Clinical effect of intra-arterial tumor necrosis factor-alpha for malignant glioma.

Recombinant human tumor necrosis factor-alpha was administered intra-arterially to treat 20 cases of malignant gliomas, mostly progressive or recurrent. The optimum dosage was determined to be 1 x 10(5) U/sq m/day. Among the 10 evaluable patients treated at this dosage, two responded (one completely and one partially), resulting in a 20% response rate. Side effects were mild and easily controllable. Improvement of neurological symptoms was noted in 47% of the patients a few days after treatment, even when computerized tomography showed no tumor regression. This might have been due to the pleiotypic biological activity of tumor necrosis factor-alpha. Neuroradiographic observations revealed narrowing of the tumor-feeding artery, a decrease in tumor staining ability, and necrosis in the central part of a tumor. The authors suggest that intra-arterial administration of tumor necrosis factor-alpha may be an effective treatment for malignant glioma, including recurrent cases.     

The effect of tumor necrosis factor-alpha and interferon-gamma on neutrophil function

Tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-gamma) have been shown to regulate cell-mediated immunity and act as effective modifiers of immune function; however, their influence on neutrophil (PMN) function is not well defined. This study investigated the effect of these cytokines on PMN phagocytosis, respiratory burst, and complement receptor (C3b) expression. Human citrated whole blood was incubated with either phosphate-buffered saline (control), 20 micrograms Escherichia coli lipopolysaccharide (LPS), TNF (1, 10, or 100 units), or IFN-gamma (1, 10, or 100 units). Synergy was also assessed between TNF and IFN-gamma. Phagocytosis and respiratory burst were assayed by sequential incubation of blood with dichlorofluorescein diacetate followed by labeled Staphylococcus aureus. C3b receptor expression was assayed by labeled anti-CR3 monoclonal antibody. Measurements were expressed as the mean channel fluorescence of 2000 PMNs counted by flow cytometry. IFN-gamma alone at all doses had no effect on any of the parameters measured. TNF 1 unit/ml increased phagocytosis (666 +/- 47 vs 542 +/- 19), respiratory burst (326 +/- 33 vs 258 +/- 17), and C3b (374 +/- 42 vs 157 +/- 14; all P less than 0.05) over those of control. TNF also demonstrated dose-dependent PMN activation. The combination of TNF + IFN-gamma increased both respiratory burst and C3b compared to either agent alone. These data indicate that TNF enhances PMN function and cytokine interaction may be important in PMN activation.     

Regulation of tumor necrosis factor-alpha and tumor necrosis factor converting enzyme in human osteoarthritis.

A snake venom-like protease isolated by a differential display screen between normal and osteoarthritis (OA)-affected cartilage (designated as cSVP) has a cDNA sequence identical to tumor necrosis factor (TNF)alpha convertase enzyme (TACE) and belongs to the adamalysin group of proteases. It has unique structural properties and when expressed in baculovirus, cleaves preferentially proTNFalpha to TNFalpha. The OA-affected cartilage has upregulated mRNA for TNFalpha and TACE as compared to normal cartilage. TNFalpha and TACE regulate inflammatory mediators in OA-affected cartilage which can be inhibited by both soluble TNFalpha receptors and inhibitors of TACE. These experiments demonstrate a functional paracrine/autocrine role of TNFalpha in OA-affected cartilage that is modulated by upregulated levels of chondrocyte-derived TACE.     

Effects of tumor necrosis factor-alpha on insulin action in cultured human muscle cells

Reported discrepancies in the effects of tumor necrosis factor (TNF)-alpha in modulating insulin sensitivity of cultured cells may relate both to cell types studied and to the time course of exposure to the cytokine. Additionally, the relationship of effects on glucose metabolism to changes in the insulin signaling pathway cannot be assumed. For in vitro study, the cell type most relevant to insulin resistance in humans is the cultured human muscle cell. In the present study, TNF brought about no change in the rate of glycogen synthesis in cultured human muscle cells unless present during differentiation. The presence of TNF (5 ng/ml) during the process of differentiation of myoblasts into mature myotubes diminished the response of glycogen synthesis to acute insulin stimulation. This finding was associated with an impairment of differentiation-dependent increases in total cellular glycogen synthase (GS) activity. Under the same conditions of TNF exposure, there was no effect on the response to acute insulin stimulation of the fractional activity of GS. Similarly, there was no effect on the insulin stimulation of protein kinase B (PKB) and inhibition of glycogen synthase kinase 3 (GSK-3). Acute insulin stimulation brought about a 4.08 +/- 0.44-fold stimulation of activity of PKB in the absence of TNF, with 4.81 +/- 0.70-fold stimulation in cells exposed to TNF. GSK-3 activity decreased to 74.0 +/- 5.8% of basal after insulin stimulation without TNF and 78.3 +/- 5.0% after TNF exposure. However, differentiation of myocytes, as defined by an increase in the acetylcholine receptor, myogenin, and mature creatine kinase isoform expression, was impaired in TNF-treated cells. These studies demonstrate that TNF, if present during differentiation, decreases insulin-stimulated rates of storage of glucose as glycogen and total GS activity but does not downregulate the insulin-signaling system to GS. More generally, TNF also inhibits differentiation of human muscle cells in culture.     

