Biomedical subjects

J Varani

Publications and source records attributed to J Varani.

At least 145 records · Page 8Linked to original sources

PubMed1989

Modulation of fibronectin production in normal human melanocytes and malignant melanoma cells by interferon-gamma and tumor necrosis factor-alpha.

Normal cultured human epidermal melanocytes and melanoma cells derived from three different malignant melanomas were examined for synthesis of extracellular matrix components before and after treatment for one day with interferon-gamma, tumor necrosis factor-alpha, or both. Treatment of the cells with either cytokine individually had minimal effects on fibronectin levels. Treatment of the cells with the two agents in combination greatly stimulated fibronectin production as indicated by biosynthetic labeling and immunoprecipitation and by enzyme-linked immunosorbent assay. Synthesis of laminin was decreased slightly by the same treatment whereas thrombospondin production was stimulated slightly. The same treatment reduced melanocyte viability slightly but significantly inhibited proliferation and altered the morphology of the melanocytes. The treated cells became flattened and polygonal in shape while the untreated cells exhibited a bipolar shape with one or more long dendritic processes. These morphologic changes were not seen in cultures treated with interferon-gamma or tumor necrosis factor-alpha individually. The effects of interferon-gamma and tumor necrosis factor-alpha on fibronectin production by epidermal melanocytes are in contrast to the effects of the same treatments on fibronectin production by epidermal keratinocytes where fibronectin production is decreased but are similar to the effects of transforming growth factor-beta on a number of other cell types in which increased synthesis of fibronectin occurs and is associated with decreased growth.

Cells, Cultured↗

PubMed1989

Activation of a murine T-cell hybridoma by cationized bacteria.

Cationic particles interact by electrostatic forces with membrane components of diverse cell types, including lymphocytes. Contact with cationized streptococci was shown to induce a murine T-cell hybridoma to transcribe lymphokine mRNA as well as secrete interleukin-2. This activation was accompanied by a rise in intracellular calcium. Cationized streptococci-induced activation of this T-cell hybridoma could be specifically inhibited by either chelating extracellular calcium or by treating with CD4 monoclonal antibody. These data indicate that the in vitro behaviour of T cells can be modulated by charged microbial particles; such interactions may have relevance for chronic inflammation associated with some bacterial infections.

Animals↗

PubMed1989

Endothelial cell killing by neutrophils. Synergistic interaction of oxygen products and proteases.

Killing of rat pulmonary artery endothelial cells by activated polymorphonuclear leukocytes (PMNs), as measured at 4 hours, is catalase sensitive, iron dependent, and unaffected by addition of protease inhibitors. If the time course for exposure of endothelial cells to activated PMNs is extended to 18 hours, progressive injury occurs. Endothelial cell injury resulting at 18 hours is partially inhibited by catalase and partially inhibited by soybean trypsin inhibitor. Together, these two inhibitors function synergistically to protect the cells from injury. Exposure of endothelial cells to reagent H2O2 and purified proteolytic enzymes (trypsin, chymotrypsin, elastase, and cathepsin G) mimics the effects of activated PMNs: H2O2 alone is cytotoxic with maximal killing achieved by 4 hours; proteolytic enzymes produce cytotoxicity only at high concentrations and only after prolonged incubation (longer than 8 hours); and, in combination, H2O2 and proteolytic enzymes act synergistically. These data provide compelling evidence that PMN-mediated injury of endothelial cells involves interaction between oxygen products and proteases.

Adult↗

PubMed1989

Attachment of neuroblastoma cells to extracellular matrix: correlation with metastatic capacity.

Extracellular matrix (ECM) serves important attachment functions during organogenesis in mammalian species. When layered on a plastic surface, ECM extracted from the rat lung, liver, or kidney enhances the attachment of C1300 murine neuroblastoma cells to that surface. Enhanced attachment to ECM by these cells correlates with their potential to form metastatic deposits in vivo. Conversely, neuroblastoma cells selected for increased metastatic potential by in vivo passaging demonstrate enhanced attachment to organ-derived ECM. However, although ECM provides attachment sites for these murine neuroblastoma cells, the attachment is not preferential for any of the organ ECMs tested (lung, liver, kidney). Histopathologic examination of the murine liver, lungs, and kidneys performed 20 to 22 days after intravenous inoculation of C1300 cells reveals notable metastatic seeding in each of these organs, but the liver clearly exhibits a greater degree of replacement by tumor metastases than the lungs or the kidneys. Therefore, the data from the attachment assays, coupled with the histopathologic findings obtained after tumor inoculation, suggest that although the ability to attach to ECM correlates with metastatic potential, additional factors are important in determining the preferential pattern of metastatic disease observed in murine neuroblastoma.

