Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An alveolar macrophage-activating factor was released from Percoll fractionated large granular lymphocytes (LGL) within minutes of contact with either the natural killer (NK)-sensitive K562 tumor or heat-killed Staphylococcus aureus. The factor enhanced the intracellular killing of S. aureus without altering the rate of phagocytosis. Factor release was blocked by treatment of LGL with monensin, a carboxylic ionophore that inhibits vesicular traffic, but was unaffected by actinomycin D and cycloheximide pretreatment, suggesting that the cytokine was performed. The cell producing the factor was found only in Percoll fractions containing high concentrations of lytic NK cells and LGL, and the phenotypes of the LGL were HNK-1+ and E rosette-. The macrophage activating factor was a small protein of 10,000 to 20,000 daltons, as determined by gel fractionation, and was sensitive to proteolytic enzymes and heat and pH labile. Active supernatants were devoid of antiviral (interferon; IFN) or interleukin 2 (IL 2) activity, and IFN-beta, IFN-gamma, IL 2, and interleukin 1 were unable to activate staphylococcidal activity, suggesting that the LGL macrophage activating factor was distinguishable from these cytokines.
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PMID:Activation of rat and human alveolar macrophage intracellular microbicidal activity by a preformed LGL cytokine. 392 1

Macrophages are pivotal cells in interactions of man and leishmania. Leishmanial disease results from intracellular infection of macrophages: parasitized cells are seen in smears or biopsy specimens of lesions; macrophages cultured in vitro support replication of parasites. Paradoxically, parasite destruction is also mediated by macrophages, which become highly cytotoxic after exposure to immune lymphocytes or their lymphokine (LK) products. The precise molecular mechanisms by which lymphocytes or LK induce macrophage activation for leishmanicidal activity, however, are not yet known. We analyzed interactions of leishmania amastigotes with human monocytes cultured in vitro as a nonadherent cell pellet. Leishmania donovani and L. major replicated in freshly isolated monocytes. Monocytes treated with greater than 200 IU/ml of the LK, human Interferon-gamma (IFN-gamma), destroyed tumor cells and L. donovani, but not L. major. Phorbol myristate acetate, endotoxic bacterial lipopolysaccharide, and recombinant human IFN-alpha and IFN-beta did not induce cytotoxicity. The time course for induction of cytotoxicity contrasted sharply with that of previously described monocyte antileishmanial activity: IFN-gamma induced cytotoxicity even when added after infection with L. donovani; induction of cytotoxicity did not require that IFN-gamma be present throughout the period of culture after infection: a 30-min preinfection pulse of IFN-gamma was sufficient to induce 70% of maximal activity; and freshly isolated monocytes and cells cultured for up to 4 days in vitro prior to infection and IFN-gamma treatment were equally responsive to IFN-gamma. These studies provide convincing evidence for intracellular cytotoxicity for L. donovani by freshly isolated human monocytes. This system provides an important base for further analysis of induction and expression of cytotoxic mechanisms against leishmania and other intracellular organisms that cause human disease.
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PMID:Human monocyte activation for cytotoxicity against intracellular Leishmania donovani amastigotes: induction of microbicidal activity by interferon-gamma. 392 73

Human blood monocytes, separated on a Percoll gradient, were not cytotoxic to allogeneic melanoma (A375) cells. Fluorescent analysis showed that the monocytes were contaminated with up to 2.0% natural killer (NK) cells. The monocytes became tumoricidal on incubation for 24 h with greater than or equal to 1,000 IU/ml interferon-alpha (IFN-alpha) derived from human lymphoblastic leukemia cells. Anti-IFN-alpha antibody abolished the ability of IFN-alpha to render the monocytes tumoricidal, whereas anti-IFN-beta antibody had no effect. Pretreatment of isolated monocyte preparations with anti-NK cell monoclonal antibodies (Leu-7 and Leu-11b), to inhibit NK cell activity, did not affect the cytotoxicity of IFN-alpha-activated monocytes on tumor cells. Full expression of cytotoxicity on tumor cells required the interaction of monocytes with IFN-alpha for 24 h. These results indicate that IFN-alpha directly activates human monocytes to become tumoricidal, although greater than or equal to 1,000 IU/ml IFN-alpha is required for maximal activation.
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PMID:Induction by interferon-alpha of tumoricidal activity of adherent mononuclear cells from human blood: monocytes as responder and effector cells. 399 64

