UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6, IL-6, is a pleiotropic cytokine which plays a central role in defense mechanisms, including the immune response, acute phase reaction and hematopoiesis. Abnormal expression of the IL-6 gene has been suggested to be involved in the pathogenesis of a variety of diseases, especially rheumatoid arthritis, Castleman's disease, mesangial proliferative glomerulonephritis, multiple myeloma and Kaposi's sarcoma. In the case of multiple myeloma and Kaposi's sarcoma, the existence of an IL-6-IL-6 receptor autocrine loop has been implicated in the oncogenesis process. On the other hand, IL-6 has a potent anti-tumor activity against certain types of tumors. This anti-tumor effect is mediated by in vivo induction of tumor specific cytotoxic T cells and in part by a growth inhibitory activity of IL-6.
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PMID:The evidence for interleukin-6 as an autocrine growth factor in malignancy. 164 91

Expression of the human IL-6 gene in EBV-immortalized normal human B lymphocytes following retroviral-mediated transduction rendered these cells highly tumorigenic in athymic mice. The tumors were lymphomas composed of the originally inoculated human lymphoblastoid cells. Co-injection of IL-6 expressing EBV-immortalized cells with IL-6 nonexpressing control cells resulted in increased tumorigenicity of the IL-6 nonexpressing cells. The lymphoblastoid cells expressing IL-6 were indistinguishable from parental cell lines in morphology and in a variety of cell surface characteristics, and did not exhibit growth advantage over parental cell lines in vitro, such that increased tumorigenicity is unlikely to depend upon a direct oncogenic effect of IL-6 on the B cells. Rather, at high concentrations, IL-6 markedly inhibits human lymphoblastoid cell killing by IL-2-activated murine splenocytes in vitro, suggesting that IL-6-related tumorigenicity might depend upon IL-6 inhibiting cytotoxicity at the tumor site. Thus, production of IL-6 by tumor cells that results in natural killer cell dysfunctions illustrates a novel mechanism of tumor cell escape from immune surveillance.
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PMID:Impairment of natural killer functions by interleukin 6 increases lymphoblastoid cell tumorigenicity in athymic mice. 164 16

The induction of proteolytic enzymes is an important mechanism in the migration of monocytes into tissues and body fluids. The monocytic cell line THP-1 was used as a model system to study the production of a particular gelatinase. Upon stimulation with phorbol myristate acetate (PMA) the cells differentiated to the adherent phenotype and produced significant amounts of a 96-kD gelatinase in a dose-dependent way. The secretion rate was maximal between 12 and 24 h after induction. Study of gelatinase mRNA steady state levels showed that the synthesis of THP-1 gelatinase is regulated by PMA at transcriptional or posttranscriptional levels. Stimulation of signal transduction pathways with other substances, including calcium ionophore A 23187, dibutyryl cyclic AMP, and dexamethasone, were ineffective in inducing gelatinase mRNA or enzyme activity. However, THP-1 cells were responsive to the cytokine interleukin (IL)-1 beta, to bacterial lipopolysaccharide (LPS), and the lectin concanavalin A (Con A), the kinetics of gelatinase induction being similar to those of induction by PMA. The THP-1 cells did not synthesize and/or secrete detectable levels of IL-6 after stimulation with PMA, Con A, LPS, or IL-1 beta. The 96-kD monocytic THP-1 gelatinase was shown to be a neutral metalloproteinase that cross-reacted with hepatoma-derived and neutrophil gelatinases in immunoprecipitation experiments. The active enzyme produced by THP-1 cells consistently showed, however, a molecular mass different from that of normal granulocyte-, monocyte-, and tumor cell-derived gelatinases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The cytokine-protease connection: identification of a 96-kD THP-1 gelatinase and regulation by interleukin-1 and cytokine inducers. 165 55

