Tumor necrosis factor in glomerular injury.
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Animals↗
Biomedical subjects
L Baud
Publications and source records attributed to L Baud.
[Tubulointerstitial lesions in progressive renal diseases: potential role of osteopontine].
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Humans↗
Insulin activates nuclear factor kappa B in mammalian cells through a Raf-1-mediated pathway.
We examined the effect of insulin on nuclear factor kappa B (NF-kappa B) activity in Chinese ovary (CHO) cells overexpressing wild-type (CHO-R cells) or -defective insulin receptors mutated at Tyr1162 and Tyr1163 autophosphorylation sites (CHO-Y2 cells). In CHO-R cells, insulin caused a specific, time-, and concentration-dependent activation of NF-kappa B. The insulin-induced DNA-binding complex was identified as the p50/p65 heterodimer. Insulin activation of NF-kappa B: 1) was related to insulin receptor number and tyrosine kinase activity since it was markedly reduced in parental CHO cells which proved to respond to insulin growth factor-1 and phorbol 12-myristate 13-acetate (PMA) activation, and was dramatically decreased in CHO-Y2 cells; 2) persisted in the presence of cycloheximide and was blocked by pyrrolidine dithiocarbamate, aspirin and sodium salicylate, three compounds interfering with I kappa B degradation and/or NF-kappa B.I kappa B complex dissociation; 3) was independent of both PMA-sensitive and atypical (zeta) protein kinases C; and 4) was dependent on Raf-1 kinase activity since insulin-stimulated NF-kappa B DNA binding activity was inhibited by 8-bromo-cAMP, a Raf-1 kinase inhibitor. Moreover, insulin activation of NF-kappa B-driven luciferase reporter gene expression was blocked in CHO-R cells expressing a Raf-1 dominant negative mutant. This is the first evidence that insulin activates NF-kappa B in mammalian cells through a post-translational mechanism requiring both insulin receptor tyrosine kinase and Raf-1 kinase activities.
8-Bromo Cyclic Adenosine Monophosphate↗
Transforming growth factor-beta stimulates arginase activity in macrophages. Implications for the regulation of macrophage cytotoxicity.
Macrophage arginine metabolism via nitric oxide (NO) synthase and arginase pathways reduces and enhances tumor cell proliferation, respectively. Transforming growth factor-beta (TGF-beta) has been shown to down-regulate the NO synthase pathway. The present study describes the effect of TGF-beta on the arginase pathway. TGF-beta up-regulated arginase activity in rat peritoneal macrophages as assessed by measuring the generation of [14C]urea from [14C]-L-arginine in the presence of NG-monomethyl-L-arginine (L-NMMA). The stimulation, which reached fivefold after a 48-h exposure of macrophages to 10 ng/ml TGF-beta, was due to reduction in Km value of arginase. TGF-beta-induced up-regulation of arginase activity led to the release of more polyamines, mainly putrescine. The role of this up-regulation on macrophage cytotoxicity toward L-929 tumor cells was analyzed in coculture experiments. Macrophages blunted DNA synthesis by L-929 cells as assessed by measuring the incorporation of [3H]TdR into the cells and the proportion of cells in the G2 phase. Addition of TGF-beta in the presence of L-NMMA permitted L-929 cells cocultured with macrophages to resume DNA synthesis. The mechanism responsible for this restoration was the up-regulation of arginase activity rather than the down-regulation of NO synthase activity since TGF-beta in the presence of L-NMMA failed to further reduce NO synthase activity whereas it still enhanced arginase activity; synthetic putrescine (1-10 microM) also blunted macrophage cytotoxicity toward L-929 cells. This is the first evidence that TGF-beta up-regulates arginase activity in macrophages and, hence, limits macrophage-dependent cytostasis.
Animals↗
Tumor necrosis factor in renal injury.
