the colony-stimulating factor-1 receptor inhibitor PLX5622 on experimental laser-induced CNV. A 98% reduction of retinal microglia cells was observed in the retina 1 week after initiation of PLX5622 treatment, preventing accumulation of macrophages within the laser site and leading to a reduction of leukocytes within the choroid after CNV induction. Mice treated with PLX5622 had a significantly faster decrease of the CNV lesion size, as revealed by invivo imaging and immunohistochemistry from day 3 to day 14 compared with untreated mice. Several inflammatory modulators, such as chemokine (C-C motif) ligand 9, granulocyte-macrophage colony-stimulating factor, soluble tumor necrosis factor receptor-I, IL-1α, and matrix metallopeptidase-2, were elevated in the acute phase of the disease when microglia were ablated with PLX5622, whereas other cytokines (eg, interferon-γ, IL-4, and IL-10) were reduced. Our results suggest that colony-stimulating factor-1 receptor inhibition may be a novel therapeutic target in patients with neovascular age-related macular degeneration.

Omega-3 Fatty Acids Do Not Improve Endothelial Function In Virologically Suppressed HIV-Infected Men: A Randomized Placebo-Controlled Trial

Omega-3 fatty acids decrease cardiovascular disease (CVD) mortality possibly due to antiinflammatory effect. Inflammation and endothelial dysfunction likely play a role in the heightened CVD risk in HIV. Our goal was to evaluate the effect of omega-3 fatty acids primarily on endothelial function and inflammation in HIV-infected adults with moderate CVD risk on stable antiretroviral therapy. We conducted a 24-week, randomized, double-blind, placebo-controlled study to evaluate the effect of omega-3-acid ethyl esters 1 g twice a day. Flow-mediated dilation (FMD) of the brachial artery, lipoproteins and markers of inflammation, endothelial activation, coagulation, and insulin resistance were measured at entry and week 24. There were no within- or between-group differences in change in FMD over 24 weeks (mean change in FMD -0.13% vs. 1.5% for treatment vs. placebo; p=0.21). There were no between-group differences in changes in lipoprotein levels or biomarkers tested, except soluble tumor necrosis factor receptor-I, which favored omega-3-acid ethyl esters. Omega-3 fatty acids did not improve endothelial function or activation, coagulation, or insulin resistance in virologically suppressed, HIV-infected men with moderate CVD risk; however, inflammation tended to improve. This suggests that omega-3 fatty acids may not be potent enough to counteract the enhanced inflammation and endothelial dysfunction due to HIV and antiretrovirals.

Changes of cytokines in cirrhosis patients with advanced hepatocellular carcinoma treated by intra-arterial chemotherapy

Tumor necrosis factor (TNF) induces cancer cell-specific apoptosis by binding to a TNF-related apoptosis-inducing ligand. Binding of the Fas ligand on cytotoxic T lymphocytes to the Fas receptor on hepatocytes is also known to induce apoptosis. The aim of this study was to clarify changes of cytokines in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) receiving intra-arterial combination chemotherapy. Twenty-one adult Japanese LC patients with aHCC received intra-arterial combination chemotherapy. The serum levels of TNF-alpha, soluble TNF receptor-I (sTNFr-I), soluble Fas ligand (sFas L), and soluble Fas (sFas) were evaluated. Thirteen of the 21 patients (group R) showed an objective response, while the other eight patients (group N) showed no response. The serum level of TNF-alpha was lower after chemotherapy than before chemotherapy in group N, but there was no difference of serum sTNFr-I levels between before and after chemotherapy and there were also no differences between the two groups. The serum sFas levels were higher after chemotherapy than before chemotherapy in group N, while there was no difference among groups. These results indicate that a high serum TNF-alpha level and a low serum sFas level might be important for successful combined arterial chemotherapy in LC patients with aHCC.

