IFN-γ Primes Macrophage Responses to Bacterial DNA

Sweet, Matthew J.; Stacey, Katryn J.; Kakuda, Donald K.; Markovich, Daniel; Hume, David

doi:10.1089/jir.1998.18.263

Cited by 79 publications

(77 citation statements)

References 42 publications

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“…24,25 Using these routes of administration, both free DNA and DNA in complex with cationic liposomes demonstrate an antitumor effect. In addition to its antitumor activity, bacterial DNA is also capable of stimulating a pro-inflammatory cytokine response 9,10,20,23,26 similar to the innate immune response to intracellular infection by bacteria and viruses. It appears that intracellular uptake of specific immunestimulatory CpG motifs are, in part, responsible for eliciting this response.…”

Section: Discussionmentioning

confidence: 99%

LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth

1999

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Our laboratory has recently developed a lipopolyplex response required assembly of DNA into a lipoplex or the consisting of DOTAP:cholesterol liposomes, protamine LPD lipopolyplex. Except for the heart, elevated levels of sulfate, and plasmid DNA (LPD) that provides improved cytokine were observed in all organs (lung, liver, kidney systemic gene delivery compared with lipoplex following and spleen) where LPD is known to have gene transfer tail vein injection in mice. Because endothelial cells are the activity. Methylation of immune-stimulatory CpG motifs in primary cells transfected in the lung, it was hypothesized the plasmid component of LPD inhibited the proinflammathat LPD might be an effective vector for gene therapy of tory cytokine response as well as the antitumor effect of pulmonary metastases. This hypothesis was examined by LPD in both tumor systems. This suggests that i.v. administesting the efficacy of cytokine (IL-12) and tumor suptration of LPD elicits a systemic proinflammatory cytokine pressor (p53) strategies for treatment of an experimental response that mediates the antitumor activity of the lipopomodel of pulmonary metastasis in C57Bl/6 mice. Surprislyplex. In addition, the antitumor activity was not observed ingly, all LPD complexes including those containing an in SCID mice suggesting a possible role for B or T lympho-'empty' plasmid provided a potent (Ͼ50% inhibition) and cytes in the antitumor response initiated by LPD. This repdose-dependent antitumor effect, compared with dextroseresents the first demonstration that an intravenously treated controls. In addition, i.v. injections of LPD containadministered cationic liposome-based nonviral vector can ing 'empty' plasmid also inhibited tumor growth in a subcutpromote a systemic, Th1-like innate immune response. aneous model of C3 fibrosarcomma. The antitumor effectThe immune adjuvant properties of LPD might prove to be correlated well with a strong and rapid proinflammatory suitable for delivering tumor-specific antigens in the context cytokine (TNF-␣, IL-12 and IFN-␥) response. Naked plasof DNA vaccination. mid DNA did not elicit a cytokine response and the

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Section: Discussionmentioning

confidence: 99%

LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth

1999

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“…ICAM-1 expression was examined using a phycoerythrin (PE)-labeled mouse anti-human mAb against ICAM-1 (HA58). FITC-labeled IgG 1 , (MOPC-21) and PE-labeled IgG 2b , (27)(28)(29)(30)(31)(32)(33)(34)(35) were used to control for specific staining.…”

Section: Surface Antigen Stainingmentioning

confidence: 99%

“…CpG stimulates murine macrophages to release IL-12 and tumor necrosis factor (TNF), 28,29 two key cytokines in immune regulation. 30,31 Murine NK cells produce IFN-␥ in response to CpG-induced TNF and IL-12 production by macrophages.…”

Section: Introductionmentioning

confidence: 99%

“…[32][33][34] IFN-␥ in turn costimulates macrophages for enhanced TNF and IL-12 synthesis. 29 Murine B-lymphocytes are directly activated by CpG to proliferate and to secrete Ig and IL-6. 5,[35][36][37] In contrast, in humans CpG-mediated induction of cytokines 9,34,38,39 and induction of B cell proliferation [40][41][42] is less well characterized.…”

Section: Introductionmentioning

confidence: 99%

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CpG DNA and LPS induce distinct patterns of activation in human monocytes

1999

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“…In comparison to the response to LPS, CpG DNA was as effective at increasing TNF-␣ mRNA in bone marrow-derived murine macrophages, whereas it was a less effective inducer of IL-1␤ and plasminogen activator inhibitor type-2 and did not, by itself, lead to production of inducible nitric oxide synthase (iNOS) [12,24]. In mixed spleen cell culture, CpG DNA-induced macrophage IL-12 promotes interferon-␥ production by NK cells [25,26].…”

Section: Recognition Of Cpg Dnamentioning

confidence: 99%

The actions of bacterial DNA on murine macrophages

Sester

Stacey

Sweet

et al. 1999

Journal of Leukocyte Biology

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Murine macrophages are able to distinguish bacterial from mammalian DNA. The response is mimicked by single-stranded oligonucleotides containing unmethylated CG dinucleotides (''CpG'' motifs) in specific sequence contexts. The dose-response curve for activation is influenced by variation in the sequence flanking the core CpG motif. CpG or bacterial DNA activates several signaling pathways in common with bacterial lipopolysaccharide (LPS), leading to induction of cytokine genes such as tumor necrosis factor ␣. Pretreatment with LPS causes desensitization to subsequent activation by CpG DNA. Both stimuli also cause cell cycle arrest in macrophages proliferating in response to the macrophage growth factor colonystimulating factor-1 (CSF-1), but prevent apoptosis caused by growth factor removal. In part, cell cycle arrest by CpG DNA and LPS may be linked to rapid down-modulation of the CSF-1 receptor from the cell surface, a response that occurs in an all-or-nothing manner. The response of macrophages to CpG DNA has aspects in common with the DNA damage response in other cell types, which may provide clues to the underlying mechanism. J. Leukoc. Biol. 66: 542-548; 1999.

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IFN-γ Primes Macrophage Responses to Bacterial DNA

Cited by 79 publications

References 42 publications

LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth

LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth

CpG DNA and LPS induce distinct patterns of activation in human monocytes

The actions of bacterial DNA on murine macrophages

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