TNF-α对成骨细胞凋亡作用的探讨

目的 探讨TNF-α诱导成骨细胞凋亡的作用,为绝经后妇女骨质疏松的发生机理和治疗方法的研究提供切实可行的依据。方法 在体外培养成骨细胞的过程中,分别加人不同浓度的TNF-α,用流式细胞仪检测其对成骨细胞的凋亡率。结果 TNF-α15ng/mL组、30ng/mL组对成骨细胞的生长均有显著的抑制作用,其中又以30ng/mL组最明显。结论 TNF-α在一定浓度中对成骨细胞的生长有显著的抑制作用, 尤以30ng/mL组最明显。     

Rapamycin inhibits release of tumor necrosis factor-alpha from human vascular smooth muscle cells

Neointimal proliferation with plaque formation is the principal cause of coronary artery disease. In the neointima, inflammatory cytokines like tumor necrosis factor-alpha (TNF-alpha) are expressed by vascular smooth muscle cells (VSMCs). These cytokines stimulate proliferation and migration of VSMCs, events that are crucial to neointima formation. Stents, liberating rapamycin, have been shown to reduce neointima formation in human coronary arteries. The purpose of this study was to determine if rapamycin could inhibit the production of TNF-alpha by VSMCs. With institutional review board approval, VSMCs were cultured from saphenous vein segments obtained from five patients. Cells were identified as VSMC by immunostaining for smooth muscle alpha-actin. Cells were exposed to bacterial lipopolysaccharide (LPS), LPS plus rapamycin, or LPS plus isoproterenol for 24 hours. Cells with no treatment served as controls. The culture medium was then removed and analyzed for TNF-alpha. Additionally, the effect of treatment on viability was determined by assay of mitochondrial activity. TNF-alpha released into the culture medium is expressed as pg TNF-alpha/mg cell protein. Statistical analysis was by ANOVA. In control cells, TNF-alpha was undetectable in the culture medium. The addition of LPS (10 microg/mL) increased TNF-alpha release to 4312 +/- 705 pg/mg at 24 hours. The addition of 1 ng/mL rapamycin with LPS reduced TNF-alpha production 50 per cent (P < 0.01 vs LPS alone). A similar reduction of TNF-alpha release was seen with 1 microM isoproterenol. LPS, rapamycin, or isoproterenol did not affect cell viability. These data show that rapamycin effectively inhibits the release of TNF-alpha from VSMCs stimulated with inflammatory mediators like LPS. Rapamycin is as effective as agents that raise intracellular cyclic AMP (e.g., isoproterenol). Therefore, a potential mechanism for the effectiveness of rapamycin-releasing stents is reduction of inflammatory cytokine expression by VSMCs.     

The lack of effect of tumor necrosis factor-alpha, interleukin-1-alpha, and interferon-gamma on human sperm motility in vitro.

Whether cytokines present in human peritoneal fluid reduce sperm motility, and thus contribute to infertility, is investigated. The human recombinant cytokines, tumor necrosis factor-alpha, interleukin-1-alpha, and interferon-gamma, were incubated with motile human sperm obtained from fertile men and separated by the swim-up technique. These cytokines, alone or in combination, in higher doses than those observed in vivo (greater than or equal to 25,000 U/ml), did not alter the percentage of motile sperm after 90 minutes, 24 hours, and 48 hours under standard culture conditions. Similarly, penetration of a column of bovine cervical mucus was unchanged after preincubation of the sperm with individual cytokines or combinations of several cytokines for 24 hours. In contrast to those given in previous reports, these dta do not support a direct effect of tumor necrosis factor-alpha, interleukin-1-alpha, or interferon-gamma on sperm motility, and suggest that other soluble factors are responsible for the observed effects of peritoneal fluid on sperm motility in vitro.     