Interluekin-6, Interleukin-8, and Soluble Tumor Necrosis Factor Receptor-I in the Cord Blood as Predictors of Chronic Lung Disease in Premature Infants

Interluekin-6, Interleukin-8, and Soluble Tumor Necrosis Factor Receptor-I in the Cord Blood as Predictors of Chronic Lung Disease in Premature Infants

CEREBROSPINAL FLUID CONCENTRATIONS OF ANTI-INFLAMMATORY MEDIATORS IN EARLY-PHASE SEVERE TRAUMATIC BRAIN INJURY

In our previous study of patients with early-phase severe traumatic brain injury (TBI), the anti-inflammatory interleukin (IL)-10 concentration was lower in cerebrospinal fluid (CSF) than in serum, whereas proinflammatory IL-1beta and tumor necrosis factor (TNF)-alpha concentrations were higher in CSF than in serum. To clarify the influence of additional injury on this disproportion between proinflammatory and anti-inflammatory mediators, we compared their CSF and serum concentrations in patients with severe TBI with and without additional injury. All 35 study patients (18 with and 17 without additional injury) had a Glasgow Coma Scale score of 8 or less upon admission. With the exception of additional injury, clinical characteristics did not differ significantly between groups. CSF and serum concentrations of two proinflammatory mediators (IL-1beta and TNF-alpha,) and three anti-inflammatory mediators (IL-1 receptor antagonist [IL-1ra], soluble TNF receptor-I [sTNFr-I], and IL-10) were measured and compared at 6 h after injury. CSF concentrations of proinflammatory mediators were much higher than the corresponding serum concentrations in both patient groups (P < 0.001). In contrast, serum concentrations of anti-inflammatory mediators were much higher than the paired CSF concentrations in patients with additional injury (P < 0.001), but serum concentrations were lower than or equal to the corresponding CSF concentrations in patients without additional injury. CSF concentrations of IL-1beta, IL-1ra, sTNFr-I, and IL-10 were significantly higher (P < 0.01 for all) in patients with high intracranial pressure (ICP; n = 11) than in patients with low ICP (n = 24), and were also significantly higher (P < 0.05 for all) in patients with an unfavorable outcome (n = 14) than in patients with a favorable outcome (n = 21). These findings indicate that increased serum concentrations of anti-inflammatory mediators after severe TBI are mainly due to additional extracranial injury. We conclude that anti-inflammatory mediators in CSF may be useful indicators of the severity of brain damage in terms of ICP as well as overall prognosis of patients with severe TBI.

Contribution of Transmembrane Tumor Necrosis Factor to Host Defense against Mycobacterium bovis Bacillus Calmette-Guerin and Mycobacterium tuberculosis Infections

To study the specific role of transmembrane tumor necrosis factor (TmTNF) in host defense mechanisms against bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis infections, we compared the immune responses of TNF/lymphotoxin (LT)-alpha(-/-) mice expressing a noncleavable transgenic TmTNF (TmTNF tg) to those of TNF/LT-alpha(-/-) and wild-type mice. Susceptibility of TNF/LT-alpha(-/-) mice to BCG infection was associated with impaired induction of systemic RANTES but not of monocyte chemoattractant protein 1 (MCP-1), the development of excessive local and systemic Th1-type immune responses, and a substantially reduced inducible nitric oxide synthase (iNOS) activity. Resistance of TmTNF tg mice to BCG infection was associated with efficient activation of iNOS in granulomas and with the regulated release of local and systemic chemokines and Th1-type cytokines. However, M. tuberculosis infection of TmTNF tg mice resulted in longer survival and enhanced resistance compared to TNF/LT-alpha(-/-) mice but higher sensitivity than wild-type mice. TmTNF tg mice exhibited reduced pulmonary iNOS expression and showed an exacerbated cellular infiltration in the lungs despite a modest bacillary content. Our data thus indicate a role for TmTNF in host defense against mycobacteria by contributing to induction and regulation of Th1-type cytokine and chemokine expression leading to development of bactericidal granulomas expressing iNOS, which critically determines susceptibility versus resistance of the host to mycobacterial infections.

Interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-I in the cord blood as predictors of chronic lung disease in premature infants

Objectives In order to predict the late-development of chronic lung disease of prematurity (CLD), cytokines in the cord blood were assessed in this study. Study design Eighteen premature infants with CLD were enrolled. Cord blood plasma levels of cytokines of these infants and 12 control infants without CLD were measured including interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, soluble TNF receptor-I, and soluble IL-6 receptor using a cytometric bead array and an enzyme-linked immunosorbent assay. Results The cord blood IL-6, IL-8, and sTNFR-I levels were significantly elevated in CLD infants compared with those in control ( P < .05). IL-1β, IL-2, IL-4, IL-10, and IFN-γ were undetectable in both groups. CLD infants with maternal chorioamnionitis had higher IL-6 than those without chorioamnionitis ( P < .01). In CLD infants, IL-6 was higher in the infants who required prolonged oxygen therapy ( P < .05). Conclusion Elevated inflammatory cytokines in the cord blood are associated with the progression to CLD.

Enzyme leakage, trypsinogen activation, and inflammatory response in endoscopic retrograde cholangiopancreatography-induced pancreatitis.

Endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis (EIP) provides an opportunity to study different pathophysiologic events early in the course of acute pancreatitis. To investigate whether the leakage of pancreatic proenzymes (anionic trypsinogen), pancreatic protease activation (carboxypeptidase B activation peptide), cytokine response (interleukin [IL]-1 receptor antagonist, IL-6, and soluble tumor necrosis factor receptor-I) and neutrophil activation (neutrophil gelatinase-associated lipocalin and polymorphonuclear elastase) differ between patients with and without EIP. A second aim was to clarify the temporal relation between these different events. Ninety-nine nonconsecutive patients undergoing ERCP were investigated in the study. Fourteen of 99 patients undergoing ERCP developed mild EIP. Six hours after the investigation the concentration of anionic trypsinogen was significantly higher in patients with EIP than in patients without EIP. The day after ERCP, higher concentrations of anionic trypsinogen, carboxypeptidase B activation peptide, IL-6, and polymorphonuclear elastase were recorded in the EIP group. No significant differences in IL-1 receptor antagonist, soluble tumor necrosis factor receptor-I or neutrophil gelatinase-associated lipocalin were found between the groups in this study. Mild EIP was accompanied by early leakage of proenzymes and later activation of trypsinogen/proteases. A significant cytokine response and neutrophil activation were recorded the day after ERCP, but further studies are needed to determine the temporal relation between these different pathophysiologic events.

The soluble tumor necrosis factor receptor I is an early predictor of local infective complications after colorectal surgery.

The clinical implications of increased cytokine levels after major surgery remain unclear. In this study, systemic concentration of a spectrum of cytokines, including interleukins IL-6, IL-8, IL-10, IL-1ra, and soluble tumor necrosis factor receptor-I (sTNF-RI) was examined in patients with and without postoperative septic complications following colorectal surgery. Although there were no significant changes in IL-1beta, TNF-alpha, and IL-8 serum levels during the observation period, there was a significant rise in IL-6, IL-1ra, and sTNF-RI concentrations in the entire group of patients between postoperative day 1 and 14. There were no differences between the group without and with local complications when IL-6, IL-1ra, and IL-10 were examined. The serum levels of sTNF-RI, IL-1ra, and IL-6 were found to be sensitive indicators of the pro- and anti-inflammatory response to the surgical trauma, but only sTNF-RI turned out to be a sensitive early marker of local septic postoperative complications in patients with colorectal carcinoma.