Animals↗

PubMed1989

Cytotoxicity of tumor necrosis factor-alpha for human umbilical vein endothelial cells.

Human umbilical vein endothelial cells were examined for sensitivity to killing by human recombinant tumor necrosis factor-alpha (TNF-alpha). Treatment of the cells with concentrations of TNF-alpha up to 50 ng/ml for 18 hours did not produce evidence of cytotoxicity. However, a marked cytotoxic effect was found when TNF-alpha pretreated cells were incubated in Hanks' balanced salt solution for a further 4 hours. Exposure of the cells to heat-inactivated or antibody-neutralized TNF-alpha did not result in cytotoxicity. Human recombinant interleukin-1 also lysed endothelial cells under the same conditions, whereas human recombinant macrophage-colony stimulating factor did not. Inclusion of superoxide dismutase, catalase, or soybean trypsin inhibitor in the culture medium during the time of endothelial cell exposure to TNF-alpha had no protective effects. Likewise, allopurinol (a xanthine oxidase inhibitor) and nordihydro-guaiaretic acid (a lipoxygenase inhibitor) were not protective under the same conditions. In contrast, the ferric iron chelator deferoxamine mesylate and three different cyclooxygenase inhibitors provided significant protection against TNF-alpha induced cytotoxicity. When human dermal fibroblasts and human squamous epithelial cells were used in place of the umbilical vein endothelial cells, these cells were resistant to TNF-alpha mediated killing. These findings demonstrate that under the experimental conditions employed, TNF-alpha is cytotoxic for human umbilical vein endothelial cells. This may have implications in a number of in vivo situations in which TNF-alpha is thought to play a role.

Cell Survival↗

PubMed1989

Xanthine oxidase activity in rat pulmonary artery endothelial cells and its alteration by activated neutrophils.

The possibility that endothelial cell-derived oxidants could contribute to neutrophil-mediated endothelial cell injury and cytotoxicity has been a subject of speculation. Rat pulmonary artery endothelial cells (RPAECs) were examined for the presence of xanthine oxidase (XO) activity, a well-known source of O2-. Using a sensitive assay based on measurements of radioactive xanthine conversion to uric acid by high performance liquid chromatography (HPLC), RPAEC extracts were found to contain both XO and xanthine dehydrogenase (XD) activities. Extracts from early passage cells have 55.3 +/- 11.7 (mean +/- SE) units/10(6) cells of total (XO + XD) activity, one unit of activity being defined as the conversion of 1% of substrate to product in 30 minutes of incubation. XO comprised 31.6 +/- 3.1% of this total activity. Addition of human neutrophils stimulated with phorbol myristate acetate (PMA) caused a rapid and dose-dependent increase in RPAEC XO activity from 31.6 +/- 3.1% to 71.7 +/- 4.8% of total without altering total (XO + XD) activity. The neutrophil dose-response curve for increase in XO paralleled closely the curve for neutrophil-mediated RPAEC cytotoxicity. The basal XO and XD activities and the neutrophil-induced increase in XO activity were inhibited by treating RPAECs with allopurinol, oxypurinol, and lodoxamide, which also inhibited cytotoxicity, but not by catalase, superoxide dismutase, or deferoxamine. Addition of H2O2 failed to cause an increase in RPAEC XO activity or XD to XO conversion. The results suggest that during neutrophil-mediated injury, rapid conversion of RPAEC XD to XO occurs, resulting in increased XO, catalyzed endogenous oxidant production, which may contribute to the oxidant burden in the killing mechanism initiated by activated neutrophils. Although the mechanism for conversion of XD to XO is uncertain, it appears that neutrophil-derived H2O2 is not sufficient to cause this phenomenon. Furthermore, neither O2- nor chelatable iron is required for neutrophil-induced XD to XO conversion. Supernatant fluids from activated neutrophils failed to induce XD to XO conversion in RPAECs. This in vitro system provides an opportunity to define the cellular and molecular mechanisms underlying the in vivo phenomenon of XD to XO conversion associated with ischemic/reperfusion or inflammatory tissue injury.

Allopurinol↗

PubMed1989

EGF does not enhance corneal epithelial cell motility.