Mouse peritoneal macrophages expressed increased cytolytic activity against tumor cells upon in vitro exposure to partially purified L cell interferon (IFN-beta). In contrast, treatment with human IFN or with mock IFN preparations did not enhance macrophage tumoricidal capacity. Macrophage activation by IFN was optimal with long exposure times and high IFN concentrations. Treatment with polymyxin B sulfate did not affect IFN-induced macrophage cytotoxicity, thus excluding the possibility that bacterial lipopolysaccharide contaminants were responsible for macrophage activation. Conversely, treatment with a highly specific anti-IFN antiserum completely abolished IFN effect on macrophages, but had no effect on lymphokine-induced cytolysis. IFN and the lymphokine macrophage-activating factor (MAF) were compared for their ability to provide the sequence of activation signals to macrophages from the normal responder C3H/HeN mice and from C3H/HeJ mice, which are defective for several macrophage responses. Like MAF, IFN was incapable of inducing tumoricidal activity in C3H/HeJ macrophages. However, whereas MAF provided the first "priming" signal to macrophages of both strains, IFN acted as first signal only for C3H/HeN macrophages, being inactive for cells of the defective C3H/HeJ strain. Furthermore, IFN was not capable of providing the second "expression" signal to "primed" macrophages. These data suggest two different macrophage activation pathways for IFN and MAF.
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PMID:Interferon-induced enhancement of macrophage-mediated tumor cytolysis and its difference from activation by lymphokines. 616 39

Resident peritoneal macrophages (M phi) from untreated mice and inflammatory M phi induced by a sterile irritant were able to exert significant suppressive activity on lymphocyte functions. M phi-mediated suppression was evident in lymphocyte proliferation and in a proliferation-independent lymphocyte response (i.e. lymphokine production). The lymphokine macrophage-activating factor (MAF), which enhances tumoricidal capacity of inflammatory but not of resident M phi in vitro, was ineffective in modulating suppressive activity of both resident and inflammatory M phi. In contrast, a significant effect on M phi-mediated suppression was observed upon treatment with IFN-beta. In fact, suppression of lymphoproliferation and of lymphokine production by either resident or inflammatory M phi was significantly decreased or abolished by IFN-beta. Like MAF, IFN-beta was able to increase M phi cytotoxicity against tumor cells. Such as effect, however, was evident in both resident and inflammatory M phi, thus confirming different M phi activation mechanisms for MAF and IFN-beta. These data indicate that IFN-beta acts mainly on mature M phi, which thus appear as the major M phi type involved in suppression. The contrasting effects of IFN-beta on M phi suppression and on M phi-mediated cytotoxicity strongly suggest a dissociation between the 2 induction mechanisms of suppression and cytotoxicity. The in vivo relevance of these two IFN activities was demonstrated by treating mice with the potent IFN inducer polyinosinic polycytidylic acid (poly(I).poly(C). M phi from poly(I).poly(C)-primed mice simultaneously showed enhanced tumoricidal activity and complete abolishment of suppressive capacity.
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PMID:Macrophage activation by interferon: dissociation between tumoricidal capacity and suppressive activity. 617 3

Partially purified mouse interferon type I (Mu IFN-beta), crude mouse interferon type II (Mu IFN-gamma) serum, and the interferon inducer polyinosinic acid-polycytidylic acid (poly I:C) were evaluated for their effects on the growth of spontaneously occurring mammary carcinomas in BALB/c mice. As soon as their tumors had reached a palpable size (diameter: 3-5 mm), the mice received three ip injections of Mu IFN-beta, Mu IFN-gamma, or poly I:C per week for 6 weeks. A significant (fourfold to fivefold) reduction in tumor size was achieved with Mu IFN-beta (at 10(6) U/mouse), Mu IFN-gamma (at 10(3) U/mouse), and poly I:C (at 1 mg/mouse). A similar reduction in tumor size was noted when the mice were treated with cyclophosphamide (2.5 mg/mouse, three ip injections per wk for 6 wk). Treatment with Mu IFN-beta combined with Mu IFN-gamma resulted in a greater tumor growth-inhibitory effect than treatment with either Mu IFN-beta or Mu IFN-gamma alone. In addition to inhibiting the growth of primary tumors, interferon also reduced the incidence of lung metastases. However, complete tumor regression was not observed in any mouse while under interferon therapy.
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PMID:Inhibitory effect of interferon on the growth of spontaneous mammary tumors in mice. 618 Feb 10

IFN-gamma is known to induce expression of Ia antigens on a variety of cell types. In the present study, this activity of IFN-gamma has been analyzed with a panel of 36 melanoma cell lines, normal melanocytes, and 97 cell lines representing a range of other differentiation lineages. 55% of the melanoma cell lines express Ia antigens in a constitutive manner without IFN-gamma induction. Of the 16 Ia-melanoma lines, 13 could be induced to express Ia antigens by IFN-gamma, whereas three were noninducible. Melanocytes, which do not normally express Ia antigens, are converted to Ia expression by IFN-gamma. Ia antigens expressed constitutively or after IFN-gamma induction were identified with antibodies detecting monomorphic and allomorphic products of DR and DC loci. IFN-gamma appeared to be unique in its ability to induce Ia expression on melanoma and melanocytes; 14 other agents (including IFN-alpha and IFN-beta) known to influence growth or differentiation did not have Ia-inducing activity. Equally striking is the restriction of antigenic changes following IFN-gamma induction to HLA-associated products; of the 38 systems of cell surface antigens examined, only HLA-A,B,C, beta 2m, and Ia antigens were affected. A variety of other Ia- cell types were shown to be Ia-inducible by IFN-gamma; these included established lines of breast, colon, pancreas, bladder, kidney, ovary, and brain cancers, and cultures of normal fibroblasts, kidney epithelia, and epidermal keratinocytes. In contrast, three tumor types, teratocarcinoma, choriocarcinoma, and neuroblastoma, were not inducible for Ia expression, even though IFN-gamma could induce expression of HLA-A,B,C products. The broad representation of Ia antigens on most somatic cell types expressed either constitutively or after IFN-gamma can be viewed in an immunological context (antigen presentation/immune regulatory signals) or could indicate that Ia products have functions other than those related to immune reactions.
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PMID:Surface antigens of melanoma and melanocytes. Specificity of induction of Ia antigens by human gamma-interferon. 620 1

