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)

The administration of murine TNF-alpha to colon (C)-26 bearing mice, significantly protects the host against the catabolic effects of the tumor. This effect of exogenous TNF-alpha can be primarily attributed to tumor lysis rather than to a direct anticachectic action. Murine peritoneal macrophages cultured with the C-26 line or with C-26 culture supernatant do not release TNF-alpha in response to LPS stimulation. The reduction in TNF-alpha levels is associated with a significant increase in IL-10 levels. Single cell suspension of freshly disaggregated C-26 tumor (which contains host macrophages), do not produce TNF-alpha but contain significant levels of PGE2 and IL-10. In contrast, PGE2 but not TNF-alpha or IL-10 can be detected in the C-26.IVX cell line that is used to generate tumors in vivo. Neutralizing anti IL-10 Ab but not isotype-matched Ab, significantly reverses the inhibitory effect of the tumor cells and their culture supernatant on macrophage TNF-alpha release. Additional evidence is presented to indicate that the C-26-derived inhibitory activity is related to PGE2. Taken together, these results support the hypothesis that tumor-derived PGE2 prevents tumor-infiltrating macrophages from producing TNF-alpha, in part by augmenting macrophage IL-10 synthesis.
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PMID:Potential involvement of IL-10 in suppressing tumor-associated macrophages. Colon-26-derived prostaglandin E2 inhibits TNF-alpha release via a mechanism involving IL-10. 789 21

CD4+ and CD8+ cytotoxic T-cell (CTL) clones, selected for T-cell-receptor (TcR)-dependent lysis of the autologous tumor and isolated from peripheral-blood lymphocytes (PBL) or tumor-infiltrating lymphocytes (TIL) of 3 melanoma patients, were characterized for the pattern of 13 different cytokines released by antibody- or tumor-mediated triggering. Induction or enhancement of cytokine release by anti-CD3 monoclonal antibody (MAb) led to the identification of 2 major sub-sets of CD8+ CTL clones on the basis of production of IL-4. Within the 2 groups of IL-4-producing or non-producing clones, further sub-sets could be identified on the basis of differential production of IL-1 beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha, TNF beta and IFN-gamma. A similar analysis performed on a panel of CD4+ CTL clones indicated multiple patterns consistent with at least 4 major sub-sets, but further complexity was evident in each sub-set on the basis of differential production of IL-1, IL2, IL-6, IL-10 and G-CSF. The cytokine profile of CD4+ and CD8+ clones, as determined after anti-CD3 stimulation, was different from the pattern seen after co-culture with autologous tumor, since many clones released cytokines such as IL-4, IL-10, IFN-alpha and -gamma, TNF-alpha and GM-CSF after activation with only 1 of the 2 stimuli. These results indicate that CD4+ and CD8+ CTL clones reacting to human melanoma belong to a highly complex repertoire of functional subsets characterized by distinct cytokine profiles. In addition, the cytokine pattern of each T-cell sub-set can be modulated by changing the activation signals delivered to the T cell.
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PMID:Multiple sub-sets of CD4+ and CD8+ cytotoxic T-cell clones directed to autologous human melanoma identified by cytokine profiles. 790 59

Interleukin (IL)-12 was cloned on the basis of its ability to activate natural killer (NK) cells and promote the development of cytolytic T cells. With further understanding of its activities, IL-12 has emerged as an important cytokine, affecting both immune and hematologic functions. It has been shown to be necessary for the T cell independent induction of interferon (IFN)-gamma, critical for the initial suppression of bacterial and parasitic infection; for the development of a Th1 response, critical for effective host defense against intracellular pathogens; and for the activation of differentiated T lymphocytes of both CD4+ and CD8+ phenotype. IL-12 thus functions to activate and to link the innate and acquired immune responses. The therapeutic potential of these activities is suggested by studies in tumor and microbial models. IL-12 has suppressed tumor growth in all murine models examined. Antimicrobial activity has been demonstrated in bacterial, yeast, parasitic, and viral models of infection. In many of these models, activity has been linked to production of IFN-gamma and, in the parasite model, to development of a Th1 response. In addition to the therapeutic potential associated with IL-12 activity in these disease models, the understanding of its role in immune development and interaction with other cytokines, particularly antagonists, such as IL-4 and IL-10, has clarified and extended our understanding of immune regulation and should lead to significant developments in understanding the progression of AIDS and the development of vaccine adjuvants able to direct the immune response.
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PMID:Interleukin 12: a key modulator of immune function. 791 Oct 46

