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Results for “Lymphotoxin-alpha”

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PubMed1992

Establishment of cytotoxic CD4+ T cell clones from cancer patients treated by local immunotherapy.

We have previously reported that the antitumor effect of OK-432, a Streptococcal preparation, is markedly augmented when injected intratumorally together with fibrinogen (Cancer, 69: 636-642, 1992). In order to elucidate the mechanism of the antitumor effects, we established T cell clones from regional lymph nodes of colorectal cancer patients who received this local immunotherapy. By culture of lymph node lymphocytes, in the presence of IL-2 and OK-432, 4 clones of T cells were established from 4 patients treated by local immunotherapy. These clones had a helper T cell phenotype (CD3+, CD4+, CD8-, CD56-, WT31+) and were successfully maintained for several months. The cells strongly expressed CD25 when stimulated with OK-432 and exhibited a high level of cytotoxic activity in part explained by the increased expression of ICAM-1 and LFA-1, and the release of TNF beta. These results suggest that the CD4+ T cells play a role in the antitumor mechanism of local immunotherapy.

CD4-Positive T-Lymphocytes↗
PubMed1991

Endothelin production by amnion and its regulation by cytokines.

Cells derived from human amnion, an avascular tissue, produced significant amounts of endothelin 1 and 2, although the rate of biosynthesis was approximately one tenth of that of human umbilical vein endothelial cells. Endothelin 1 and 2 was not produced in measurable amounts by cells derived from chorion laeve or decidua. Production of endothelin 1 and 2 by amnion cells was increased by treatment with the cytokines interleukin-1 beta, tumor necrosis factor, and interleukin-6. The biosynthesis of endothelin 1 and 2 by an avascular tissue is suggestive of a wider role for endothelins than has been recognized.

Amnion↗
PubMed1987

Quantitative molecular hybridization with unfractionated, solubilized cells using RNA probes and polyacrylamide gel electrophoresis.

Molecular hybridization with RNA probes was performed on unfractionated cells solubilized in guanidine thiocyanate solutions. Unhybridized probe was digested with ribonuclease, and protected probe fragments were resolved by polyacrylamide gel electrophoresis (PAGE). Since the same medium was used both for solubilization of the cells and as the hybridization buffer, RNA purification was not required and the analysis of large numbers of samples was facilitated. Using this method, specificity is superior to dot blot analysis because the size of hybridized fragments is determined and the signal of the probe hybridized to target RNA is separated from the background by PAGE.

Animals↗
PubMed1989

Characterization of recombinant human lymphotoxin (tumor necrosis factor-beta) produced by a mammalian cell line.

Lymphotoxin (LT) was purified from serum-free conditioned media of a recombinant mammalian cell line transfected with human lymphotoxin cDNA. The purification scheme consisted of controlled pore glass chromatography, Q-Sepharose ion-exchange chromatography, and concanavalin A-Sepharose chromatography. The purified protein was found to be homogeneous by reverse-phase high-performance liquid chromatography and had an approximate specific activity of 130 X 10(6) units per milligram protein as determined by the L-929 cytotoxicity assay. Purified LT had an isoelectric point of approximately 6.85 and an apparent molecular weight of 50,000 by gel permeation high-pressure liquid chromatography. However, when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, two distinct bands at approximate molecular sizes of 25 and 20 kDa were observed. Both the bands were immunoreactive by Western blot analysis and found to be associated with biological activity. The two forms of lymphotoxin differed from each other with respect to protein structure. Amino-terminal amino acid sequence analysis revealed that the 25-kDa LT sequence starts with Leu-Pro-Gly-residues whereas that of the 20-kDa LT begins with His-Leu-Ala; thus the latter form is truncated by 20 amino acid residues from the amino terminal. Two species of LT also differed from each other with respect to carbohydrate structure. Enzymatic removal of sialic acid reduced the molecular weight of 25 kDa by approximately 5 kDa whereas that of the 20-kDa LT was unchanged. A reduction in an apparent molecular size by approximately 4 kDa of both species of LT was observed on removal of N-linked oligosaccharides. Treatment with O-Glycanase had minimal effect on either form of LT. The recombinant lymphotoxin described here was found superior in its solubility behavior as compared to bacterial cell derived LT. Overall, mammalian cell line derived recombinant LT appears closer in its properties to natural LT than does bacterial cell derived recombinant LT.

