Tumor necrosis factor alpha induces migration of human eosinophils

In order to evaluate the role of tumor necrosis factor alpha (TNF alpha) in the recruitment of eosinophils and neutrophils into the tissues, we studied the effect of TNF alpha on the migration of those cells in vitro, employing a modified Boyden's chamber technique. TNF alpha induced a significant migration of human eosinophils in a dose-dependent manner, and the preincubation of eosinophils with TNF alpha enhanced platelet activating factor (PAF)-induced eosinophil migration. Checkerboard analysis revealed that the eosinophil migration induced by TNF alpha was mainly due to chemokinesis. On the other hand, TNF alpha induced neither neutrophil migration nor enhancement of PAF-induced neutrophil migration. These results indicate that TNF alpha possesses a chemokinetic effect on human eosinophils and that TNF alpha augments the migration of eosinophils by PAF.     

Effects of interferons on tumour necrosis factor alpha production from human keratinocytes

Interferons (IFNs) have been reported to have pleiotrophic effects including the ability to induce the production of other cytokines in several cell types. Tumour necrosis factor alpha (TNF-alpha) is pro-inflammatory cytokine a known to be produced by a variety of cells including human keratinocytes. In the present study, we sought to determine the effects of IFNs on TNF-alpha production from human keratinocytes. IFN-gamma (50-100 ng/ml) induced TNF-alpha production dose dependently, but no induction of TNF-alpha was observed with IFN-alpha or IFN-beta. Since in the epidermis cytokines often work with in a cascade fashion and keratinocytes are a source of primary cytokine, IL-1 alpha, whether combined treatment with IFN-gamma and IL-1 alpha had a synergistic effect on TNF-alpha production was examined. Combined treatment with IFN-gamma (100 ng/ml) and IL-1 alpha (10 ng/ml) induced 2-3-fold higher level of TNF-alpha than IL-1 alpha alone. These results suggest that IFN-gamma is a positive regulator for the production of TNF-alpha from human keratinocytes and likely to increase skin inflammation.     

Tumor necrosis factor alpha (TNF-alpha) modulates rat mast cell reactivity

The Walker carcinosarcoma cells were cultured in the medium with low concentration (0.25%) of fetal calf serum, in the presence of native or methylamine-treated (modified) human alpha 2-macroglobulin (alpha 2-MG) in vitro. The proliferative activity (3H-thymidine incorporation) of these cells increased in the presence of one or the other alpha 2-MG preparation. It allows to suppose that the human alpha 2-MG may serve as a growth-stimulating factor of tumour cells.     

Tumor necrosis factor alpha regulates proliferation in a mouse intestinal cell line

BACKGROUND & AIMS: Tumor necrosis factor (TNF)-alpha is a prominent cytokine in the pathogenesis of inflammatory bowel disease, yet its effects on the intestinal epithelium remain poorly understood. This study was designed to investigate the action of TNF-alpha on intestinal cell proliferation. METHODS: Young adult mouse colon cells were studied under nontransformed conditions with epidermal growth factor, keratinocyte growth factor, insulin-like growth factor 1, or serum in the presence or absence of TNF-alpha and cell numbers determined. The expression and independent actions of the 55-kilodalton TNF-alpha R1 and 75-kilodalton TNF-alpha R2 receptors were studied by immunologic methods. RESULTS: TNF-alpha stimulated proliferation at 0.1 and 1 ng/mL and inhibited proliferation at 100 and 1000 ng/mL without altering cell viability. TNF-alpha inhibited the mitogenic effect of growth factors and epidermal growth factor receptor tyrosine phosphorylation. TNF-alpha R1 receptor agonist antibody inhibited proliferation, whereas a TNF-alpha R2 receptor-blocking antibody prevented the proliferative effect of low-dose TNF-alpha. CONCLUSIONS: TNF-alpha displays a novel influence on intestinal cell growth, stimulating proliferation at physiological concentrations and inhibiting proliferation at pathological concentrations. The regulation of intestinal cell mitogenesis by TNF-alpha seems to be mediated differentially by the two TNF-alpha receptors, with the TNF-alpha R1 receptor inhibiting proliferation and the TNF-alpha R2 receptor promoting proliferation.     