Inflammatory diseases of the renal glomerulus and tubulointerstitium are characterized by destructive and restorative processes. These alterations are mediated by soluble molecules, including cytokines that instruct target cells to alter their proliferation, differentiation phenotype, secretion and migration. One of these cytokines is tumor necrosis factor-alpha (TNF alpha). Its expression within the glomerulus has been observed in both resident cells and infiltrating monocytes/macrophages in response to cell stimulation with chemicals, immune complexes, bacterial lipopolysaccharides, and advanced glycosylation end products. Its release can be amplified by deposits of terminal complement proteins (C5b-9) or formation of platelet-activating factor and reactive oxygen species, and, on the contrary, blunted by that of prostaglandins or anti-inflammatory interleukin (IL)-6 and IL-10. The roles of TNF alpha in the pathogenesis of glomerular diseases include reduction of blood flow and filtration rate, alteration of the barrier function of capillary wall, formation of capillary thrombi and infiltration of the structure by blood-borne cells. Expression of TNF alpha has been observed in tubulointerstitium as well, mainly in proximal tubular epithelial cells. In vitro, this expression can be amplified by IL-1 and, inversely, suppressed by immunosuppressive drugs. Roles of TNF alpha in tubulointerstitium remain largely undefined, but may include infiltration of the interstitium by inflammatory cells and alteration in tubular transport of fluid and electrolytes. Extensive study will be necessary to further elucidate intracellular signals induced by TNF alpha binding to target cells within the kidney and thus to establish possibilities of therapeutic intervention.
Animals↗
Mesangial cell-derived interleukin-10 modulates mesangial cell response to lipopolysaccharide.
Interleukin (IL)-10 is a novel cytokine produced by a variety of cells, including monocytes/macrophages, upon exposure to lipopolysaccharide (LPS). Recent observations indicate that, in turn, IL-10 exerts suppressive effects on macrophage response to LPS. Because mesangial cells are also a target for LPS, we have examined the potential role of IL-10 in the regulation of mesangial cell response to LPS. To this aim, we have studied the synthesis and the autocrine/paracrine function of IL-10 in cultured mouse mesangial cells. IL-10 mRNA expression and IL-10 protein secretion were determined by a reverse transcription polymerase chain reaction technique and a specific enzyme-linked immunosorbent assay, respectively. No IL-10 mRNA expression was detectable in unactivated cells. LPS induced IL-10 mRNA expression in a dose-dependent fashion (1 to 100 micrograms/ml). In addition, LPS induced IL-10 protein release that was both dose dependent (1 to 100 micrograms/ml) and time dependent (24 to 72 hours). We have also studied the effect of IL-10 on the production of inflammatory mediators by LPS-activated mouse mesangial cells. Whereas recombinant IL-10 inhibited the generation of tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta by 90 and 60%, respectively, it did not affect the formation of nitric oxide-derived nitrite (NO2-) and nitrate (NO3-). As shown by the use of anti-IL-10 monoclonal antibody, endogenously produced IL-10 affected the generation of TNF-alpha but neither that of IL-1 beta nor that of NO2- and NO3-. Finally, we have examined whether conditions known to also reduce the generation of TNF-alpha modified the expression of IL-10. Of all the conditions tested, only the addition of desferrioxamine and transforming growth factor-beta were found to increase IL-10 release. Together, these data demonstrate that mesangial cell-derived IL-10 has important regulatory effects on the inflammatory response of these cells to LPS because of its capacity to blunt TNF-alpha generation.
Animals↗
[Production and proinflammatory activity of tumor necrosis factor alpha in the glomerulus].
The production and the effects of tumor necrosis factor alpha (TNF alpha) have been studied in isolated glomeruli and cultured glomerular cells from animal or human origin. Glomeruli from rats injected with E. coli lipopolysaccharide (LPS) and glomeruli exposed to LPS in vitro release TNF alpha into the medium. The glomerular cells responsible for TNF alpha synthesis are mesangial cells. Production of TNF alpha is controlled by other locally produced mediators. Prostaglandin E2 and interleukin-10 are inhibitory. Hydroxyl radicals stimulate the transformation of the transmembrane form of TNF alpha into its soluble form which is secreted into the medium. TNF alpha acts on its producing cells and on the neighbouring cells. It induces contraction of mesangial cells, increases the synthesis of a variety of local mediators including prostaglandins, platelet-activating factor and chemotactic agents, particularly interleukin-8. Synthesis of this cytokine implies activation of tyrosine kinase and of transcription factors, essentially NFkB. Taken together, these results suggest that TNF alpha plays a marked role in the development of glomerular injury and incite us to search for treatments inhibiting its synthesis and its effects.
Animals↗
Involvement of tumor necrosis factor-alpha in glomerular injury.
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Animals↗
Fish oil supplementation and essential fatty acid deficiency reduce nitric oxide synthesis by rat macrophages.
