Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00017 (IFN-gamma)
 28,919 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant interferon-gamma (rIFN-gamma) is currently undergoing clinical trials in cancer patients. In this paper, we assessed the in vivo antitumor effects of this lymphokine in rodents. Recombinant murine IFN-gamma or control medium was injected intraperitoneally for 5 days into mice with subcutaneous Meth A tumors. An injection of a suboptimal dose of endotoxin (2 micrograms) on the fifth treatment day caused significant necrosis of tumors in the IFN-gamma-treated group while causing essentially no necrosis of tumors in the control group. Next, we examined macrophages isolated from rats treated for 9 days with either IFN-gamma or saline. Endotoxin stimulated release of significantly higher amounts of TNF-alpha from macrophages from the IFN-gamma-treated group compared to macrophages from the control group. A polyclonal antiserum against recombinant murine TNF-alpha abrogated all of the TNF cytotoxic activity from these rat macrophage supernatants, while control rabbit serum had no effect. These results provide strong evidence that rIFN-gamma can prime macrophages in vivo for TNF-alpha synthesis.
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PMID:In vivo effects of recombinant interferon-gamma: augmentation of endotoxin-induced necrosis of tumors and priming of macrophages for tumor necrosis factor-alpha production. 211 81

The Ly-6 locus contains multiple genes encoding cell surface proteins, two of which, when cross-linked by antibodies, effect antigen-independent activation of T lymphocytes. In this study, cDNA for Ly-6-encoded antigens have been used as probes to examine RNA from various tissues and transformed cell lines for constitutive levels of Ly-6 RNA expression. Analyses of RNA prepared from several different tissues revealed a high level of expression of Ly-6 RNA in kidney, spleen, heart and thymus, with a more moderate level of expression in liver, brain and lung tissue cells. A survey of various cell lines demonstrated the presence of Ly-6 RNA in many, but not all T lymphocytic cell lines, in L cells, the Meth A fibrosarcoma, in the TCMK kidney cell line, and in the Neuro-2a neuroblastoma. We also evaluated the expression of Ly-6 RNA in cells after treatments with interferons (IFN) and interleukin 1 (IL1). Treatment of lymphoid cells with IFN (alpha/beta and gamma), known to increase cell surface Ly-6 antigen expression in normal T cells, was correlated with increases in Ly-6 RNA levels. Increases in levels of RNA correlated with increases in levels of the Ly-6A/E or Ly-6C antigens. Several T lymphoid cell lines exhibiting Ly-6 RNA inducibility by IFN were similarly inducible with IL1. Kinetic experiments using one such line, (YAC-1), showed that the induction of Ly-6 RNA mediated by IFN-alpha/beta occurred rapidly (within 4 h), while the induction by IL1 required relatively more time (approximately 8 h). Although the actions of IFN-alpha/beta were not blocked by cycloheximide, the presence of this protein synthesis inhibitor significantly attenuated the effects of IL1 and IFN-gamma on Ly-6 RNA transcription. Induction by IFN-gamma as well as IL1 could be blocked completely by co-culture with anti-IFN-gamma, implicating IFN-gamma as a mediator of the induction by IL1.
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PMID:Kinetic analysis of Ly-6 gene induction in a T lymphoma by interferons and interleukin 1, and demonstration of Ly-6 inducibility in diverse cell types. 247 47

The development of non-specific resistance to tumors following stimulation with poly(maleic-acid-styrene)-conjugated neocarzinostatin (SMANCS), a polymer-conjugated derivative of neocarzinostatin, was investigated in mice. The growth of syngeneic solid tumors (Meth-A fibrosarcoma and RL male 1 leukemia) inoculated into BALB/c mice was suppressed after one treatment with SMANCS at doses ranging from 0.14 mg/kg to 3.4 mg/kg i.v. 24 h before tumor implantation. Since previously observations concerning SMANCS have shown that it disappeared within 1.5 h after i.v. administration in mice and that it was inactivated quickly in plasma, SMANCS evidently inhibited tumor growth by mediating non-specific resistance. In addition, the non-specific resistance to tumors stimulated by SMANCS could be passively transferred to untreated mice by serum which was shown to contain interferon (IFN) from 12 h to 20 h after SMANCS administration. However, the resistance was not produced by serum prepared from mice at 8 h or 32 h after administration presumably because of the observation that the interferon activity was only demonstrated from 12 h to 28 h after SMANCS stimulation. When the serum specimens were treated with anti-IFN-gamma antiserum, the antitumor activity of the sera was abrogated. However, no significant change was detected in the antitumor activity of the specimens following treatment with anti-IFN-alpha/beta antiserum. Treatment of mice with SMANCS and anti-IFN-gamma antiserum together resulted in the elimination of the non-specific resistance to tumors. The IFN induced in the sera of mice by SMANCS was shown to be 57% IFN-gamma and 41% IFN-alpha/beta. Half of the interferon produced in SMANCS-stimulated mice could be eliminated by treatment with anti-IFN-gamma, and treatment of SMANCS-stimulated mice with both anti-IFN-gamma and anti-IFN-alpha/beta antisera resulted in a total absence of detectable interferon. These findings suggest that while the administration of SMANCS induces both IFN-gamma and IFN-alpha/beta production, in this case, it is only the former which mediates the non-specific resistance to tumors.
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PMID:Stimulation of non-specific resistance to tumors in the mouse using a poly(maleic-acid-styrene)-conjugated neocarzinostatin. 248 Aug 46