A high-cloning efficiency, filler cell-free limit-dilution culture system for the growth and differentiation of single cytotoxic T lymphocyte precursors (CTLp) was tested for its ability to maintain the lytic specificity of the resultant clones of cytotoxic T lymphocytes (CTL). The system used non-specific stimulation with phorbyl ester and calcium ionophore, maintenance of growth over the first 6 days of culture with interleukin (IL)-2 and interferon-gamma, and maintenance of growth and differentiation over the last 2 days of culture with IL-2 and IL-6. Under these defined conditions around 50% of all CD4- 8+ T cells developed into CTL clones that were specific in their lytic activity. In contrast, a culture system maintained by irradiated filler cells showed non-specific lysis of both YAC-1 type natural killer targets and of P815 type targets, while a culture system maintained by IL-2 and a crude growth factor preparation showed non-specific lysis of natural killer targets but not of P815. The defined lymphokine culture system was suitable for determining the specificity repertoire of primary CTLp. Using this system, the frequency of reactivity with allogenic tumor targets was found to be approximately one CTLp in 30 for several mouse strain/target cell combinations.
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PMID:The maintenance of lytic specificity during the development of clones of cytotoxic T lymphocytes from single precursor cells. 168 90

Analysis of lymphokine mRNA expression and protein secretion by about 100 short-term alloreactive T-cell clones revealed marked heterogeneity in the combinations of lymphokines synthesized. This finding argues against a simple model in which T cells express either an unrestricted (Th0) or a restricted (Th1 or Th2) lymphokine profile. Lymphokine titers appeared to be normally distributed, with the percentage of positive clones for any one product determined by the threshold of detection. Accordingly, the observation that CD4+ clones on average produced higher titers of most lymphokines than CD8+ clones indicated that apparent differences between the lymphokine profiles of these two subsets were quantitative rather than qualitative. Patterns of lymphokine gene expression detected in whole tissues or by analysis of single cells and clones were markedly influenced by in vivo priming. Relative levels of expression of IL-4, IFN-gamma and GM-CSF in lymphoid tissues differed in mice undergoing a GvHR or following contact sensitization with OX or immunization with KLH in adjuvant. Consistent with the finding that IL-4 was the major lymphokine mRNA detected in lymph nodes of KLH-primed mice, most short-term KLH-specific clones derived from such mice also expressed IL-4. A similar approach to the detection of lymphokine-secreting T-cell precursors activated late in L. major infection showed that most clones from the L. major-resistant strain, C57BL/6, secreted IFN-gamma without IL-4 whereas most clones from the susceptible strain, BALB/c, secreted IL-4 without IFN-gamma. Differences were also noted in anti-CD3-induced IL-3 production at the single-cell level between CD8+ cells activated in the GvHR or against a tumor allograft. Con A-induced, filler cell-dependent cloning of CD4+ T cells from unprimed mice gave rise both to IFN-gamma-producing and to IL-4-producing clones. A requirement for an undefined, filler cell-dependent signal for development of IL-4-secreting clones was suggested by the finding that clones of normal CD4+ and CD8+ T cells activated in an anti-CD3-induced, filler cell-free system exclusively produced IFN-gamma and IL-3 without detectable IL-4 or IL-6. With a view to developing a single-cell approach to the analysis of lymphokine profiles of in vivo-activated T cells, sensitive assays for IL-3 and other lymphokines were used to measure secreting cells activated in the GvHR or against a tumor allograft.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Heterogeneity in lymphokine profiles of CD4+ and CD8+ T cells and clones activated in vivo and in vitro. 168 85