Tumor necrosis factor alpha in human kidney transplant rejection--analysis by in situ hybridization

Macrophagic infiltration and necrosis of rejected kidney transplants represent two pejorative patterns. It has been assumed that the macrophagic toxicity is mediated partly by secretion of tumor necrosis factor alpha. On the other hand, TNF is also involved in many inflammatory and immunological phenomena. We thus evaluated the expression of TNF mRNA by in situ hybridization in 6 rejected kidney transplants using a radiolabeled TNF-c DNA probe. Then the synthesis of TNF alpha protein was studied by immunohistochemistry using an anti-TNF alpha antibody. In severely rejected kidney grafts, TNF mRNA is expressed in some monomorphic infiltrating cells, mostly located in the deepest part of the cortex and around the tubes. These cells do not bind other probes, such as dopa-decarboxylase DNA or preproenkephalin RNA. They are also recognized by a monoclonal antibody directed against TNF alpha. What is more, this antibody binds with some glomerular endothelial and tubular epithelial cells that do not express TNF mRNA. These cells are likely target cells for TNF. In the normal kidney, there are no cells expressing TNF-alpha mRNA.     

Tumour necrosis factor alpha and interleukin 2 in normal and infected human seminal fluid

The presence of cytokines such as the tumour necrosis factor alpha (TNF alpha) and interleukin 2 (IL2) in human spermatozoa is still to be defined. The aim of this study was to measure the concentration of both soluble factors in seminal fluid. Data from normal semen samples (n = 24) confirmed the presence of IL2 (258 +/- 84 fmol/ml corresponding to 953 +/- 369 fmol/total volume of ejaculate) and TNF alpha (62.2 +/- 16.4 fmol/ml corresponding to 231.3 +/- 86 fmol/total volume of ejaculate). A significant positive correlation (r = 0.59; P < 0.01) was observed between the TNF alpha and the IL2 concentrations. The concentrations of these cytokines were not related to sperm parameters. In contrast, IL2 concentrations (196.9 +/- 60.4 fmol/ml; 686.2 +/- 236.7 fmol/total volume of ejaculate) evaluated in 16 seminal fluids with identified bacterial agents were lower than in the control group, whereas TNF alpha concentrations (68.6 +/- 12.3 fmol/ml; 241.3 +/- 78.9 fmol/total volume of ejaculate) were not significantly different from the controls. Further studies are needed to determine the potential role of these cytokines in the physiology of semen and their usefulness as indicators of reproductive pathology.     

Tumor necrosis factor and AIDS

OBJECTIVE: The primary objective of this study was to assess the interrelationship between protein-energy nutritional status, disease severity, and life-threatening complications in a population of elderly rehabilitation patients. METHODS: Three-hundred and fifty randomly selected admissions to Geriatric Rehabilitation Unit of a Veterans Administration hospital were prospectively studied. The average age of the study subjects was 76 years, nearly all (99%) were male, and 75% were white. At admission, each patient completed a comprehensive medical, functional, neuropsychological, socioeconomic, and nutritional assessment. While remaining in the hospital, each subject was monitored on a daily basis for the development of complications. RESULTS: Of the 96 variables evaluated, the best predictors of developing at least one life-threatening complication were serum albumin, body mass index, the presence of renal disease (i.e. blood urea nitrogen > 30 mg/L), the Katz Index of Activities of Daily Living score, and the amount of weight loss in the year prior to admission. When all of these variables were included in the logistic regression analysis, the final model was highly significant by the -2Log Likelihood Chi-square goodness-of-fit criterion (Chi-square of 64.1 with 5 d.f., p < 0.0001) with a sensitivity of 77%, a specificity of 77% and an overall predictive accuracy of 77%. When the predictive accuracy of the logistic model was tested using a second sample of 110 patients, the model differentiated those who developed a life-threatening complication from those who had not with a sensitivity of 88%, a specificity of 61%, and an overall predictive accuracy of 65%. As indicated by the Chi-square test, these results were significant (p < 0.0001). CONCLUSIONS: Protein-energy undernutrition appears to be a strong independent risk factor for life-threatening morbidity during hospitalization.     