We investigated the characteristics of macrophage-mediated tumor cytotoxicity (MTC) against Meth A target, H2O2 generation and release of effector molecule(s) for MTC, by comparing with those of peritoneal macrophages (PMP) and macrophage cell line J774.1 during stimulation with recombinant gamma interferon (IFN-gamma). In PMP, MTC was demonstrated when they were stimulated with IFN-gamma for 12 hr (short-term stimulation) and was abrogated when they were stimulated for 48 hr (long-term stimulation). Enhanced H2O2 generation was observed in PMP activated by long-term stimulation followed by triggering with PMA, but not observed by triggering with Meth A cells. By contrast, whereas non-treated J774.1 cells have already attained a definite level of MTC, a higher MTC level was demonstrated both by short- and long-term stimulations. Conversely, J774.1 cells were unable to generate H2O2 at any stage of IFN-gamma stimulation followed by triggering both with PMA or Meth A cells. The time course for stimulation of PMP by IFN-gamma for release of cytotoxic factor (CF) corresponded to that for MTC by PMP, and activities of the CF released from both activated PMP and J774.1 cells also closely corresponded to those of MTC by both cells. The serological and physicochemical characteristics of CF released from both activated PMP and J774.1 cells were determined to be closely related to those of tumor necrosis factor (TNF). These results indicate that in contrast to PMP, the J774.1 cell line is free from suppression stage for MTC and CF release during stimulation with IFN-gamma. The results suggest that TNF-like CF plays a crucial role for MTC against Meth A target, and that H2O2 is irrelevant for MTC against Meth A.
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PMID:Characteristics of macrophage activation by gamma interferon for tumor cytotoxicity in peritoneal macrophages and macrophage cell line J774.1. 251 28

The production of alpha, beta and gamma interferons (IFN) and interleukin 2 (IL-2) by Lyt-2+-dependent cytotoxic T-cell lines/clones was investigated. Cloned and uncloned T-cell lines specific for H-2Dd or the unique RL male 1 leukemia antigen were studied. After infection with Sendai virus (SV) or Newcastle disease virus (NDV) all cell lines produced IFN-alpha and -beta. Induction of IFN-gamma was attempted with the mitogens Con A, PHA, PWM, SEA, and SEB, with poly(I:C), with antibodies Lyt-1.2, -2.2, and Thy-1.2, or with the target cells Meth A (H-2Dd+) and RL male 1. All mitogens were effective inducers. However, the antibodies and poly(I:C) were not. One uncloned RL male 1-specific cell line CTLL-RP, produced IFN-gamma after induction with RL male 1. Production of IFN-alpha, beta depended on IL-2, whereas production of IFN-gamma did not, although addition of highly purified IL-2 increased IFN-gamma production even in the absence of other inducers. Crude IL-2 inhibited the production of IFN-gamma but not IFN-alpha, beta. In response to mitogens, some T-cell clones also produced IL-2. The results demonstrate that Lyt-2+ cells can produce a broad spectrum of lymphokine activities after appropriate stimulation. Their availability now affords us the opportunity to study the regulation of lymphokine production at the clonal level.
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PMID:Characterization of interleukin 2-dependent cytotoxic T-cell clones. IV. Production of alpha, beta and gamma interferons and interleukin 2 by Lyt-2+ T cells. 619 26