Both fish oil-derived omega-3 polyunsaturated fatty acid (omega 3 PUFA) supplementation and essential fatty acid (EFA) deficiency have been shown to exert anti-inflammatory effects and, hence, to ameliorate immune-mediated glomerulonephritis. The mechanisms underlying these effects include alterations in the production of eicosanoids, cytokines (that is, tumor necrosis factor, TNF-alpha) and reactive oxygen species by blood borne cells. Because, in addition to these mediators nitric oxide (NO) is also implicated in glomerular injury, we have examined if both diets affected macrophage NO production as well. Rats were fed a standard chow, an omega 3 PUFA-supplemented diet, or an EFA-deficient diet for six weeks before resident peritoneal macrophages were isolated. These cells were exposed to lipopolysaccharide (LPS) and the NO metabolite, nitrite (NO2-), was measured in the medium using the Griess reagent. Release of NO2- was enhanced by LPS in a dose-dependent manner. With 10 ng/ml LPS challenge, NO2- release was reduced by 37% and 57% by omega 3 PUFA supplementation and EFA deficiency, respectively. NO2- returned to control levels two weeks after the end of diet. Macrophage production of TNF-alpha responded in a similar manner. Diet-induced reduction of NO2- release was neither attributable to a reduction of inducible NO synthase mRNA levels as shown by Northern blot analysis, nor to an increased competition of NO synthase and arginase for the substrate (L-arginine). Indeed, arginase activity of macrophages was even slightly reduced by both omega 3 PUFA-supplemented diet and EFA-deficient diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Oxidoreductases↗
Tumor necrosis factor alpha in glomerular injury.
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Animals↗
[Therapeutic perspectives in primary glomerulonephritis from recent physiopathological data].
In this review the authors describe the physiopathological mechanisms responsible for inflammatory lesions in primary glomerulonephritis. Primary glomerular nephropathies can be reproduced experimentally: models have been set up for non-proliferative kidney diseases such as minimal change disease or membranous glomerulopathies, and for proliferative kidney diseases such as Berger's disease. Studies performed with these models have resulted in the identification of inflammatory mechanisms creating glomerular lesions which may be acute (proteinuria) or progressive (glomerular sclerosis). These mechanisms include activation of resident cells, notably mesangial cells, and recruitment of circulating cells such as neutrophils, monocytes/macrophages and platelets. These cells participate in the local inflammatory reaction by releasing soluble mediators including biologically active lipids, such as eicosanoids, reactive oxygen and nitrogen derivatives, proteases, cytokines and vasoactive polypeptides. The importance of these mediators has been deduced from the fact that they are produced locally in excess, their introduction produces lesions and, above all, their suppression by inhibitory or antagonistic pharmacological agents reduces the severity of the lesions. Several observations have shown that the development of all the lesions can be prevented simply by blocking the activity of only one of these mediators. It is therefore possible to consider replacing the conventional glucocorticoid treatment, which has multiple pharmacological actions, by a more specific treatment directed against a single mediator.
Animals↗
Involvement of reactive oxygen species in kidney damage.
There is considerable evidence suggesting that reactive oxygen species (ROS) are implicated in the pathogenesis of ischemic, toxic, and immunologically-mediated renal injury. In experimental renal ischemia, ROS sources include the electron transport chain, oxidant enzymes (xanthine oxidase), phagocytes, and auto-oxidation of epinephrine. ROS cause lipid peroxidation of cell and organelle membranes and, hence, disruption of the structural integrity and capacity for cell transport and energy production, especially in the proximal tubule segment. In experimental immune glomerulonephritis, ROS are generated by both infiltrating blood-borne cells (polymorphonuclear leukocytes and monocytes) and resident glomerular cells, mainly mesangial cells. Their formation results in morphologic lesions and in modifications of glomerular permeability to proteins through activation of proteases and reduction of proteoglycan synthesis. Additionally, they promote a reduction in glomerular blood flow and glomerular filtration rate through liberation of vasoconstrictory bioactive lipids (prostaglandins, thromboxane, and platelet activating factor) and, possibly, inactivation of relaxing nitric oxide. Further studies are needed to address the role of ROS in human glomerular diseases.
Humans↗
Increased expression and occupancy of receptors for tumour necrosis factor on blood monocytes from tuberculosis patients.