Human autologous tumor-specific T-helper 2 (Th2) cells were investigated in melanoma tumor-infiltrating lymphocytes (TILs). Both a CD4+ T-cell line and its 5 potential T-cell clones established from TILs of a patient with metastatic melanoma produced significant levels of IL-4, IL-6, IL-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to autologous, but not any of 12 allogeneic, melanoma cell lines. They also produced IL-3 and IL-8 but not IL-2, IFN-gamma, TNF-alpha or TNF-beta in response to autologous tumor cells. Furthermore, they showed autologous melanoma-specific cytotoxicity only in an 18-hr 51Cr-release assay. Specific IL-4, IL-6 or IL-10 production by the CD4+ M73 T-cell line and its clone was inhibited by anti-class II DR (but not anti-class I) MAb, whereas their specific cytotoxicity was inhibited by anti-class I (but not anti-class II) MAb. Anti-CD3 and -CD4 MAb (but not anti-CD8) abrogated both IL-4, IL6 and IL-10 production and cytotoxicity, while anti-IL-4 antibody did not inhibit cytotoxicity. CD4+ potential T-cell clones, but not CD8+ clones, that were established from freshly isolated TILs without in vitro sensitization by autologous tumor cells also produced IL-4, IL-6 and IL-10 but not IFN-gamma or tumor necrosis factor (TNF) alpha in an autologous tumor-specific fashion. These Th2 cells were neither reactive to EBV-B cells nor suppressive against CD8+ T-cell clones. PMA and PHA stimulated these potential T-cell clones, regardless of their specific lymphokine production, to produce IL-3, IL-4, IL-6, IL-8, IL-10, GM-CSF, TNF alpha and IFN-gamma. Our results demonstrate the presence of autologous tumor-specific Th2 cells at the melanoma sites.
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PMID:Characterization of autologous tumor-specific T-helper 2 cells in tumor-infiltrating lymphocytes from a patient with metastatic melanoma. 791 81

To evaluate the efficacy of vaccinations with cytokine-gene-transduced tumor cells, BALB/c mice were challenged with 1 x 10(5) parental cells of a syngeneic adenocarcinoma cell line (TSA-pc). No protection was observed in mice immunized 30 days earlier with 1 x 10(5) nonreplicating mitomycin-C-treated TSA-pc alone, or with Corynebacterium parvum or Complete Freund Adjuvant (CFA). Ten to 30% of mice immunized with nonreplicating cells engineered to produce interleukin (IL)-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and gamma-interferon gene were protected. Fifty % of mice immunized with replicating TSA-pc admixed with C. parvum and 80-100% of mice immunized with replicating tumor cells transduced with IL-2, IL-4, IL-7, IL-10, or gamma-interferon gene were protected. No cure was afforded by TSA cells admixed with C. parvum or CFA, nor by TSA cells engineered with IL-6, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha gene injected starting 1 day after TSA-pc challenge. Complete tumor regression, however, was obtained in 10-20% of mice treated with TSA cells transduced with IL-2, IL-4, IL-7, or IL-10 and in 30% of those treated with TSA cells transduced with gamma-interferon gene.
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PMID:Immunizing and curative potential of replicating and nonreplicating murine mammary adenocarcinoma cells engineered with interleukin (IL)-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and gamma-interferon gene or admixed with conventional adjuvants. 795 38

