Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that the antibody fusion proteins anti-HER2/neu IgG3 fused to IL-12 [(IL-12)-IgG3] or GM-CSF [IgG3-(GM-CSF)] independently or in combination are effective anti-tumor agents against D2F2/E2 murine mammary cancer cells expressing human HER2/neu in the peritoneum. Importantly, the long-term survivors were immune to the subcutaneous challenge with D2F2/E2 and the parental D2F2 not expressing HER2/neu. We now show that these long-term survivors also exhibit significant protection against subsequent subcutaneous challenge with the murine colon carcinoma CT26-HER2/neu, and later against subcutaneous challenge with the parental CT26. These results suggest that the long-term systemic protection against mammary cancer elicited by treatment with antibody-cytokine fusion proteins can be extended to prevent the growth of a tumor from different origin expressing HER2/neu, and that this protection is not limited to this antigen alone, since it also prevented the growth of the parental tumor cells.
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PMID:Long-term immunity elicited by antibody-cytokine fusion proteins protects against sequential challenge with murine mammary and colon malignancies. 1731 Mar 81

Mutations in the p53 tumor suppressor are very frequent in human cancer. Often, such mutations lead to the constitutive overproduction of mutant p53 proteins, which may exert a cancer-promoting gain of function. We now report that cancer-associated mutant p53 can augment the induction of nuclear factor kappaB (NFkappaB) transcriptional activity in response to the cytokine tumor necrosis factor alpha (TNFalpha). Conversely, down-regulation of endogenous mutant p53 sensitizes cancer cells to the apoptotic effects of TNFalpha. Analysis of human head and neck tumors and lung tumors reveals a close correlation between the presence of abundant mutant p53 proteins and the constitutive activation of NFkappaB. Together, these findings suggest that p53 mutations may promote cancer progression by augmenting NFkappaB activation in the context of chronic inflammation.
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PMID:Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor alpha in cancer cells. 2633 8

Proinflammatory cytokines induce both sickness behavior and depression, but their respective neurobiological correlates are still poorly understood. The aim of the present study was therefore to identify in mice the neural substrates of sickness and depressive-like behavior induced by lipopolysaccharide (LPS, 830 microg/kg, intraperitoneal). LPS-induced depressive-like behavior was dissociated from LPS-induced sickness by testing mice either at 6 h (at which time sickness was expected to be maximal) or at 24 h post-LPS (at which time sickness was expected to be minimal and not to bias the measurement of depressive-like behavior). Concurrently, the expression of acute and chronic cellular reactivity markers (c-Fos and FosB/DeltaFosB, respectively) was mapped by immunohistochemistry at these two time points. In comparison to saline, LPS decreased motor activity in a new cage at 6 h but not at 24 h. In contrast, the duration of immobility in the tail suspension test was increased at both 6 and 24 h. This dissociation between decreased motor activity and depressive-like behavior was confirmed at 24 h post-LPS in the forced swim test. LPS also decreased sucrose consumption at 24 and 48 h, despite normal food and water consumption by that time. At 24 h post-LPS, LPS-induced depressive-like behavior was associated with a delayed cellular activity (as assessed by FosB/DeltaFosB immunostaining) in specific brain structures, particularly within the extended amygdala, hippocampus and hypothalamus, whereas c-Fos labeling was markedly decreased by that time in all the brain areas at 6 h post-LPS. These results provide the first evidence in favor of a functional dissociation between the brain structures that underlie cytokine-induced sickness behavior and cytokine-induced depressive-like behavior, and provide important cues about the neuroanatomical brain circuits through which cytokines could have an impact on affect.
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PMID:Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. 1748 71

Firefly luciferase (Fluc) has been widely used as a reporter gene. The aim of this study was to investigate immune response to luciferase protein after an intradermal injection of pcDNA3.1-Fluc in immunocompetent BALB/c mice. We observed bioluminescence at injection sites from one to seven days post-injection when pcDNA3.1-Fluc was intradermally injected into ear-pinnae. To observe induced immune response, the percentages of CD8+IFNgamma+ cells in the draining lymphoid cells of immunocompetent BALB/c mice immunized by pcDNA3.1-Fluc were measured. And the tumor growths of CT26/Fluc in pcDNA3.1-Fluc group were monitored by observing bioluminescent signals and measuring tumor mass, and these were compared with those of the pcDNA3.1 group in immunocompetent BALB/c mice and immunodeficient Nu/Nu mice. In the immunocompetent BALB/c mice, percentages of CD8+IFNgamma+ cells in the pcDNA3.1-Fluc group were higher than those in the pcDNA3.1 group. Ten days after tumor inoculation, tumor growth inhibition was found in the pcDNA3.1-Fluc group, but not in the pcDNA3.1 group in the immunocompetent BALB/c mice. No significant difference in tumor growth inhibition was observed when CT26/Fluc was injected into immunodeficient Nu/Nu mice. In terms of cytokine profiles of draining lymphoid cells of immunized mice, IFNgamma protein levels in the pcDNA3.1-Fluc group were higher than in pcDNA3.1 group animals among the immunocompetent BALB/c mice. In conclusion, Fluc induced a Th1 immune response to Fluc protein delivered by injecting pcDNA3.1-Fluc into immunocompetent BALB/c mice. We suggest that immune response to the Fluc gene is cautionary in preclinical or clinical trials involving the Fluc gene, and that the immunologic potential of firefly luciferase as a naked DNA may be useful in cancer immunotherapy.
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PMID:Immune response to firefly luciferase as a naked DNA. 1749 21