Blood monocytes from tuberculosis patients release high amounts of tumour necrosis factor-alpha (TNF-alpha). Because the biological efficiency of TNF-alpha would depend on the expression of TNF-alpha receptors on target cells, we thought to analyse the capacity of blood monocytes from a group of patients with pulmonary tuberculosis to bind 125I-TNF-alpha. We report a slight but not significant enhancement in specific binding of 125I-TNF-alpha on monocytes of 15 consecutively studied patients compared with 10 controls. Per cent cell surface bound and internalized 125I-TNF-alpha was identical in the two groups. To evaluate the receptor occupancy by endogenously generated TNF-alpha, similar experiments were performed after cell exposure to low-pH glycine buffer. Under these conditions, specific binding of 125I-TNF-alpha was significantly higher on tuberculosis monocytes compared with control monocytes. Moreover, the occupancy of TNF-alpha receptors by endogenously generated TNF-alpha that was found to be significantly higher on tuberculosis monocytes than on control monocytes, was directly related to the enhanced capacity of mononuclear cells to generate TNF-alpha in vitro. It normalized after 3 months of antituberculous therapy. Scatchard analysis of the binding data revealed that tuberculosis infection caused a significant increase in high affinity 125I-TNF-alpha binding to monocytes without any significant change in the dissociation constant. Collectively, these results indicate an up-regulation of TNF-alpha generation and binding to blood monocytes in patients with pulmonary tuberculosis. They provide support to the hypothesis that TNF-alpha is of critical importance in the pathogenesis of this infection.
Adult↗
Cytokine formation within rat glomeruli during experimental endotoxemia.
Increasing evidence supports a role of cytokines, tumor necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), and IL-6 in the development of endotoxin-induced acute renal failure. Several activities of these cytokines require a local rather than a systemic production and function. Thus, this study investigates the chronology of cytokine expression in glomeruli isolated from normal rats or rats given iv lipopolysaccharide injections. Detectable levels of TNF alpha could be found in glomeruli isolated from normal rats as assessed by L-929 fibroblast lytic assay and ELISA. Glomeruli isolated from rats given lipopolysaccharide transiently released increased amounts of TNF alpha in relation to the dose of lipopolysaccharide (10 to 500 micrograms/kg body wt) and the lag period between lipopolysaccharide injection and glomerular isolation (20 to 120 min). TNF alpha was released in similar amounts by glomeruli from normal rats that were exposed in vitro to lipopolysaccharide challenge (0.01 to 10 micrograms/mL), indicating that lipopolysaccharide had direct effects on the release of TNF alpha from glomerular cells. These cells consisted mainly of resident cells because reduction of glomerular infiltration by bone marrow-derived cells after the irradiation of normal rats did not affect TNF alpha release. Glomerular IL-1 and IL-6 production was evaluated by specific bioassays under identical conditions. No IL-1 activity could be detected in the medium or within the glomerular cells at any time within 120 min after lipopolysaccharide injection. By contrast, glomerular IL-6 production was induced after lipopolysaccharide challenge both in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Glomerular expression of tumor necrosis factor alpha (TNF-alpha) and of its receptors].
TNF alpha is generated in inflammatory lesions of the glomerulus. Both resident mesangial cells and infiltrating macrophages contribute to this generation, when exposed to bacterial lipopolysaccharide and immune complexes, respectively. TNF alpha has multiple actions on glomerular cells and on distant target cells that appear to promote in turn either amplification or limitation of TNF alpha release and TNF alpha binding. For instance, there is in vitro evidence that locally generated reactive oxygen metabolites: 1) cause increased release of TNF alpha into the extracellular space by accelerating the cleavage of its cell-associated precursor, and 2) reduce the expression of both cell-associated and soluble TNF alpha receptors. Thus it might be expected that reactive oxygen metabolites released at the site of glomerular inflammation limit autocrine, juxtacrine and paracrine effects of TNF alpha and simultaneously increase its widespread release into the circulation.
Humans↗
Protection from tumor necrosis factor-mediated cytolysis by platelets.