Tumor necrosis factor and AIDS

A guinea pig model with surgically induced endolymphatic hydrops of the inner ear has been developed and studied over the past thirty years. The aim of such studies is to obtain insight into physiological processes associated with endolymphatic hydrops in man and in particular in Menière's disease where endolymphatic hydrops is systematically encountered at post-mortem examination of the temporal bones. The present review attempts to draw together the data pertaining to functional modifications of inner ear function in the animal model. For simplicity the data are categorised under five main titles: electrochemical modifications, electrophysiological modifications, pressure and hydrops, sensitivity to other insults and vestibular dysfunction. One of the most striking observations that can be made is that the data originating from different authors are very variable. There is, however, some evidence suggesting that the evolution of the auditory dysfunction could be considered as consisting of a series of different phases. This kind of information could serve as a basic framework for future research on the animal model.     

The growth response to tumour necrosis factor alpha of human gynaecological cancer cell lines

Academic computing initiatives rank high on the list of priorities of many dental schools. However, outcomes of academic computing initiatives have not been presented. The objectives of this program evaluation were to: 1) document a strategic initiative for academic computing over a five-year period; 2) assess outcomes; and 3) demonstrate how outcomes assessment changed strategic goals for the future. In 1992, Temple University School of Dentistry developed an academic computing plan. The plan proposed to develop the computer literacy of faculty, teach students the computer skills they need to be successful in their careers, and introduce computer-aided instruction as a new teaching tool. Before a new five-year plan was developed in 1997, the original plan's outcomes were summarily assessed. Assessment instruments included faculty and student surveys, budgets, inventory records, and utilization statistics. The school has reached two of three goals of the 1992 plan. Eighty percent of all full-time faculty have computers, are computer literate, and use computers for a variety of purposes. The school has implemented a comprehensive predoctoral dental informatics curriculum. However, the implementation of computer-aided instruction has not met expectations. Goals of the 1998-2003 plan include establishing an online learning infrastructure, improving student access, implementing computer-based oral health records, and further improving the computer literacy of faculty and students. Planning and supporting academic computing initiatives is a substantial challenge. Factors such as institutional culture, capital investment, ongoing support, and technological change influence plans and their success. While process and structure can be assessed relatively easily, measures for changed educational outcomes are still lacking.     

Tumor necrosis factor alpha enhances antifungal activities of polymorphonuclear and mononuclear phagocytes against Aspergillus fumigatus

Invasive aspergillosis is a serious complication in immunocompromised patients. The effects of recombinant human tumor necrosis factor alpha (TNF-alpha) on antifungal activities of human neutrophils (polymorphonuclear leukocytes [PMNs]), human monocytes (MNCs), and rabbit pulmonary alveolar macrophages (PAMs) against Aspergillus fumigatus were studied. The percentage of PMN-induced hyphal damage was increased after 30 min of incubation of PMNs with 0.1 ng of TNF-alpha per ml at 37 degreesC (P = 0.043). At 0.1 to 10 ng/ml, TNF-alpha also increased superoxide anion (O2-) produced by PMNs in response to phorbol myristate acetate, N-formylmethionyl leucyl phenylalanine, and unopsonized hyphae (P < 0.01) but did not exert any effect on PMN phagocytosis of conidia in the presence of serum. By comparison, TNF-alpha induced only a slight increase in O2- production by MNCs in response to phorbol myristate acetate (P = 0.05) and no concomitant increase in the percentage of MNC-induced hyphal damage. Incubation of MNCs with TNF-alpha at 0.001 to 10 ng/ml for 2 days had no effect on phagocytosis or conidiocidal activity. By contrast, incubation of PAMs with TNF-alpha at 0.1 to 10 ng/ml for 2 days increased phagocytosis of conidia (P = 0.03). Thus, TNF-alpha augments the capacity of PMNs to damage Aspergillus hyphae, possibly through enhanced oxidative mechanisms, and increases PAM phagocytic activity against conidia. As such, TNF-alpha may have an important role in host defense against aspergillosis, and neutralization of its activity may be complicated by increased susceptibility to aspergillosis.     