Although it is well known that epidermal growth factor (EGF) accelerates corneal epithelial wound healing by stimulating mitosis, it is also believed that EGF may directly stimulate the motility of individual corneal epithelial cells. We employed three different experimental methods to determine if EGF does indeed enhance the motility of corneal epithelial cells (independent of mitotic effects). First, the effects of EGF on the motility of tissue-cultured rat and rabbit corneal epithelial cells were investigated by a Boyden chamber assay. In rat corneal epithelium, these effects were further investigated by a second method, the agarose drop assay. Both assay techniques demonstrated no increase in corneal epithelial cell motility in the presence of EGF. These findings were corroborated by a third method which consisted of measuring the closure rate of epithelial wounds in organ-cultured rat corneas in the presence and absence of EGF, while concurrently arresting mitosis with colchicine. The wound closure rate before addition of any drug was 0.46 +/- 0.03 mm2/hr. The wound closure rate with EGF (50 ng/ml) was 0.55 +/- 0.03 mm2/hr, significantly (P less than 0.005) more rapid than the drug-free controls. However, when EGF (50 ng/ml) and colchicine (40 micrograms/ml) were used simultaneously, the acceleration of wound closure by EGF was completely negated by the presence of colchicine, resulting in a wound closure rate (0.46 +/- 0.06 mm2/hr) that did not differ significantly (P greater than 0.50) from that of the drug-free control.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Biosynthesis and secretion of laminin and laminin-associated glycoproteins by nonmalignant and malignant human keratinocytes: comparison of cell lines from primary and secondary tumors in the same patient.

Laminin biosynthesis was compared in four pairs of human squamous cell carcinoma cultures derived from primary and recurrent or metastatic tumors in four patients with cancer of the larynx and hypopharynx to determine if changes in laminin production accompany tumor progression. Laminin profiles of the malignant cells were compared with laminin biosynthesized by nonmalignant human keratinocytes. Pulse-chase biosynthetic labeling of the cultures with [35S]methionine established that all of the squamous carcinoma cell lines synthesize immunoreactive A (Mr 400,000), B1 (Mr 205,000), and B2 (Mr 200,000) laminin subunits; assemble them to form the intact laminin molecule (Mr 950,000); and secrete a portion of the laminin they produce into the culture media. One aspect of laminin expression unique to keratinocytes, both malignant and nonmalignant, was the occurrence of three additional glycoprotein forms (Mr 195,000, 170,000, and 160,000) in the laminin immunoprecipitates. In contrast to the laminin subunits, these glycoproteins were not immunoreactive with the anti-laminin antiserum on Western blots. Two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis without and with reduction of disulfide bonds revealed that the laminin immunoprecipitates contained a family of oligomeric molecules. These ranged in apparent molecular weight from 370,000 to 950,000 and were composed of laminin subunits and the glycoprotein forms linked by interchain disulfide bonds. The malignant keratinocyte cell lines from different patients were distinguishable in terms of the array of laminin and glycoprotein forms displayed on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the rate of [35S]methionine incorporation into laminin during the pulse-labeling, the fraction of [35S]methionine-labeled laminin secreted into the medium during the chase incubation, and the absolute amount of laminin secreted into the culture medium as determined by enzyme-linked immunosorbent assay. However, cell lines established from primary and metastatic or recurrent cancer in the same patient were indistinguishable in their profile of laminin biosynthesis and secretion. In comparison to primary cultures of nonmalignant foreskin basal keratinocytes, the malignant cells secreted into the culture medium a larger fraction of the laminin that they produce. This is an indication that the malignant keratinocytes in culture deposited a less stable basal lamina-like extracellular matrix than their malignant counterparts. The diminished integrity of the basal lamina matrix may be an important factor in the invasive growth of human epithelial cancer.

Carcinoma, Squamous Cell↗

PubMed1988

Induction of carcinoembryonic antigen secretion and modulation of protein secretion/expression and fibronectin/laminin expression in human colon carcinoma cells by transforming growth factor-beta.