The aim of this study was to evaluate to what extent tumor necrosis factor alpha (TNF-alpha) and interleukin 1 may explain the development of experimental cancer cachexia. For this purpose, C57BL/6J mice bearing a transplantable low differentiated rapidly growing tumor were passively immunized every other day with rabbit or rat neutralizing immunoglobulins against either TNF-alpha (anti-TNF) or against an interleukin 1 receptor (anti-IL-1r). Anti-IL-1r in itself had no agonistic effect to the type I, T-cell/fibroblast IL-receptor. Tumor-bearing mice receiving either preimmune antiserum or nonimmune rat hybridoma IgG served as controls. Anti-TNF and anti-IL-1r inhibited tumor growth significantly, as measured by a lower wet and dry tumor weight at the end of 11 days of antiserum treatment (P less than 0.05). The acute phase response in tumor-bearing animals, measured as an increase in liver weight, hepatic RNA content, and increases in plasma concentrations of circulating IL-6, serum amyloid P, transferrin, complement (C3), and a decrease in plasma albumin, were unaffected by the specific antiserum treatments. Food intake, which declined significantly in pre/nonimmune injected tumor-bearing controls, was significantly improved in tumor-bearing animals immunized against TNF-alpha or the IL-1r. Whole body lipid content showed a trend to improvement in specifically immunized animals (P less than 0.07). The effects on whole body fat-free dry weight were insignificant, although numerically higher in specifically immunized tumor-bearing animals. The combination of anti-TNF and anti-IL-1r antiserum had no additive effects compared to single antiserum treatment suggesting that the two antibody treatments acted through a common mechanism. Cultured tumor cells, established from growing tumors, were sensitive to anti-TNF and anti-IL-1r, which both reduced tumor growth in vitro. This inhibitory effect by the antiserum could in part be reversed by the addition of recombinant IL-1 alpha and TNF alpha. We conclude that both TNF and IL-1 are involved in tumor growth and thus the progression of cancer cachexia. It seems as if the role of TNF and IL-1 was to promote tumor growth rather than restrict tumor growth in the present model. In this sense both TNF and IL-1 may act as tumor growth factors.
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PMID:Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia. 170 40

Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells results in significant tumor regression in patients with advanced cancer. We have investigated the kinetics of circulating erythroid (BFU-E) and granulocytic-macrophage (CFU-GM) progenitors after IL-2 therapy in 11 cancer patients, mainly affected by metastatic melanoma and renal cell carcinoma. Administration of IL-2 from day 1 through day 5 constantly induced a dramatic decrease of the number of circulating BFU-E and CFU-GM, which then showed a striking rebound (up to values fourfold and sevenfold higher, respectively, than the pretherapy levels) on discontinuation of IL-2, ie, from day 5 through day 10. A similar kinetic pattern was observed during and after the second cycle of IL-2 administration. 3[H]-thymidine killing experiments showed that the cycling activity of the progenitors was virtually unmodified in the rebound phases. To explore the mechanism(s) underlying this kinetic pattern, we have analyzed the plasma concentration of several hematopoietic growth factors, including IL-1 beta, IL-3, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and erythropoietin (Ep). No modifications in the levels of IL-3, GM-CSF, or IL-1 beta were observed, whereas a pronounced increase of IL-6 and G-CSF concentration was monitored, starting at day 3 and peaking at day 5 of treatment (a parallel, but modest, increase of Ep level was also observed). The elevation of IL-6 and G-CSF concentration is directly correlated with and may, at least in part, underlie the subsequent rebound of circulating hematopoietic progenitors. Furthermore, the increase in IL-4 level observed at day 10 of therapy may mediate the eosinophilia gradually starting at this stage of treatment.
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PMID:Adoptive immunotherapy with high-dose interleukin-2: kinetics of circulating progenitors correlate with interleukin-6, granulocyte colony-stimulating factor level. 170 62