In cancer-related anorexia, body weight loss is paradoxically associated with reduced appetite, which is contrary to the situation during starvation, implying that the normal coupling of food intake to energy expenditure is disarranged. Here we examined brainstem mechanisms that may underlie suppression of food intake in a rat model of cancer anorexia. Cultured Morris 7777 hepatoma cells were injected subcutaneously in Buffalo rats, resulting in slowly growing tumor and reduced food intake and body weight loss after about 10 days. The brainstem was examined for induced expression of the transcription factors Fos and FosB as signs of neuronal activation. The results showed that anorexia and retarded body weight growth were associated with Fos protein expression in the area postrema, the general visceral region of the nucleus of the solitary tract, and the external lateral parabrachial nucleus, structures that also display Fos after peripheral administration of satiating or anorexigenic stimuli. The magnitude of the Fos expression was specifically related to the size of induced tumor, and not associated with weight loss per se, because it was not present in pair-fed or food-deprived rats. It also appeared to be independent of proinflammatory cytokines, as determined by the absence of increased cytokine levels in plasma and induced cytokine and cyclooxygenase expression in the brain. The findings thus provide evidence that cancer-associated anorexia and weight loss in this model is associated with activation of brainstem circuits involved in the suppression of food intake, and suggest that this occurs by inflammatory-independent mechanisms.
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PMID:Identification of rat brainstem neuronal structures activated during cancer-induced anorexia. 1764 50

Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.
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PMID:Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. 1798 62

Treatment with pro-inflammatory cytokine, IFNalpha was documented to result in neuropsychiatric complications including depression and treatment with antidepressant, paroxetine could improve the depressive symptoms. Therefore, the effects of IFNalpha on behaviour and cytokine changes in the whole blood culture and in the prefrontal cortex, hypothalamus and hippocampus areas of the brain in wistar rats were investigated with emphasis on the role of paroxetine in the prevention of depressive behaviour induced by pro-inflammatory cytokines. The group of rats treated with IFNalpha (s.c. 50,000 IU/kg for 3 days/week for 5 weeks) was compared with three other groups; 1) saline control group (s.c. normal saline 0.2 ml/kg/day for 7 weeks), 2) paroxetine control group (paroxetine suspension orally 10 mg/kg/day for 7 weeks) and 3) group treated with paroxetine for 2 weeks followed by IFNalpha for 5 weeks. In open filed, the IFNalpha treated rats showed anxiety behaviour compared to the rats from the other groups. There was no significant difference in home cage emergence test, Morris water maze and object recognition test. There is no significant difference in plasma corticosterone between groups. The pro-inflammatory cytokines (TNFalpha, IL1beta and IFNgamma), were significantly higher whereas the anti-inflammatory cytokine, IL10 was lower in the stimulated whole blood culture of IFNalpha treated rats. In the brain, both pro-inflammatory cytokine IL1beta and anti-inflammatory cytokine IL10 were higher in hypothalamus of the IFNalpha treated rats; by contrast the concentration of IL10 was lowest in hippocampus region of this group compared to the other groups. The paroxetine pretreated rats did not show these cytokine changes following IFNalpha treatment. Thus it appears that paroxetine pretreatment prevents the pro-inflammatory changes in blood and brain following IFNalpha treatment in turn prevents the anxiety behaviour.
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PMID:Role of paroxetine in interferon-alpha-induced immune and behavioural changes in male Wistar rats. 1798 61