We have recently reported that TGF-beta induces a response similar to that of planar polar differentiation promoters in human colon carcinoma MOSER cells. N,N-Dimethylformamide and TGF-beta had similar effects on MOSER cells with respect to reversible inhibition of growth (both in monolayer culture and semisolid medium), induction of fibronectin expression and the induction of morphological alterations (Cancer Res., 47:2950-2954, 1987). Since the expression of carcinoembryonic antigen (CEA) has been reported to be modulated by planar polar compounds that promote differentiation in colon carcinomas, we addressed the issue of whether the differentiation-like effects of TGF-beta on these cells would also encompass modulation of CEA expression in the MOSER cells. The biological modulating effects of TGF-beta on extracellular matrix glycoprotein expression and the expression and secretion of cellular proteins were also studied in view of the reported modulating effects of this growth factor on untransformed, noncolonic cells. In this communication we report that TGF-beta induced the synthesis of fibronectin and laminin but not collagen IV. TGF-beta also induced CEA secretion in a dose-dependent manner. Elevated CEA secretion was detected following 48 h of TGF-beta treatment and a 16-fold increase in CEA secretion was observed following 7 days of treatment. The cells were committed to secrete CEA following one dose of TGF-beta treatment. The enhanced expression of four cellular proteins (Mr 42,000, Mr 48,000, Mr 52,000, and Mr 55,000) and the enhanced secretion of three proteins (Mr 66,000, Mr 200,000, and Mr 400,000) were also induced. Some of these protein alterations were detected as early as 6-24 h following TGF-beta treatment. It is concluded that TGF-beta modulated the production and secretion of CEA, the synthesis of fibronectin and laminin, and the expression and secretion of several cellular proteins in the colon carcinoma MOSER cells. To our knowledge, this is the first report on the modulation of CEA and laminin by TGF-beta in tissue-cultured cells, and is the first report on the modulation of cellular proteins by this growth factor in human colon carcinoma cells.

Carcinoembryonic Antigen↗

PubMed1988

Marker polypeptide differences between spontaneous strongly and weakly metastatic cancer cells identified by 2-dimensional gel electrophoresis.

A recent 2-dimensional gel electrophoresis study revealed several polypeptide differences between a strongly metastatic and a weakly metastatic clone from a single chemically induced murine fibrosarcoma (Jellum et al., 1984). To exclude the possibility that this was merely coincidental, the study is extended here to 2 other fibrosarcomas recently and similarly induced in mice of the same inbred strain. Metastatic potential was defined by the number of lung metastases spontaneously formed from a transplanted primary footpad tumor. One strongly (or moderately) metastatic cell line and I weakly metastatic line from each of the 3 fibrosarcomas were examined in the same experiments. In confirmation of our previous results, the same polypeptides consistently occurred in considerably greater amounts in the weakly metastatic than in the strongly metastatic cells. One of these marker polypeptides was absent from the strongly metastatic cell lines. In comparison with 2 of the 3 most metastatic lines, the third line was only moderately metastatic, and differed least strongly from the 3 weakly metastatic cell lines with regard to expression of th marker polypeptides. Marker polypeptide expression showed no consistent correlation with tumorigenicity. No other consistent polypeptide differences between strongly metastatic and weakly metastatic cells could be identified among the approximately 2,000 cellular polypeptides separated on the gels.

Animals↗

PubMed1988

Lipoteichoic acid-antilipoteichoic acid complexes induce superoxide generation by human neutrophils.

Human neutrophils (PMNs) which have been incubated with lipoteichoic acid (LTA) from group A streptococci generated large amounts of superoxide (O2- chemiluminescence and hydrogen peroxide when challenged with anti-LTA antibodies. Cytochalasin B further enhanced O2- generation. The onset of O2- generation by the LTA-anti-LTA complexes was much faster than that induced by BSA-anti-BSA complexes. LTA-treated PMNs generated much less O2- when challenged with BSA complexes, suggesting that LTA might have blocked, nonspecifically, some of the Fc receptors on PMNs. PMNs treated with LTA-anti-LTA complexes further interacted with bystander nonsensitized PMNs resulting in enhanced O2- generation, suggesting that small numbers of LTA-sensitized PMNs might recruit additional PMNs to participate in the generation of toxic oxygen species. Protelolytic enzyme treatment of PMNs further enhanced the generation of O2- by PMNs treated with LTA-anti-LTA. Superoxide generation could also be induced when PMNs and anti-LTA antibodies interacted with target cells (fibroblasts, epithelial cells) pretreated with LTA. This effect was also further enhanced by pretreatment of the target cells with proteases. PMNs incubated with LTA released lysosomal enzymes following treatment with anti-LTA antibodies. The amounts of phosphatase, beta-glucoronidase, N-acetylglucosaminidase, mannosidase, and lysozyme release by LTA-anti-LTA complexes were much smaller than those released by antibody or histone-opsonized streptococci, suggesting that opsonized particles are more efficient lysosomal enzyme releasers. However, since the amounts of O2- generated by the LTA complexes equaled those generated by the opsonized particles, it is assumed that the signals for triggering a respiratory burst and lysosomal enzyme secretion might be different. Generation of O2- by LTA complexes was strongly inhibited by lipoxygenase inhibitors but not by cyclooxigenase inhibitors. Also phenylbutazone, trifluorperazine, and DASA markedly inhibited O2- generation induced by LTA complexes. These data suggest that bacterial products in the presence of antibody might have important biological effects on phagocytic cells and that these effects may be inimical to the host.