The antiproliferative effect of human interferons (IFNs) and double-stranded RNAs (dsRNAs) was measured in eight human tumor cell lines, five of which were derived from carcinomas of the bladder. Dose-response curves were generated for a 72-hr treatment period. The concentration of interferon or dsRNA necessary to inhibit tumor cell growth 50% compared to untreated cells was generated by linear regression analysis of the dose-response data. In the seven of eight cell lines in which a direct comparison could be made, IFN-beta was a more potent inhibitor than IFN-alpha. Polyriboinosinic acid X polyribocytidylic acid consistently gave an increased antiproliferative response compared to its mismatched analogue, rln X r(C12,U)n. Correlations could not be made between either IFN-alpha or IFN-beta and the dsRNA effect. No correlation was seen between IFN or dsRNA sensitivity and cell type, ability to bind IFN, growth rate, or tumorigenicity in nude mice. The antiproliferative effect of dsRNA was studied in the presence of antibodies against IFN-beta in HT1080 Cl 4, a cell line sensitive to both IFN and dsRNA, and A2182, a cell line relatively resistant to IFN-beta but sensitive to dsRNA. In both cell lines, the anti-IFN-beta antibodies inhibited the antiproliferative effect of the dsRNAs. After treatment with a concentration of dsRNA necessary to inhibit tumor cell growth 50% compared to untreated cells, a concentration of IFN-beta necessary to inhibit tumor cell growth 50% was induced in the HT1080 Cl 4 cells; however, only a low level of IFN-beta was detected in the culture medium of the A2182 cells.
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PMID:Independent sensitivity of human tumor cell lines to interferon and double-stranded RNA. 620 44

Conditioned media from cultures of marmoset monkey T-lymphoid cell lines transformed by Herpesvirus saimiri or Herpesvirus ateles were found to contain interferon (IFN) activity. Titers between individual cell lines varied by a factor of 100; large amounts (up to 10(5) units/ml, assayed on human cells) were produced in one of the cell lines. IFN production was enhanced by the diterpene tumor promoters, TPA and mezerein, but not by classical T-cell mitogens. The IFN resembles human IFN-gamma by the following criteria: lability at pH 2, stability against 2-mercaptoethanol, cross-species activity, shape of dose-response curves, and molecular weight determined by size-exclusion chromatography (50,000-55,000). Its activity was not inhibited, however, by antiserum against human IFN-gamma or antisera against human IFN-alpha or IFN-beta.
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PMID:Lymphokines produced by herpesvirus-transformed marmoset monkey lymphoid cell lines. I. Characterization of a constitutively produced interferon. 620 45

Macrophages (M phi diameter) from three mouse strains with genetically distinct M phi diameter deficits (C3H/HeJ, A/J, and P/J) were unable to develop high cytolytic and cytotoxic activity against tumor cells in vitro when exposed to agents (MAF and IFN-beta) that strongly increased the tumoricidal capacity of M phi diameter from nondefective C3H/HeN mice. Nevertheless, the tumoricidal deficits of M phi diameter from the defective strains did not affect their suppressive capacity on Con A-induced lymphoproliferation, nor their ability to react to IFN-beta by decreasing suppressive activity. In fact, natural suppressive activity and IFN-beta-induced changes in the suppression of M phi diameter from C3H/HeJ, A/J, and P/J mice were highly comparable to those of C3H/HeN M phi diameter, thus stressing the dissociation between the mechanisms governing M phi diameter suppression and M phi diameter tumoricidal activity. Analysis of the modulation by MAF and IFN-beta of M phi diameter ability to release the oxygen metabolites O2- and H2O2, molecules possibly involved in the effector mechanism of both M phi diameter cytotoxicity and suppression, revealed a close correlation with the patterns of suppressive activity in both nondefective and defective strains. In contrast, no correlation between the production of oxygen-reactive species and M phi diameter tumoricidal activity was observed. The ability of MAF- and IFN-beta-treated M phi diameter to produce PGE, a molecule of major importance in M phi diameter-mediated suppression and possibly involved also in the regulation of M phi diameter tumoricidal activity, again paralleled M phi diameter suppressive capacity. Thus, the mechanisms controlling M phi diameter antitumor activity appeared to be clearly distinct from those involved in M phi diameter suppression.
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PMID:Dissociation between macrophage tumoricidal capacity and suppressive activity: analysis with macrophage-defective mouse strains. 631 95


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