Glucocorticoid-induced TNF receptor family related protein (GITR) is a member of the TNFR superfamily. Previous studies have shown that in vivo administration of a GITR agonistic Ab (DTA-1) is able to overcome tolerance and induce tumor rejection in several murine syngeneic tumor models. However, little is known about the in vivo targets and the mechanisms of how this tolerance is overcome in a tumor-bearing host, nor is much known about how the immune network is regulated to achieve this antitumor response. In this study, we demonstrate that the in vivo ligation of GITR on CD4(+) effector T cells renders them refractory to suppression by regulatory T (T(reg)) cells in the CT26 tumor-bearing mouse. GITR engagement on T(reg) cells does not appear to directly abrogate their suppressive function; rather, it increases the expansion of T(reg) cells and promotes IL-10 production, a cytokine important for their suppressive function. Moreover, CD4(+) effector T cells play a crucial role in mediating DTA-1-induced immune activation and expansion of CD8(+), NK, and B cells in the tumor-draining lymph nodes. This includes increased CD69 expression on all of these subsets. In addition, NK and tumor-specific CD8(+) T cells are generated that are cytolytic, which show increased intracellular IFN-gamma production and CD107a mobilization, the latter a hallmark of cytolytic activities that lead to tumor killing.
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PMID:Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors. 1802 80

Recent findings from our laboratory and others indicate that exposure to stress can increase expression of the pro-inflammatory cytokine interleukin-1 (IL-1). In a series of studies examining this response, we observed pronounced differences in baseline levels of hypothalamic IL-1 of pair-housed rats. We hypothesized that these pair-wise differences might be a result of prolonged social stress associated with dominance/submissiveness, and that the submissive animal would show heightened baseline levels of IL-1. In order to test this hypothesis, we utilized a food competition paradigm (access to cheerios) to assess dominance within a dyad prior to the assessment of hypothalamic IL-1 levels. Based on the results of this test, clear dominance hierarchies were observed in approximately 50% of the dyads, a ratio comparable to what has been reported previously. More importantly, this dominant/submissive categorization could be used to predict pair-wise differences in hypothalamic IL-1 with greater than 90% accuracy. Specifically, the submissive rat in each dyad (determined a priori) consistently evinced hypothalamic IL-1 levels that were nearly double that of its dominant cage mate. Further studies demonstrated that submissive rats showed a more rapid and pronounced hyperthermic response to novel environment stress relative to dominant rats. Interestingly, social status had no effect on corticosterone reactivity, even when the nature and intensity of the stressor was varied. Finally, maintenance of a clear dominance hierarchy obfuscated hypothalamic IL-1 responses to footshock exposure, with the most robust increases in hypothalamic IL-1 provoked by footshock being observed in pairs where there was no clear dominance hierarchy. Together, these findings suggest that social status can have a significant impact on stress reactivity and neuroimmune consequences of stressor exposure even in the unperturbed home cage environment.
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PMID:Social status modulates basal IL-1 concentrations in the hypothalamus of pair-housed rats and influences certain features of stress reactivity. 1803 66

Hepatocellular carcinoma (HCC) is a male-predominant cancer associated with chronic hepatitis. Like human viral hepatitis, murine Helicobacter hepaticus infection produces inflammation and HCC with a masculine bias. We used this model to identify potential mechanisms of male HCC predisposition. Male weanling A/JCr mice (n = 67) were gavaged with H. hepaticus or vehicle. At 1 year, mice were distributed into four groups: surgical castration, chemical castration, castration followed by dihydrotestosterone supplementation, or sexually intact controls. Responses to infection were compared with IFN-gamma challenge alone. At 21 months, there was no significant difference in hepatitis between groups. Neither castration nor androgen receptor agonism altered tumor incidence. Infected mice with severe, but not mild, disease exhibited a mosaic of alterations to sexually dimorphic genes and microsomal long-chain fatty acids. By microarray, tumorigenic hepatitis was strongly associated with liver-gender disruption, defined as the loss of a gender-identifying hepatic molecular signature. IFN-gamma alone produced similar changes, demonstrating a role for proinflammatory cytokines in this process. In conclusion, hepatocarcinogenesis in male mice with chronic hepatitis is maturationally imprinted and androgen-independent. Proinflammatory cytokines may promote HCC in a male-predominant fashion due to high sensitivity of the masculinized liver to loss of sex-specific transcriptional balance. Liver-gender disruption has pleiotropic implications for hepatic enzyme activity, lipid processing, nuclear receptor activation, apoptosis, and proliferation. We propose a multistep model linking chronic hepatitis to liver cancer through cytokine-mediated derangement of gender-specific cellular metabolism. This model introduces a novel mechanism of inflammation-associated carcinogenesis consistent with male-predominant HCC risk.
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PMID:Hepatocellular carcinoma associated with liver-gender disruption in male mice. 1808 82


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