Antigen-Antibody Complex↗

PubMed1988

Thrombospondin binding by human squamous carcinoma and melanoma cells: relationship to biological activity.

Human squamous carcinoma cells attach and spread on thrombospondin (TSP)-coated culture dishes but exhibit significant variability among individual cell lines in their degree of responsiveness. Using a highly responsive squamous carcinoma line and a cell line which is much less responsive (as well as a human melanoma cell line which does not respond at all in the adhesion assay), we have examined binding of exogenous radiolabeled TSP. The cells which were the most responsive to TSP in the adhesion assay bound the greatest amount of radiolabeled ligand. Binding was time- and dose-dependent, saturable, inhibitable with excess unlabeled TSP, reversible, and specific. The less-responsive squamous carcinoma cells bound only 25-30% of the amount of TSP bound by the highly responsive cells while the nonresponsive melanoma cells bound less than 10% of the amount bound by the highly responsive squamous carcinoma cells. Our previous studies (J. Varani et al. (1986) Exp. Cell Res. 167, 376) have shown that the highly responsive squamous carcinoma cells also synthesized the greatest amount of TSP as indicated by biosynthetic labeling studies. The less-responsive squamous carcinoma cells were intermediate in synthetic activity and no synthetic activity was seen with the melanoma cells. These findings suggest that the amount of ligand bound may determine the degree of biological responsiveness and that endogenously synthesized TSP may be the source of that ligand.

Antibodies, Monoclonal↗

PubMed1988

The effect of substrate on the production of infectious virus by cells in culture.

Herpes simplex virus type I (HSV-1), infectious bovine rhinotracheitis virus (IBR) and turkey herpesvirus were examined for growth in cells cultured on three different substrates. The substrates were glass, DEAE-dextran and collagen gel. With two of the viruses, HSV-1 and IBR, there were no apparent differences in production as a function of substrate. In contrast, the amount of the turkey herpesvirus which was recovered varied greatly with the substrate. Titers were highest on glass, followed by DEAE-dextran and then collagen gel. Our previous studies have indicated that the substrate on which anchorage-dependent cells are grown in vitro has an affect on a number of biological and biochemical properties. The present study indicates that the production of commercially important biologicals can be affected by the substrate.

Animals↗

PubMed1988

Inhibitory effect of gamma interferon on cultured human keratinocyte thrombospondin production, distribution, and biologic activities.

Rapidly proliferating keratinocytes (KCs) maintained in low calcium, serum-free medium produce and utilize thrombospondin (TSP) as an attachment and spreading factor. To begin to understand the modulation of KC TSP metabolism, gamma interferon (IFN-gamma), a product of activated T lymphocytes, was added to KC cultures. IFN-gamma was chosen because activated T cells appear at sites of cutaneous injury. Two additional cytokines including tumor necrosis factor (TNF) and IFN-beta were also examined. IFN-gamma (600 U/ml), but not TNF (500 U/ml) or IFN-beta (10(3) U/ml), as single agents decreased KC TSP biosynthesis, secretion, and utilization as an attachment factor. IFN-gamma alone did not detectably decrease TSP mRNA levels suggesting a post-transcriptional effect in KCs. However, the combination of IFN-gamma (600 U/ml) and TNF (500 U/ml) inhibited TSP mRNA production. These results demonstrate the modulation of KC TSP metabolism and biologic activity.

Cell Adhesion↗

PubMed1988

Thrombospondin-induced adhesion of human keratinocytes.