Recent reports on the antitumor activity of interferon-gamma were reviewed and compared to a study on interferon-alpha beta. Secondly our results on the antitumor effects of murine IFN-gamma on Meth-A sarcoma in syngeneic BALB/c mice were described in detail. Topical injection of IFN-gamma to the tumor site, Winn neutralization test of IFN-gamma activated spleen cells and adoptive transfer of IFN-gamma activated cells to the tumor site all resulted in positive antitumor effects. Finally, data on clinical trials of natural and recombinant IFNs presented at the 13th International Congress of Chemotherapy were summarized and the development of future IFN research was discussed.
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PMID:[Antitumor effect of interferons]. 642 Dec 41

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

Soluble effector molecules involved in the rejection of allografted mouse Meth A (3-methylcholanthrene-induced ascites type tumor) cells were examined. A potent antiproliferative activity against the tumor cells was detected in the culture supernatant of leukocytes that had infiltrated into the peritoneal cavity of C57BL/6 mice on days 6-8 after transplantation, when the i.p. transplanted Meth A cells were undergoing rejection. Studies with neutralizing antibodies indicated that both IFN-gamma and IL-1 alpha/beta were required for the activity but that TNF-alpha was not. Actually, mouse rIFN-gamma and rIL-1 alpha/beta used, at the concentrations found in the culture supernatant determined by ELISA, were able to reconstitute the potent antiproliferative activity, although each cytokine alone had a weak growth inhibitory activity against Meth A cells. The half-maximal inhibition was observed with 0.02-0.03 U/ml of rIL-1 alpha/beta at 1-100 U/ml of rIFN-gamma. The synergistic growth inhibitory effect of these cytokines also was observed with four of 15 mouse transformed cell lines tested, indicating that the effect was not specific to Meth A cells. These findings suggest that IFN-gamma and IL-1 alpha/beta participate as soluble effector molecules in the rejection of some allografted tumor cells including Meth A cells.
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PMID:Synergism between IFN-gamma and IL-1 alpha/beta in growth inhibition of an allografted tumor. 834 96

We observed that an influenza-specific cytotoxic T lymphocyte (CTL) clone (B7B7) stimulated with peptide-antigen could produce TNF-alpha and IFN-gamma simultaneously. The culture supernatant containing both TNF-alpha and IFN-gamma of antigen-stimulated CTL clone B7B7 significantly enhanced the lysis of influenza A/PR/8 virus-infected L-M2d6 cells or Meth A cells. Enhanced lysis of influenza virus-infected cells by the supernatants was inhibited by pretreatment of the supernatant with antimurine TNF-alpha antibody and antimurine IFN-gamma antibody. In addition to a single CTL clone, we observed that bulk-cultured CTLs were able to produce TNF and IFN when incubated with target cells. These results suggest that the protective mechanism mediated by TNF-alpha and IFN-gamma secreted from CTL may be possible in the course of an influenza infection.
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PMID:Antiviral effect of TNF-alpha and IFN-gamma secreted from a CD8+ influenza virus-specific CTL clone. 847 5

The use of interleukin-2 (IL-2) in the treatment of cancer has shown limited efficacy and dose-limiting toxicity. Combination therapy with other cytokines and/or chemotherapeutic agents has been attempted to enhance the antitumor activity and to reduce the effective therapeutic dose of IL-2. We recently showed, in vitro and in vivo, a synergistic activity between the synthetic immunomodulator murabutide, which is in clinical stage of development, and another therapeutic cytokine, interferon-alpha (IFN-alpha). The present study was performed to assess a possible potentiation of the biologic activities of IL-2 by its association with murabutide. Human PBMC stimulated in vitro with IL-2 and murabutide showed synergistic levels of induced mRNA accumulation and protein secretion for IFN-gamma, IL-12, and colony-stimulating factors (CSFs). No such effects were obtained on the induction of most inflammatory cytokines, including IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha). Furthermore, the combined administration of murabutide with IL-2 into Meth-A sarcoma-bearing mice resulted in a very significant tumor inhibition as well as in complete tumor regression in nearly 70% of the treated mice. Under the same conditions, treatment with either compound separately had little or no antitumor effect. These preclinical findings will be pursued by the evaluation of the clinical tolerance and biologic activity of the murabutide/IL-2 combination therapy in cancer patients.
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PMID:Synergistic effects between recombinant interleukin-2 and the synthetic immunomodulator murabutide: selective enhancement of cytokine release and potentiation of antitumor activity. 874 70


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