Predominant T helper 1 cells in patients with idiopathic portal hypertension

The pathologic mechanism of idiopathic portal hypertension (IPH) is unknown. Because cytokines and the balance of T helper (h) 1 and Th2 CD4+ T cells have been reported to be important for regulating the immune response, in the present study we investigated the role of cytokines and the distribution of cytokine-producing cells in IPH patients. Serum levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor-I, -II, interferon (IFN)-gamma and interleukin (IL)-4 were measured in IPH patients, fatty liver patients, chronic hepatitis patients and control subjects. The percentages of Th0, Th1 and Th2 CD4+ T cells were examined in peripheral and spleen lymphocytes in IPH patients by intracellular staining. Serum levels of TNF-alpha, soluble TNF receptor-I, interferon-gamma and IL-4 of IPH patients were not increased in comparison with control subjects. Only the mean value of soluble TNF receptor-II was significantly higher than that of control subjects and fatty liver patients. The ratios of Th1 and Th2 in both peripheral and spleen lymphocytes of IPH patients were significantly increased compared with the ratios found in peripheral lymphocytes of control subjects. The increase in the ratios was due to a decrease in the percentage of Th2 CD4+ T cells. These results suggest that the imbalance of Th1 and Th2 CD4+ T cells and TNF may be associated with the pathogenesis of IPH.

Significance of soluble TNF receptor-I in acute-type fulminant hepatitis

OBJECTIVE: Fulminant hepatitis is associated with apoptosis of hepatocytes, which is mediated via Fas and tumor necrosis factor (TNF) receptors. The clinical significance of apoptotic factors and these receptors was investigated in fulminant hepatitis. METHODS: Serum levels of TNF-α, soluble TNF receptor-I and -II, soluble Fas antigen, and Fas ligand were measured. Then, the relationships between these parameters and the severity or prognosis of fulminant hepatitis were studied. RESULTS: Serum levels of TNF-α, soluble TNF receptor-I, and soluble TNF receptor-II were increased in acute-type fulminant hepatitis. In particular, soluble TNF receptor-I was significantly higher than in patients with subacute-type fulminant hepatitis, severe acute hepatitis, acute hepatitis, or healthy controls. The soluble TNF receptor-I level continued to increase or remained high in patients who died of acute-type fulminant hepatitis, and eight of nine patients had a level >10 ng/ml. In contrast, the soluble TNF receptor-I level remained <10 ng/ml in survivors. Soluble Fas and soluble Fas ligand levels tended to increase in all types of acute liver disease and were not specific to fulminant hepatitis. CONCLUSION: Our findings suggested that monitoring the soluble TNF receptor-I level may help to assess the prognosis of acute-type fulminant hepatitis and that TNF might be associated with massive hepatic necrosis.

Significance of soluble TNF receptor-I in acute-type fulminant hepatitis.

Fulminant hepatitis is associated with apoptosis of hepatocytes, which is mediated via Fas and tumor necrosis factor (TNF) receptors. The clinical significance of apoptotic factors and these receptors was investigated in fulminant hepatitis. Serum levels of TNF-alpha, soluble TNF receptor-I and -II, soluble Fas antigen, and Fas ligand were measured. Then, the relationships between these parameters and the severity or prognosis of fulminant hepatitis were studied. Serum levels of TNF-alpha, soluble TNF receptor-I, and soluble TNF receptor-II were increased in acute-type fulminant hepatitis. In particular, soluble TNF receptor-I was significantly higher than in patients with subacute-type fulminant hepatitis, severe acute hepatitis, acute hepatitis, or healthy controls. The soluble TNF receptor-I level continued to increase or remained high in patients who died of acute-type fulminant hepatitis, and eight of nine patients had a level >10 ng/ml. In contrast, the soluble TNF receptor-I level remained <10 ng/ml in survivors. Soluble Fas and soluble Fas ligand levels tended to increase in all types of acute liver disease and were not specific to fulminant hepatitis. Our findings suggested that monitoring the soluble TNF receptor-I level may help to assess the prognosis of acute-type fulminant hepatitis and that TNF might be associated with massive hepatic necrosis.