Infiltrating macrophages elicit tumor-destructive reactions by releasing cytolytic factors including tumor necrosis factor alpha (TNF-alpha). Because platelets represent another major component of the cell infiltrate in tumors, we examined whether they could affect TNF alpha-induced cell death. Exposure of L-929 fibrosarcoma cells to human platelets reduced TNF alpha-induced cytotoxicity and cytolysis, as determined by 51Cr release assay and DNA fragmentation assay. This inhibitory effect, which depended on the concentration of platelets (0.1 to 10 x 10(6)/0.1 ml), was as high as 50%. The decrease in responsiveness to TNF-alpha reflected neither a degradation of TNF-alpha nor an inability of L-929 cells to bind TNF-alpha. Indeed, even though Scatchard analysis indicated the presence of 100 to 150 125I-TNF-alpha binding sites/platelet with a kd of 3.8 to 6.4 nM, addition of platelets up to 5 x 10(6)/0.1 ml did not compete with 125I-TNF-alpha binding to L-929 cells. Furthermore, addition of platelets 1 or 2 hours after that of TNF-alpha was still protective suggesting that platelets rather promoted hyporesponsiveness of L-929 cells to a postbinding effect of TNF-alpha Platelet-induced reduction of TNF-alpha response could be reproduced with supernatant fluids from platelets incubated at 37 degrees C for 24 hours. The platelet-derived factor responsible for this effect was found to be a lipid of low molecular weight with high affinity for albumin and charcoal. A role for 12(S) hydroxyeicosatetraenoic acid is proposed because this metabolite reduced TNF-alpha-induced cytolysis in a dose-dependent manner, whereas other platelet-derived lipids including thromboxane A2 and platelet activating factor were inactive. These observations indicate that the role of associated platelets has to be considered when analyzing the cytotoxic and cytolytic activity of macrophage-derived TNF-alpha on tumor cells.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Membrane expression and shedding of tumour necrosis factor receptors during activation of human blood monocytes: regulation by desferrioxamine.
Previous studies have shown that desferrioxamine (DFX), an iron chelator preventing the synthesis of hydroxyl radical (OH.), up-regulates the cell-surface expression of tumour necrosis factor-alpha (TNF-alpha) receptors on unactivated human blood monocytes. In the present study, we investigated the regulatory action of DFX on 125I-TNF-alpha binding to monocytes upon exposure to bacterial lipopolysaccharide (LPS). Exposure to LPS (1 microgram/ml) resulted in almost complete loss of 125I-TNF-alpha binding to the surface of monocytes. This down-regulation was reversible and the recovery observed after 18 hr was enhanced by addition of DFX (5 mM). However, binding studies on monocytes pre-exposed to low pH suggested that the DFX-induced increase of 125I-TNF-alpha binding was not due to differences in the number of receptors available but was probably due to a reduction of receptor occupancy by endogenously generated TNF-alpha. Time-course studies of TNF-alpha release from monocytes confirmed the ability of DFX to reduce the extracellular concentration of bioactive TNF-alpha through a decrease of its synthesis and an increase of its inactivation. The latter process was associated with an increased expression of the soluble form of TNF-alpha receptor type II. These results indicate that, in the presence of LPS, DFX increases the release of soluble TNF-alpha receptors from monocytes. Thus, conversely, OH. generated in situ could reduce the shedding of soluble TNF-alpha receptors and, hence, increase the widespread release of bioactive TNF-alpha.
Cell Membrane↗
Tumor necrosis factor-induced contraction of cultured rat mesangial cells: interaction with angiotensin II.
The role of tumor necrosis factor alpha in the regulation of renal function, particularly glomerular filtration rate, has not been completely defined. This study was designed to assess the intrinsic role of this cytokine on glomerular filtration rate by analyzing its short-term effect on the degree of contraction in cultured rat mesangial cells, not only directly but also in the presence of angiotensin II. Contraction was evaluated both morphologically--by measuring planar cell surface area of cultured rat mesangial cells and glomerular cross-sectional area of isolated rat glomeruli--and biochemically--by analyzing myosin light-chain phosphorylation in cells. Tumor necrosis factor alpha significantly decreased planar cell surface area in a dose-dependent and time-dependent manner, an effect completely abolished by preincubation of the cells with platelet-activating factor receptor antagonists BN 52021 and alprazolam. This effect was also observed in the presence of angiotensin II, whether tumor necrosis factor alpha was added before or after angiotensin II, increasing the reduction in planar cell surface area induced by angiotensin II in both cases. Changes in planar cell surface area were evident not only when the absolute values of this parameter were considered but also when the percentage of contracted cells (cells with a planar cell surface area reduction > 10%) was analyzed. Tumor necrosis factor alpha also induced a significant reduction of glomerular cross-sectional area in isolated rat glomeruli. The results of the morphologic studies were supported by myosin light-chain phosphorylation experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