Distinct P-cadherin expression in cultured normal human keratinocytes and squamous cell carcinoma cell lines

A thermal threshold measurer (TTM) apparatus was developed and tested in 12 dry, nonpregnant, culled cows with the purpose of measuring the thermal nociceptive threshold and of finding the response to morphine sulphate dosages. The cows received a cumulative dose (from 0.00 to 0.40 mg/kg BW) of morphine sulphate through a catheter in the jugular vein. The interval between doses was 20 min, and a nociceptive test was performed 15 min after each injection. The TTM device consisted of a 60 W halogen bulb mounted in a 15 cm PVC tube, with a 0.6 s response time probe attached to its end, connected to a thermocouple. The probe measured the response temperature on the skin over the middle phalanges on the dorsum of the forefoot. The radiating heat stimulus from the bulb was instantaneously terminated with the foot-lift response of the tested animal. The nociceptive response to the 0.00 mg/kg dose was considered the baseline and subsequent measurements were expressed in difference from it. Data were evaluated in a regression analysis using the GLM procedure. A significant elevation (P < 0.0001) in the nociceptive threshold of the cows with cumulative dosing of morphine sulphate was noticed. A high variability (P < 0.0001) in the response among animals was also detected, suggesting that a 2-step dose of morphine sulphate is necessary to achieve a certain degree of induced analgesia in all cows. The nociceptive assay described, using the TTM device, was able to detect an elevation of the thermal threshold of cows due to morphine sulphate induced analgesia. An increase in locomotory behaviour or other side effects due to morphine sulphate were not noticed.     

Tumor necrosis factor alpha is involved in the induction of plasminogen activator inhibitor-1 by endotoxin

We report a boy 20 months of age with encephalopathy, petechiae, and ethylmalonic aciduria (EPEMA). Other clinical features were severe hypotonia, orthostatic acrocyanosis, and chronic diarrhea. Magnetic resonance imaging (MRI) of the brain demonstrated bilateral lesions in the lenticular and caudate nuclei, periaqueductal region, subcortical areas, white matter, and brainstem. Short and medium chain Acyl-CoA dehydrogenase and cytochrome c oxidase (COX) activities in fibroblasts were normal. Muscle histochemistry disclosed diffuse COX deficiency, and respiratory chain activities in muscle disclosed severe COX deficiency. Twelve other patients with similar clinical features have been reported. Muscle COX activity, studied only in four, demonstrated a clear-cut defect.     

Retinoids downregulate vascular endothelial growth factor/vascular permeability factor production by normal human keratinocytes

PURPOSE: We describe the clinical presentation, angiographic findings, and clinical outcome in a group of patients with pseudoaneurysms treated by a new endovascular technique using Guglielmi electrolytically detachable platinum coils (GDCs). METHODS: We retrospectively reviewed the angiographic and clinical findings in a series of 11 patients with pseudoaneurysms occurring in a variety of locations: seven in the cavernous carotid artery, one in the petrous carotid artery, two in the anterior cerebral artery, and one in the cervical vertebral artery. RESULTS: All aneurysms were cured with GDC embolization. The only complication was a branch occlusion, which resolved with heparinization and produced no clinical sequelae. CONCLUSION: Pseudoaneurysms can be safely and effectively treated by embolization with GDCs. Consideration needs to be given to the anatomic location of the pseudoaneurysm and the acuity of onset. Treatment efficacy may by improved if there are bony confines around the aneurysm or if therapy takes place in the subacute period, when the wall of the pseudoaneurysm has matured and stabilized.     