In this report, we present evidence that the CTL response directed against MHC Class I allo-determinants can be inhibited as a result of IL-10 expression in vivo. The presence of localized IL-10 secretion at the site of allogeneic tumor cell challenge resulted in marked inhibition of the CTL response and allowed growth of the tumor in the allogeneic host. Using purified CD4+ T cells from mice immunized in the presence or absence of IL-10, we have shown that the loss of alloreactivity as a consequence of IL-10 expression results from the inhibition of CD4+ T cell function. The expression of either IL-2 or IFN-gamma with IL-10 locally at the time of allogeneic cell challenge completely restored CTL alloreactivity, suggesting that the action of IL-10 could be bypassed by providing helper T lymphocyte-derived cytokines of the Th1 type at the site of immunization. Inhibition of alloreactivity by IL-10 was observed using either purified macrophages or dendritic cells as APC in an in vitro assay. Thus, the expression of IL-10 following antigenic challenge (such as that observed in Th2-like immune responses) may profoundly limit the ability for generating functional CTL in vivo.
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PMID:IL-10 inhibits alloreactive cytotoxic T lymphocyte generation in vivo. 799 51

Tumor infiltrating lymphocytes (TIL) of many tumors express surface activation markers. An antigen driven stimulation of T-lymphocytes is expected to induce not only cell membrane activation molecules but also a unique pattern of cytokine gene transcripts. These cytokines are relevant modulators and potent effectors of immune responses, and therefore play a crucial role in tumor-immune system interaction. The gene transcription of interleukin(IL)-2, IL-4, IL-7, IL-10 and interferon(IFN)-gamma of lymphocyte infiltrated, freshly excised tumor specimens from 10 renal cell carcinomas and 6 melanomas were investigated by reverse polymerase chain reaction (PCR) technique. Autologous, peripheral mononuclear cells (PBMC) and healthy tissue of the affected organs served as controls. In all samples the transcription of the beta-actin gene as a methodological control turned out to be positive. In contrast, no cytokine gene transcription was detected in healthy tissue specimens and PBMC. IL-2 transcripts were detectable in no melanomas but in half of the renal tumor samples. IL-10 never transcribed in melanomas but was positive in 7 out of 10 renal cell carcinomas. In only 2 respectively 1 of the resected tissue probes was transcription of IL-4 and IFN-gamma detected. IL-7 was positive in 1 melanoma and in 6 urological neoplasias. The most impressive fact is the frequent transcription of the inhibiting factor IL-10 in renal cell carcinomas (7/10). This pattern of cytokine gene transcription may explain functional deficits of TIL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Tumor-immune system interaction in renal cell carcinoma and melanomas. Cytokine transcription in tumors at the time of surgical resection]. 802 72

In vitro-activated macrophages (Mphi) co-express cytotoxicity for tumor cells and suppression of lymphocyte proliferation. These Mphi functions increase during tumor growth and are mediated by soluble molecules. Because Mphi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Meth-KDE) growth increased Mphi-mediated suppression of T cell proliferation by increasing Mphi NO and TNF-alpha production. Tumor-bearing host peritoneal Mphi produced more NO and TNF-alpha than normal host Mphi when activated with IFN-gamma or LPS, respectively. This tumor-induced increase in Mphi NO and TNF-alpha production mediated suppression of alloantigen-driven T cell proliferation, because treatment with either NG-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bearing host Mphi-mediated suppression. TNF-alpha did not directly suppress T cells, but it induced Mphi NO production that down-regulated proliferation. When non-tumor-infiltrating peritoneal Mphi were cultured with Meth-KDE cell supernatants, Mphi production of NO and TNF-alpha was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta 1, and prostaglandin E2. The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Recombinant forms of these cytokines suppressed NO and TNF-alpha production. 3) Ab-mediated absorption of these cytokines from tumor cell supernatants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TGF-beta 1 Ab addition to IFN-gamma-stimulated Mphi restored NO production. Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed Mphi NO and TNF-alpha production, which was partly mediated by TGF-beta 1 and prostaglandin E2. Collectively, these results suggest that tumor growth promotes distal Mphi suppressor activity by increasing Mphi production of cytotoxic molecules and concomitantly down-regulating the local production of these antitumor molecules.
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PMID:Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-alpha production. Role of tumor-derived IL-10, TGF-beta, and prostaglandin E2. 804 39