Production of tumor necrosis factor-alpha in patients on hemodiafiltration.

The systemic production of tumor necrosis factor (TNF)-alpha was evaluated in uremic patients before and after hemodiafiltration (HDF) and paired filtration dialysis (PFD) and in the interdialytic period. Both HDF and PFD were performed using polysulfone dialyzers with either standard or ultrapure dialysis fluid. TNF-alpha was quantitated by using a specific biological assay based on its cytotoxic effect on a TNF-sensitive human melanoma cell line SK-MEL-109. Postdialytic mean plasma TNF-alpha levels decreased, albeit not significantly, in regard to predialytic values. These results differ from those obtained in patients on HDF using other high-permeability membranes such as polymethylmethacrylate and polyacrylonitrile (AN 69) as recently described by us. Of interest, the adoption of ultrapure dialysis fluid resulted in a marked reduction in the interdialytic production of TNF-alpha. These results suggest that the enhanced production of TNF-alpha in patients dialyzed with high-permeability membranes is mainly dependent upon the bacteriological purity of dialysis fluid.     

肿瘤坏死因子对周围神经损伤后感觉神经元的保护作用

目的 探讨肿瘤坏死因子－α（ｔｕｍｏｒ ｎｅｃｒｏｓｉｓ ｆａｃｔｏｒ ａｌｐｈａ，ＴＮＦ－α）对周围神经损伤后感觉神经元的保护作用。方法 取Ｗｉｓｔａｒ大鼠２０只，分成ＴＮＦ－α他ＳＡＬ两组。右侧坐骨神经切断后，将神近断端套入硅胶管内。ＴＮＦ－α组自硅胶管内注入１６αｌＴＮＦ－α（３０Ｕ／ｍｌ）。ＳＡＬ组在硅胶管内注射等量生理盐水。术后２周观察脊神经节内感觉神经元乙酰胆碱脂酶（ＡＣｈＥ０、一氧化     

Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes

BACKGROUND: A systemic inflammatory response (SIR) is seen in approximately 75% of patients with complex blunt liver injuries treated nonoperatively. Many feel this response is caused by blood, bile, and necrotic tissue accumulation in the peritoneal cavity. Our current treatment for these patients is a delayed laparoscopic washout of the peritoneal cavity, resulting in a dramatic resolution of the SIR. Spectrophotometric analysis of the intraperitoneal fluid has confirmed the presence of high concentrations of free hemoglobin (Hb). We hypothesize that free Hb enhances the local peritoneal response by increasing tumor necrosis factor-alpha (TNF-alpha) production by monocytes, contributing to the local inflammatory response and SIR. METHODS: Monocytes from five healthy volunteers were isolated and cultured in RPMI-1640 for 24 hours. Treatment groups included saline controls, lipopolysaccharide ([LPS], 10 ng/mL, from Escherichia coli), human Hb (25 microg/mL), and Hb + LPS. Supernatants were analyzed by enzyme-linked immunosorbent assay. Student's t test with Mann-Whitney posttest was used for statistical analysis with p < or = 0.05 considered significant. RESULTS: Free Hb significantly increased TNF-alpha production 915 +/- 223 pg/mL versus saline (p = 0.02). LPS and Hb + LPS further increased TNF-alpha production (2294 pg/mL and 2501 pg/mL, respectively, p < 0.001) compared with saline controls. CONCLUSION: These data confirm that free Hb is a proinflammatory mediator resulting in the production of significant amounts of TNF-alpha. These in vitro findings support our clinical data in which timely removal of intraperitoneal free hemoglobin helps prevent its deleterious local and systemic inflammatory effects in patients with complex liver injuries managed nonoperatively.     

Induction of apoptosis in chondrocytes by tumor necrosis factor-alpha.

