Diminished PKC activity and decreased binding of transcription factors are involved in the impaired production of nitric oxide by macrophages from tumor-bearing mice

Napoli, Michael R. Di; Torroella-Kouri, Marta; Perry, Giselle; López, Diana M.

doi:10.3892/ijmm.15.3.503

Cited by 3 publications

(4 citation statements)

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“…Deficient nuclear factor nB (NFnB) and CCAAT/enhancer binding protein (C/EBP) expressions, as well as diminished nuclear translocation and DNA binding activities of these transcription factors, were observed in host macrophages. Because similar findings have been noted in studies of the iNOS gene promoter of tumor bearers' macrophages (16), these functional dysregulations may represent a manifestation of a more general phenomenon by which tumorderived factors contribute to tumor evasion by interfering with the expression and function of key transcription factors.…”

Section: Introductionmentioning

confidence: 58%

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Diminished Expression of Transcription Factors Nuclear Factor κB and CCAAT/Enhancer Binding Protein Underlies a Novel Tumor Evasion Mechanism Affecting Macrophages of Mammary Tumor–Bearing Mice

Torroella-Kouri

Perry

et al. 2005

Cancer Research

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Interactions between malignant tumors and the host immune system shape the course of cancer progression. The molecular basis of such interactions is the subject of immense interest. Proinflammatory cytokines produced by macrophages are critical mediators of immune responses that contribute to the control of the advancement of neoplasia. We have shown that the expressions of interleukin 12 (IL-12) and inducible nitric oxide synthase (iNOS) are decreased in macrophages from mammary tumor-bearing mice. In this study, we investigated the causes of IL-12 dysregulation and found deficient nuclear factor KB (NFKB) and CCAAT/enhancer binding protein (C/EBP) expression and function in tumor bearers' peritoneal macrophages. The constitutive expressions of NFKB p50, c-rel, p65, and C/EBPA and B, as well as the lipopolysaccharideinduced nuclear translocation and DNA binding of NFKB components and C/EBPA and B, are profoundly impaired in macrophages from mice bearing D1-DMBA-3 tumors. Because similar findings occur with the iNOS gene, it seems that it represents a novel mechanism by which tumor-derived factors interfere with the host immune defenses. (Cancer Res 2005; 65(22): 10578-84)

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Section: Introductionmentioning

confidence: 58%

“…Isolation of nuclear extracts, sequences, preparation of oligonucleotide probes, electrophoretic mobility shift assay (EMSA), and supershift assays were conducted as previously described (15,16); all antibodies used were from Santa Cruz Biotechnology (Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

Diminished Expression of Transcription Factors Nuclear Factor κB and CCAAT/Enhancer Binding Protein Underlies a Novel Tumor Evasion Mechanism Affecting Macrophages of Mammary Tumor–Bearing Mice

Torroella-Kouri

Perry

et al. 2005

Cancer Research

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“…In this regard, we have shown that although macrophages from tumor-bearing mice activated with LPS have significantly diminished levels of NO, dual stimulation of these cells with LPS and IFN-γ, results in their normal production of NO (3,7). Further analysis of macrophages from tumorbearing mice have shown that these cells display a diminished PKC activity and a decreased binding activity of transcription factors such as NFκB that appear to lead to their impaired production of NO as compared to the levels seen in macrophages from normal mice (8). In this study, an investigation of the mechanisms by which PS-pretreatment affects the synthesis of iNOS by macrophages was undertaken.…”

Section: Involvement Of Protein Kinase C and Not Of Nfκ κB In The Modmentioning

confidence: 99%

“…Electrophoretic mobility shift assay. Isolation of nuclear extracts, sequences and preparation of oligonucleotide probes, EMSA and supershift assays were conducted as previously described (8); all antibodies used were from Santa Cruz Biotechnologies (Santa Cruz, CA). Briefly, ten million N-PEM pretreated or not with PS were activated with LPS (10 μg/ml) for 4 h prior to the extraction of nuclear proteins.…”

Section: Reagents Lipopolysaccharide (Lps) [Escherichia Coli 055:b5]mentioning

confidence: 99%

Involvement of protein kinase C and not of NFκB in the modulation of macrophage nitric oxide synthase by tumor-derived phosphatidyl serine

et al. 2008

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Nitric oxide (NO) is one of the main cytotoxic effector molecules involved in the killing of tumor cells by macrophages. In macrophages, lipopolysaccharide (LPS) alone or in combination with IFN-γ causes the generation of NO by an inducible form of NO synthase (iNOS). We have previously reported that macrophages from mammary tumor bearers have a downregulation of their NO production leading to a diminished cytotoxic activity. Further studies lead to the isolation and characterization of phosphatidyl serine (PS) as a NO inhibitory factor produced by mammary tumor cells. Pretreatment of macrophages with PS was shown to downregulate their cytotoxic potential and NO production upon stimulation with LPS. Activation of PS-pretreated macrophages with LPS and IFN-γ resulted in higher levels of NO than those observed with LPS alone, but lower than those of untreated macrophages activated with LPS and IFN-γ. These results correlated with the levels of iNOS RNA as detected by Northern blot analyses. A study of the expression and binding activity of the transcription factor NFκB in macrophages pretreated with PS revealed no differences with untreated macrophages. Investigation of the possible signaling pathways leading to the induction of iNOS revealed that in LPS-stimulated macrophages, increases in internal calcium concentration [Ca 2+ ]i were not observed, while NO was normally produced even under calcium-deprived conditions. In contrast, an effective synergism of IFN-γ with LPS in the production of NO by macrophages required an optimal increase in [Ca 2+ ]i stimulated by IFN-γ. This increment in [Ca 2+ ]i was significantly reduced in PS-pretreated macrophages. Further experiments demonstrated that pretreatment of macrophages with PS did not change the normal pattern of tyrosine phosphorylation stimulated by LPS but strikingly inhibited PKC activity. Combinations of LPS and IFN-γ did not alter the latter result, suggesting that IFN-γ enhances LPS-induction of iNOS through a pathway other than activation of PKC. Importantly, expression of PKC isozymes in both untreated and PS-pretreated macrophages stimulated with LPS remained constant. Out data suggest that, in tumor bearers, PKC and not NFκB is the main target for PS to exert its NO inhibitory action on LPS-activated macrophages. An excess of PS in PS-PKC interaction may be responsible, at least in part, for this type of PKC inhibition. Furthermore, PS also appears to downregulate the rise in [Ca 2+ ]i promoted by IFN-γ in macrophages, reducing the synergism of this cytokine with LPS and leading to a less effective production of NO.

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Immunosuppressive myeloid cells under normal and neoplastic conditions

Hamilton¹

2011

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Diminished PKC activity and decreased binding of transcription factors are involved in the impaired production of nitric oxide by macrophages from tumor-bearing mice

Cited by 3 publications

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Diminished Expression of Transcription Factors Nuclear Factor κB and CCAAT/Enhancer Binding Protein Underlies a Novel Tumor Evasion Mechanism Affecting Macrophages of Mammary Tumor–Bearing Mice

Diminished Expression of Transcription Factors Nuclear Factor κB and CCAAT/Enhancer Binding Protein Underlies a Novel Tumor Evasion Mechanism Affecting Macrophages of Mammary Tumor–Bearing Mice

Involvement of protein kinase C and not of NFκB in the modulation of macrophage nitric oxide synthase by tumor-derived phosphatidyl serine

Immunosuppressive myeloid cells under normal and neoplastic conditions

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