Tumor necrosis factor alpha enhances secretion of transforming growth factor beta2 in MCF-7 breast cancer cells

We studied the effect of tumor necrosis factor alpha (TNF-alpha) on transforming growth factor beta (TGF-beta) secretion by human breast cell lines to further characterize the antitumor effects of TNF-alpha. We found that TNF-alpha increased the secretion of TGF-beta in two established breast cancer cell lines (MCF-7 and ZR-75-1) but not in two immortalized human mammary epithelial cell lines (184B5 and MCF-10A). In MCF-7 cells, TNF-alpha increased the secretion of total TGF-beta 6.1-fold within 72 h in a dose-dependent manner. The secretion of both latent and active forms of TGF-beta was increased, and their ratio altered from 25:1 to 12:1 in the medium. TNF-alpha converted the secretory pattern of TGF-beta by MCF-7 cells from the heterodimeric form TGF-beta1.2 to the homodimeric form TGF-beta2. Immunoblot analysis under nonreducing conditions identified four molecular mass species of TGF-beta secreted in the culture media of untreated MCF-7 cells (238, 210, 40-55, and 25 kDa). Under reducing conditions, three molecular mass species of TGF-beta were identified: 88, 44, and 12 kDa. Gel filtration analysis demonstrated that the secreted TGF-beta within the range of 12-88 kDa was biologically active. TNF-alpha treatment did not alter the size of molecular mass species secreted by MCF-7 cells and did not change steady-state levels of mRNA for TGF-beta1 or TGF-beta2. These findings indicate that TNF-alpha may regulate quantitatively and qualitatively TGF-beta secretion by human breast cancer cells in vitro. The diverse biological activities of TGF-beta may also allow TNF-alpha to regulate the growth and metabolism of human mammary epithelial cells and/or stromal cells in a paracrine manner.     

The promoting effect of tumour necrosis factor alpha in radiation-induced cell transformation

The aim of this study was to evaluate the efficacy and safety of gemcitabine, a pyrimidine antimetabolite, in the treatment of advanced transitional cell carcinoma of the urinary tract. 35 patients with unresectable or metastatic transitional cell carcinoma of the urinary tract previously treated with a platinum-based regimen were studied. Gemcitabine was administered at a dosage of 1200 mg/m2 as a 30-min intravenous infusion on days 1, 8 and 15, repeated every 28 days. 31 patients were evaluable for efficacy. 4 patients achieved a complete response (12.9%), 3 a partial response (9.6%) and 13 (42%) were stable for at least 4 weeks (overall response 22.5%; 95% confidence interval 8-37%). The median response duration was 11.8 months (range 3.6-17.7 + months) and median survival for all patients entered was 5 months (range 2-21 + months). 2 patients with complete response are still alive with no evidence of disease after 14 and 21 months. Gemcitabine also provided subjective symptomatic relief from pain, cystitis, dysuria, haematuria and peripheral oedema. Patients experienced little WHO grade 3-4 toxicity, with anaemia in 8 patients (23%), thrombocytopenia in 5 (14.2%), leucopenia in 4 (11.4%) and neutropenia in 7 (20%). WHO grade 3-4 hepatic toxicity occurred in 4 patients (11.4%) and transient elevations of transaminase was noted in 3 (8.6%). No patient had WHO grade 3-4 elevation of serum creatinine level. There was no WHO grade 4 symptomatic toxicity and no alopecia was noted. Transient influenza symptoms with gemcitabine occurred in 18 patients (51.4%) with 13 patients (37.1%) experiencing fever (2.9% WHO grade 3). In conclusion, gemcitabine is an new active agent for the treatment of transitional cell carcinoma of the urinary bladder with a mild toxicity profile; it warrants further investigation in combination with cisplatin in chemotherapy naive patients.