Tumor necrosis factor alpha (TNF-alpha) induces apoptosis in a number of cell types and plays an essential role in bone remodeling, both stimulating the proliferation of osteoblasts and activating osteoclasts. During endochondral ossification, apoptosis of chondrocytes occurs concurrently with new bone formation and the resorption and replacement of mineralized cartilage with woven bone. In the present study, the role of TNF-alpha in promoting chondrocyte apoptosis was examined. Chondrocyte cell populations, enriched in either hypertrophic or non-hypertrophic cells, were isolated from the cephalic and caudal portions of 17-day chick embryo sterna, respectively, and treated in vitro with 0.1-10 nM recombinant human TNF-alpha. As a positive control, apoptosis was also induced by Fas receptor antibody binding. Dye exclusion assays of the live/dead ratios of cells showed that TNF-alpha caused a dose-dependent 1.5- and 2.0-fold increase in the number of dead cells in both hypertrophic and non-hypertrophic chondrocytes. Induction of apoptosis was independently assayed by measurement of interleukin-1beta-converting enzyme (ICE) activity, and analyzed by a semi-quantitative determination of DNA fragmentation. When compared to untreated cells, these analyses also showed dose-dependent increases in TNF-alpha induced apoptosis in both chondrocyte populations, with increases in the levels of ICE activity for all doses of TNF-alpha (from approximately 5 to approximately 20 fold). Osteoblasts, however, were not affected by treatment with TNF-alpha or by Fas antibody/protein G induction. Immunostaining of chondrocytes for Fas receptor and caspase-2 protein expression showed that most of the chondrocytes expressed these two markers of apoptosis after treatment with TNF-alpha. Although cell killing and ICE induction were higher in the more hypertrophic cells, TNF-alpha induced apoptosis in both hypertrophic and non-hypertrophic chondrocyte populations. These results demonstrate that apoptosis may be induced in both hypertrophic and non-hypertrophic chondrocytes through both Fas and TNF-alpha receptor mediated signaling, and suggest that chondrocytes are more sensitive to apoptotic effects of TNF-alpha within the skeletal lineage than are osteoblasts.     

Immunomodulatory effect of pentoxifylline during human allograft rejection: involvement of tumor necrosis factor-alpha and adhesion molecules

BACKGROUND: Pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor, is poorly active as an immunosuppressant but prevents the synthesis of proinflammatory cytokines. In a randomized double-blind study comparing PTX versus placebo in 140 patients receiving cadaveric kidney grafts under cyclosporine and prednisone, we have shown that PTX weakened the consequences of rejection on graft survival. To assess the mechanism underlying the beneficial effect recorded during this trial, we analyzed the impact of PTX on tumor necrosis factor (TNF-alpha) production and expression of cell adhesion molecules. METHODS: Plasma levels of TNF-alpha and its soluble receptors (sTNF-RI, sTNF-RII) and of soluble vascular cell adhesion molecule 1 (sVCAM-1) were monitored over the 6 months postgraft period when PTX or placebo were administered. Expression of VCAM-1 and intercellular cell adhesion molecule 1 was scored by immunohistochemical staining of biopsy specimens from patients who underwent rejection crisis. Lymphocyte subset composition was analyzed longitudinally during cytomegalovirus (CMV) infections. RESULTS: Plasma TNF-alpha levels were significantly reduced in the PTX-treated group over the 6 months of administration, and specifically during isolated rejection episodes and during CMV infections. Plasma levels of sTNFR-I, sTNFR-II, and sVCAM-1 did not differ between the two groups of patients, but a decrease in renal tubular VCAM-1 expression was observed in the PTX group. During CMV infections, CD8 lymphocytosis and expansion of CD57+ (CD28-) CD8+ T cells were similar in the two groups. CONCLUSION: The data collected during this double-blind study point to an immunomodulatory role of PTX, the beneficial effect on graft survival resulting from a restraining effect of the drug on the inflammatory conditions involved in acute graft rejection.     

肿瘤坏死因子-α在心肌缺血预处理中的变化及其意义

目的 探讨缺血预处理(IP)对心肌细胞的保护机制.方法 在我院行瓣膜置换手术的患者36例,根据是否采取缺血预处理分为预处理组(20例)和对照组(16例),比较两组炎症因子肿瘤坏死因子(TNF)-α和心肌细胞bcl-2、Caspase-3的变化,观察IP对机体炎症反应的影响.结果 两组患者细胞因子TNF-α均在主动脉开放6 h时达到高峰,术后5 d恢复到术前水平.预处理组开放后6 h、术后1 d、术后2 d TNF-α水平明显低于对照组(P＜0.05).复灌后对照组心肌细胞bcl-2蛋白表达轻度提高,与阻断前比较差异无统计学意义;而复灌后IP组心肌细胞bcl-2蛋白表达明显提高,与阻断前和对照组比较,差异有统计学意义(P＜0.05).对照组复灌后心肌细胞Caspase-3、TNF-α蛋白表达显著提高,IP组心肌细胞中Caspase-3、TNF-α蛋白表达也增高,但比对照组降低,两组间差异有统计学意义(P＜0.05).术后2 d血清TNF-α与bcl-2呈负相关;术后2 d血清及开放后心肌TNF-α与Caspase-3有相关性.结论 缺血预处理可能通过降低机体的炎症反应途径达到心肌细胞保护的效果.     