We established a human carcinoma cell line (KHC 287) from a patient with large-cell-typing lung carcinoma associated with marked leukocytosis. The culture supernatant of KHC 287 cells promoted granulocytic colony formation of human bone-marrow cells in semi-solid culture. Colony formation was almost completely suppressed by treatment of the supernatant with a monoclonal anti-granulocyte colony-stimulating factor (G-CSF) antibody. Not only G-CSF but also interleukin-1 alpha (IL-I alpha), IL-I beta and IL-6 were detected in the culture supernatant by an ELISA method. Northern blot analysis of KHC 287 cells revealed distinct expression of these cytokine genes. Southern blot hybridization of KHC 287 DNA showed 20- and 40-fold co-amplification of c-myc and c-ki-ras, respectively. The chloramphenicol acetyl transferase (CAT) activity was distinctly enhanced in the KHC 287 cells which were transfected with the 360 bp upstream region of G-CSF gene inserted into pSV00CAT, but not in non-G-CSF-producing tumor cell lines. These results suggest that overproduction of the transactivating factor(s) which binds to the 360 bp of the G-CSF upstream region is responsible for the abnormal expression of G-CSF gene in KHC 287 cell line.
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PMID:Analysis of abnormal expression of g-csf gene in a novel tumor cell line (KHC 287) elaborating G-CSF, IL-1 and IL-6 with co-amplification of c-myc and c-ki-ras. 171 Feb 8

Blood monocytes (MO) undergo maturation into macrophages (MAC) upon migration from the capillary bed to tissue sites of inflammation where they are exposed to environmental signals. Functional competence and phenotype heterogeneity is the result of both differentiation-inducing and -activating events. In vitro, MO to MAC maturation is induced by serum factors, can be followed by the expression of specific maturation-associated antigens and is accompanied by a characteristic change in the secretory repertoire of MAC in comparison to MO. Here we report that bacterial lipopolysaccharides (LPS) at subnanogram quantities very effectively inhibited the serum-induced maturation of human MO in vitro. At the same time LPS induced the up-regulation of CD14 antigens. The lipid A moiety was shown to be responsible for this novel biological activity of the LPS molecule. Inhibition of maturation was not due to secondary LPS-induced signals like interleukin (IL)-1, IL-6, tumor-necrosis factor (TNF)-alpha or interferon (IFN)-alpha--even though the latter by itself suppressed MAC maturation in vitro. The inhibitory activity of IFN-alpha could be abolished by neutralizing anti-IFN-alpha antibodies whereas these antibodies had no effect on LPS-induced suppression of MAC maturation. Functional analysis of LPS-treated MO long-term cultures showed that the pattern of secretory products released was similar to that of freshly-isolated immature blood MO: compared with mature MAC, LPS-treated MO released high amounts of IL-6 but significantly less TNF-alpha, neopterin, lysozyme and beta-2-microglobulin. At the same time, in LPS-treated MO cultures the MAC maturation-associated molecules alpha-2-macroglobulin and fibronectin could be detected only in trace amounts. The ability to secrete IL-1, however, was lost both in control as well as in LPS-treated MO cultures. The results indicate that endotoxins may influence the biology of the MO/MAC system distinctively: they not only induce a functional activation but also interfere with the ontogeny of this cell family.
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PMID:Inhibition of in vitro differentiation of human monocytes to macrophages by lipopolysaccharides (LPS): phenotypic and functional analysis. 171 Sep 26

CD4+ T cells require two signals to produce maximal amounts of IL-2, i.e., TCR occupancy and an unidentified APC-derived costimulus. Here we show that this costimulatory signal can be delivered by the T cell molecule CD28. An agonistic anti-CD28 mAb, but not IL-1 and/or IL-6, stimulated T cell proliferation by tetanus toxoid-specific T cells cultured with Ag-pulsed, costimulation-deficient APC. Furthermore, the ability of B cell tumor lines to provide costimulatory signals to purified T cells correlated well with expression of the CD28 ligand B7/BB-1. Finally, like anti-CD28 mAb, autologous human APC appeared to stimulate a cyclosporine A-resistant pathway of T cell activation. Together, these results suggest that the two signals required for IL-2 production by CD4+ T cells can be transduced by the TCR and CD28.
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PMID:CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. 171 61

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