Amino Acid Sequence↗
PubMed1989

Increase in permeability of human endothelial cell monolayer by recombinant human lymphotoxin.

The effect of lymphotoxin (LT) on transendothelial permeability was examined using in vitro human endothelial cell (EC) culture system. To assess permeability, we measured the movement of human IgG labeled with horseradish peroxidase (HRP-huIgG) across an EC monolayer cultured on a fibronectin and collagen-coated membrane. LT increases the permeability dose dependently within 16 hours. Similar results were obtained with tumor necrosis factor (TNF)-alpha. The results suggest that increase in vascular permeability by LT and TNF-alpha plays an important role in initiating hemorrhagic necrosis of tumors in vivo.

Cell Membrane Permeability↗
PubMed1989

Recombinant human lymphotoxin effects on osteoblastic cells.

Lymphotoxin, or tumor necrosis factor beta, has been shown to be a potent bone resorbing cytokine. In the present study, the effect of recombinant human lymphotoxin on osteoblastic cell proliferation and prostaglandin synthesis was investigated. Lymphotoxin (10(-10)-10(-7) M) caused a significant, dose-dependent decrease of rat osteoblastic cell proliferation. This appeared to be an indirect, prostaglandin-dependent action, since in the presence of indomethacin (1 microM) the lymphotoxin effect was reversed. Subsequently, prostaglandin E2 and prostacyclin (assayed as 6-keto-prostaglandin F1 alpha) levels produced by the osteoblastic cells in response to lymphotoxin were measured. The cytokine caused a dose-dependent increase of these arachidonic acid metabolites, with the maximum effect at 10(-8) M. These results suggest that lymphotoxin's mechanism of action on bone may involve increases in arachidonic acid metabolite synthesis and an indirect, prostanoid-mediated decrease in the proliferation rate of osteoblastic cells.

Animals↗
PubMed1992

Inhibition of ligand binding and antiproliferative effects of tumor necrosis factor and lymphotoxin by soluble forms of recombinant P60 and P80 receptors.

Tumor necrosis factor (TNF) is one of the mediators of inflammatory responses. Recently, the cDNA for two distinct receptors of TNF with predicted molecular masses of 60 kDa and 80 kDa, respectively, were isolated. In this report, we compare the inhibitory effects of these two forms of recombinant soluble TNF receptors (extracellular domains) on the ligand binding and on the antiproliferative effects of TNF and lymphotoxin (LT) in a human histiocytic lymphoma cell line (U-937). Our results show that the soluble form of the p60 receptor is approximately 100-fold more potent than the soluble form of the p80 receptor in inhibiting both the antiproliferative effects of TNF as well as in blocking TNF binding to U-937 cells. In contrast, the antiproliferative effects of LT and its binding to cells is inhibited equally by both the p60 and p80 forms of the soluble receptor. Thus, overall our results indicate that the two soluble receptors differ in their ability to inhibit TNF and LT. The impotance of these soluble receptors in blocking the harmful effects of TNF and LT is discussed.

Cell Division↗
PubMed1989

Tumour necrosis factor-alpha and lymphotoxin have opposite effects on sympathetic efferent nerves to brown adipose tissue by direct action in the central nervous system.

Intracerebral injection of recombinant human tumour necrosis factor-alpha (rTNF alpha) decreased, whereas lymphotoxin increased the activity of the sympathetic efferent nerves to interscapular brown adipose tissue (IBAT). The changes in firing rates were accompanied by a significant dose-dependent change in IBAT and rectal temperatures (which were decreased with rTNF alpha and increased with lymphotoxin treatment). These results indicate that rTNF alpha and lymphotoxin act directly in the CNS to modulate the sympathetic outflow to IBAT. The opposite effects of the two peptides also suggest that in the CNS, separate receptor systems exist.

Action Potentials↗