The effect of tumor necrosis factor on human sperm motility in vitro

Tumor necrosis factor (TNF alpha) is present in elevated levels in peritoneal fluid from infertile women with endometriosis. The effect of TNF alpha on human sperm motility in vitro was evaluated utilizing peritoneal fluid from infertile women with minimal endometriosis containing 0, 100, 400, or 800 U of TNF alpha/ml as well as similar concentrations of recombinant human TNF alpha. No reduction in progressive and total motility was found at recombinant TNF alpha concentrations of 100 U ml. However, 500 and 1000 U of recombinant TNF alpha/ml caused a significant reduction in progressive and total sperm motility after 4 and 21 hours of incubation when compared with controls. Similarly, peritoneal fluid containing 100 U of TNF alpha/ml did not significantly reduce progressive and total sperm motility after either 4 or 21 hours of incubation; but peritoneal fluid containing 400 U of TNF alpha/ml reduced progressive sperm motility after 4 and 21 hours and total sperm motility after 21 hours of incubation. Peritoneal fluid with a TNF alpha concentration of 800 U/ml caused a significant reduction in both progressive and total sperm motility after 4 and 21 hours when compared with controls of TNF alpha-negative peritoneal fluid. The addition of polyclonal rabbit anti-TNF alpha antibody or 30-min heat inactivation at 56 C of TNF alpha-positive peritoneal fluid reversed the inhibitory effect on sperm motility. The ability of TNF alpha to cause a significant reduction of sperm motility in vitro suggests that this may be a mechanism for the infertility observed in women with minimal endometriosis.     

Heparin and enoxaparin enhance endotoxin-induced tumor necrosis factor-alpha production in human monocytes

OBJECTIVE: To determine whether heparin or the low-molecular-weight heparin enoxaparin alter lipopolysaccharide (LPS)-induced monocyte activation. SUMMARY BACKGROUND DATA: Heparin is widely used in clinical practice to inhibit the coagulation cascade. However, heparin also is a naturally occurring glucosaminoglycan and a pleiotropic immunomodulator that binds to a variety of proteins. LPS is a component of gram-negative bacteria and is thought to be responsible for many of the deleterious effects seen in sepsis. The binding of LPS to CD14 induces a signaling cascade that results in the release of many inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha). METHODS: Monocytes from healthy volunteers were isolated and cultured in the presence of saline, LPS (10 ng/ml), heparin (0.1 to 1000 microg/ml), or enoxaparin (0.1 to 1000 microg/ml). In blocking experiments, cells were pretreated for 60 minutes with the monoclonal anti-CD14 antibody MY4 (10 microg/ml) or with isotype-matched control IgG2 (10 microg/ml). TNF-alpha values were measured with enzyme-linked immunosorbent assay. Significance was assessed with analysis of variance. RESULTS: Heparin (10 to 1000 microg/ml) and enoxaparin (1000 microg/ml) significantly enhanced LPS-induced TNF-alpha release. Heparin (1000 microg/ml) or enoxaparin (1000 microg/ml) did not produce TNF-alpha in the absence of LPS. Blockade of CD14 abrogated both LPS-induced TNF-alpha release and the effect of heparin or enoxaparin to enhance LPS-induced TNF-alpha release. CONCLUSIONS: The effect of heparin to enhance LPS-induced TNF-alpha release is a biologic phenomenon that reveals a novel and potentially important host defense mechanism during endotoxemia and sepsis. Binding of LPS to CD14 is necessary to induce this phenomenon, suggesting that both heparin and enoxaparin induce signaling mechanisms that are downstream from the initial binding of LPS on CD14.     

Isoproterenol inhibits bacterial lipopolysaccharide-stimulated release of tumor necrosis factor-alpha from human heart tissue