Murine IL-10, initially identified as a product of Th2 CD4+ T cell clones, is known to be produced by a variety of hematopoietic cells. The cellular and tissue expression of IL-10 in vivo is not known and could be relevant to understanding its functions. We examined in vivo, expression of IL-10 mRNA using RT-PCR in various normal and mutant mice and after irradiation. In addition, expression was studied during rejection of an i.p. injection of P815 tumor cells. Total RNA was extracted from whole organs; standard RT-PCR, semiquantitative PCR, and RNase protection assays were performed. In normal mice IL-10 mRNA was detectable in all tissues surveyed. Semiquantitative PCR allowed an estimation of the relative levels of IL-10 mRNA in tissues. IL-10 mRNA in spleen and kidney of nude mice and SCID mice was detectable in normal amounts. Expression of IL-10 mRNA was increased in spleen and kidney in a dose-dependent fashion after irradiation. During allogeneic stimulation IL-10 mRNA was increased in spleen and kidney as demonstrated by the PCR and RNase protection assays. In conclusion, IL-10 mRNA is detectable by PCR in many organs of normal mice and is largely T and B cell-independent. The increase of IL-10 mRNA in spleen and kidney during an intraperitoneal T cell response, at a time when IFN-gamma mRNA is known to be increased in the same organs, suggests a complex systemic interaction between IL-10 and other cytokines during rejection. Moreover, the ubiquitous tissue distribution and the increased levels of steady state IL-10 mRNA after irradiation suggest that this molecule plays a general role in the biology of all tissues and may explain some of the immunosuppressive effects of ionizing radiation.
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PMID:Tissue distribution of IL-10 mRNA in normal mice. Evidence that a component of IL-10 expression is T and B cell-independent and increased by irradiation. 811 46

Exposure to UV radiation suppresses tumor rejection and delayed-in-time hypersensitivity reactions and depresses splenic APC function. Because almost all of the UV radiation is absorbed in the upper layers of the skin, it appears unlikely the direct irradiation of APC can account for the impaired ability of splenic adherent cells to present Ag after total-body UV exposure. Because UV-irradiated keratinocytes release IL-10, and in light of the well-documented effects of IL-10 on Ag presentation, we tested the hypothesis that keratinocyte-derived IL-10 is responsible for the systemic impairment of APC function following UV exposure. Injecting supernatants from UV-irradiated keratinocytes suppressed the ability of splenic adherent cells to present Ag. Treating the supernatants with anti-IL-10 mAb neutralized the suppressive effect. Similarly, when splenic adherent cells were isolated from mice exposed to UV radiation, APC function was suppressed. Injecting the UV-irradiated animals with anti-IL-10 restored APC function. In addition, spleen cells from UV-irradiated mice did not efficiently present Ag to Th1 clones, and injecting anti-IL-10 after UV exposure restored APC function. The reverse was observed when spleen cells from UV-irradiated mice were used to present Ag to Th2 clones; in which case, UV exposure enhances APC function, and anti-IL-10 reverses this effect. These findings suggest that UV-induced, keratinocyte-derived IL-10 can modulate splenic APC function.
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PMID:Mechanism involved in the systemic suppression of antigen-presenting cell function by UV irradiation. Keratinocyte-derived IL-10 modulates antigen-presenting cell function of splenic adherent cells. 814 24

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