Human epidermal keratinocytes obtained from normal skin attached and spread on thrombospondin (TSP)-coated plastic dishes but failed to attach and spread on untreated plastic culture dishes or dishes coated with fibronectin or laminin. These cells produced minimal amounts of immunoreactive TSP. Keratinocytes established in culture on MCDB 153 medium and maintained for one to three passages in an undifferentiated state by continued cultivation in this low Ca2+-containing medium attached and spread on plastic dishes as well as on TSP-coated dishes. These cells also secreted significant amounts of TSP into the culture medium. When the keratinocytes were incubated for one day in MCDB 153 medium supplemented with high Ca2+ or in MEM (which also contains high Ca2+), there was decreased secretion of TSP into the culture medium concomitant with a reduction in attachment and spreading on plastic culture dishes. Proteolytic fragments of TSP were examined for stimulation of keratinocyte attachment and spreading. A 140-kd fragment produced by removal of the 25-kd heparin-binding domain had similar activity to the intact molecule while the 25-kd fragment was without effect. Further proteolytic treatment of the 140-kd fragment gave rise to a fragment consisting of 120 kd and 18-D moieties held together in disulphide linkage. This fragment did not support attachment or spreading. This study reveals that normal epidermal keratinocytes grown under conditions that maintain the undifferentiated state are able to produce TSP and utilize it as an attachment factor. When keratinocytes are grown under conditions that promote differentiation, ability to produce and utilize TSP is diminished. Since TSP is present at the dermal-epidermal junction and because TSP promotes keratinocyte attachment and spreading, this molecule may play an important role in maintaining normal growth of the basal cell layer and may also participate in reepithelialization during wound repair.

Antibodies, Monoclonal↗

PubMed1988

Modulation of keratinocyte motility. Correlation with production of extracellular matrix molecules in response to growth promoting and antiproliferative factors.

Normal human epidermal keratinocytes (KC) grown under conditions that maintain the undifferentiated state are highly motile. Migration of these cells as measured in two different assays (migration out of an agarose drop explant, and into micropore filters in a modified Boyden chamber), is stimulated by fibronectin (FN) and to a lesser extent by thrombospondin (TSP). In contrast, laminin (LN) inhibits KC migration. Cultivation of the cells for 1 day under conditions that induce differentiation (ie, in the presence of 1.4 mM Ca2+) suppresses KC motility. A number of soluble growth modulating polypeptide factors also influence KC migration. Transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) stimulate KC motility. These factors simultaneously induce KC production of FN and a significant portion of the stimulated motility can be inhibited with antibodies to FN. EGF and somatomedin-C (SM-C), but not TGF-beta, also stimulate TSP production while EGF and SM-C (but not TGF-beta) induce KC proliferation. In contrast to these factors, interferon-gamma (INF-gamma) inhibits KC production of both FN and TSP and concomitantly inhibits both motility and proliferation. These data suggest that KC properties essential for normal wound healing (ie, motility and proliferation) are regulated by both extracellular matrix molecules and soluble peptide factors. Finally, these effects of various growth promoting and antiproliferative factors on KCs may, in part, be mediated through alteration in the endogenous production of extracellular matrix molecules by KCs.

Cell Division↗

PubMed1988

Treatment of mice with anti-asialo-GM1 antibody or poly-I:C: effects on metastasis dissociable from modulation of macrophage antitumor activity.

Treatment of C57BL/6J mice with poly-I:C or antibodies to asialo-GM1 enhances and depresses respectively natural killer (NK) cell activity while inversely altering lung metastasis, suggesting a critical role for these cells in controlling tumor formation. We assessed the effect of these treatments on antitumor activity mediated by macrophage (M phi) populations likely to be important in lung metastasis. Alveolar and lung interstitial M phi were asialo-GM1 positive (98%) and were sensitive to in vitro treatment with the antibody plus complement; however, treatment of mice with antibodies to asialo-GM1 failed to alter their tumoricidal activity in vitro. Few blood monocytes (4%) or spleen M phi (2%) were asialo-GM1 positive and their antitumor activity was similarly unaffected. In contrast, however, this same in vivo treatment resulted in a 14-fold increase in lung metastasis. Intraperitoneal injection of poly-I:C greatly reduced metastasis formation but also failed to significantly affect in vitro cytolytic activity of the M phi populations. These findings suggest that the major metastasis altering effects of these agents result from modulation of NK rather than M phi function.

Animals↗

PubMed1988

Tumor necrosis factor enhances susceptibility of vascular endothelial cells to neutrophil-mediated killing.

Tumor necrosis factor has a variety of effects on different types of cells in vitro, including endothelial cells. The current studies show that pretreatment of rat pulmonary artery endothelial cells with tumor necrosis factor increases in a time- and dose-dependent manner their sensitivity to killing by neutrophils stimulated with phorbol myristate acetate or C5a. Similar effects are seen with interleukin-1. These data suggest that tumor necrosis factor and interleukin-1 may have important pro-inflammatory effects on endothelial cells.

Animals↗