Recent evidence suggests that inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-alpha), may play a role in heart disease. Elevated plasma levels of the cytokine have been reported in congestive heart failure and severe angina and after myocardial infarction. The exact role of TNF-alpha in heart disease and how production is stimulated and regulated in the heart are current areas of investigation. Regarding regulation of production, isoproterenol elevates cyclic AMP and inhibits TNF-alpha release in macrophages. Therefore we hypothesized that stimulation of beta-adrenergic receptors of the sympathetic nervous system would inhibit release of the cytokine from heart tissue. With Institutional Review Board approval and patient consent atrial tissue was obtained during preparation for cardiac bypass. The tissue was divided into segments, placed in culture medium, and incubated for various times in the presence or absence of lipopolysaccharide (LPS) (20 microg/mL) and/or isoproterenol (1 microM). The medium was removed and analyzed for biologically active TNF-alpha by the L929 cell cytotoxicity assay. Tissue samples were weighed and TNF-alpha release was expressed as pg TNF-alpha/mg tissue. Initially, to determine the time course of release, measurements were made at 2, 5, 10, 15, 30, 60, 120, 180, and 360 minutes after the addition of LPS. Elevated TNF-alpha levels in the culture medium were reliably detected at 360 minutes after exposure to LPS. In atrial tissue obtained from seven patients TNF-alpha released into the culture medium at 360 minutes was 6 +/- 3 pg/mg tissue. In the presence of LPS, levels of the cytokine in the culture medium increased to 604 +/- 233 pg/mg tissue (P < 0.05 vs LPS alone). When isoproterenol and LPS were simultaneously added to the culture medium release of TNF-alpha was reduced by 87 per cent to 82 +/- 40 pg/mg tissue (P < 0.05 vs LPS alone). Our results show that activation of the beta-adrenergic receptor inhibits myocardial production of TNF-alpha. This finding suggests that the sympathetic nervous system inhibits production of the cytokine and that impaired sympathetic function in heart failure may play a role in the elevated levels of TNF-alpha.     

Interleukin-1 beta and tumor necrosis factor-alpha release in normal and diseased human infrarenal aortas.

The presence of chronic inflammatory cells in the adventitia and media of abdominal aortic aneurysms and aortic occlusive disease suggest an immunologic response. The purpose of this study is to determine whether normal or diseased infrarenal aortas liberate the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). Twenty-six infrarenal aortic biopsies (5 aortic occlusive disease, 15 abdominal aortic aneurysms, and 6 cadaveric donors) were weighed, minced into small pieces, and incubated in media for 48 hours. Conditioned media was harvested at 48 hours and assayed for IL-1 beta or TNF-alpha with use of an ELISA assay. Comparison of groups was performed with a one-way analysis of variance. The constitutive IL-1 beta produced by abdominal aortic aneurysms was significantly different than that in cadaveric donors (908 +/- 194 pg/ml [SE] vs 100 +2- 30 pg/ml). There was no statistically significant difference between abdominal aortic aneurysms and aortic occlusive disease (908 +/- 194 pg/ml vs 604 +/- 256 pg/ml) or aortic occlusive disease and cadaveric donor (604 +/- 256 vs 100 +/- 30). In time-course studies for the release of IL-1 beta, abdominal aortic aneurysms demonstrated maximal release at 48 hours. IL-1 beta release was augmented by lipopolysaccharide in all categories. A dose response curve demonstrated maximal IL-1 beta release on stimulation with 5 micrograms/ml LPS. Constitutive TNF-alpha production was low, ranging from 13 +/- 1.5 pg/ml in cadaveric donor, to 20 pg/ml in aortic occlusive disease, and 24 +/- 11 pg/ml in abdominal aortic aneurysms. There was no augmentation in TNF-alpha with lipopolysaccharide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-alpha produced by renal parenchymal cells

Cisplatin is a chemotherapeutic agent that induces tumor necrosis factor-alpha (TNF-alpha) production in many cell types with unfortunate renal toxicity. We sought to determine the contributions of renal parenchymal cells and bone marrow-derived immune cells to the pathogenesis of cisplatin-induced renal injury in vivo. To do this we created chimeric mice in which the bone marrow was ablated and replaced with donor bone marrow cells from wild-type or from TNF-alpha knockout mice. Six weeks after reconstitution, the chimeric mice were treated with cisplatin and renal structural and functional parameters were measured. Chimeras with kidneys of wild-type animals all developed significant renal failure after 72 h of cisplatin treatment regardless of the immune cell source. Chimeras with kidneys of TNF-alpha knockout mice showed significantly less renal dysfunction (blood urea nitrogen, serum creatinine, and glomerular filtration rate), renal histologic injury, and serum TNF-alpha levels; again regardless of the immune cell source. Urinary excretion of several proinflammatory cytokines was lower in the wild-type bone marrow-knockout kidney chimera mouse than in wild-type background mice. Our results indicate that a substantial portion of circulating and urinary TNF-alpha is derived from nonimmune cells after cisplatin administration. We conclude that the production of TNF-alpha by renal parenchymal cells, rather than by bone marrow-derived infiltrating immune cells, is responsible for cisplatin-induced nephrotoxicity.