A Monocyte Conditioned Medium Is More Effective Than Defined Cytokines in Mediating the Terminal Maturation of Human Dendritic Cells

Reddy, Anita; Sapp, Mark; Feldman, M; Subklewe, Marion; Bhardwaj, Nina

doi:10.1182/blood.v90.9.3640

Cited by 216 publications

(62 citation statements)

References 30 publications

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“…1). TNF-␣ or PGE2, used individually, were not effective inducers of DC differentiation (data not shown), consistent with previous reports [31,32]. Of the mature DC marker and effector genes induced by TNF-␣ ϩ PGE2, CD40, CD86, and HLA-DR are Stat1-dependent, IFNinducible genes [33,34] whose induction by LPS is dependent on an IFN-Stat1-mediated autocrine loop [3-5, 8 -10, 29].…”

Section: Comparable Maturation Of Human Dcs By Lps and Tnf-␣ Plus Pge2supporting

confidence: 87%

“…TNF-␣ has a maturation-inducing effect on human monocyte-derived DCs but does not induce a fully mature phenotype relative to LPS. Addition of PGE2 enhances TNF-␣-mediated maturation of DCs [15,16,31,32]. Our results show that TNF-␣ alone induced Stat1 serine phsphorylation and Stat4 tyrosine phosphorylation but only modestly increased IRF1 expression.…”

Section: Discussionmentioning

confidence: 60%

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Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-α and PGE2

Park‐Min

Yarilina

et al. 2008

Journal of Leukocyte Biology

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Maturation of dendritic cells (DCs) by TLR ligands induces expression of IFN-beta and autocrine activation of IFN-inducible Stat1-dependent genes important for DC function. In this study, we analyzed the regulation of STAT signaling during maturation of human DCs by TNF-alpha and PGE2, which induced maturation of human DCs comparably with LPS but did not induce detectable IFN-beta production or Stat1 tyrosine phosphorylation. Consistent with these results, TNF-alpha and PGE2 did not induce Stat1 DNA binding to a standard Stat1-binding oligonucleotide. Instead, TNF-alpha and PGE2 increased Stat1 serine phosphorylation and Stat4 tyrosine phosphorylation and activated expression of the NF-kappaB and Stat1 target gene IFN regulatory factor 1 (IRF1), which contributes to IFN responses. TNF-alpha and PGE2 induced a complex that bound an oligonucleotide derived from the IRF1 promoter that contains a STAT-binding sequence embedded in a larger palindromic sequence, and this complex was recognized by Stat1 antibodies. These results suggest that TNF-alpha and PGE2 activate STAT-mediated components of human DC maturation by alternative pathways to the IFN-beta-mediated autocrine loop used by TLRs.

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Section: Comparable Maturation Of Human Dcs By Lps and Tnf-␣ Plus Pge2supporting

confidence: 87%

Section: Discussionmentioning

confidence: 60%

Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-α and PGE2

Park‐Min

Yarilina

et al. 2008

Journal of Leukocyte Biology

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“…0%; Sigma, St. Louis, MO), penicillin (100 U/ml; Gibco BRL, Gaithersburg, MD), streptomycin (100 mg/ml; Gibco BRL), GM-CSF (800 IU/ml; R & D Systems, Minneapolis, MN) and IL-4 (1000 IU/ml; R & D Systems), as described in ref. 19 except for the omission of IL-6. On days 3 and 5, 1 ml of the medium (modi®ed by an increase of GM-CSF to 1600 IU/ml) was added to each well.…”

Section: Isolation Of Cd14-positive Cells and Culture Of Dendritic Cellsmentioning

confidence: 99%

Cyclooxygenase‐independent inhibition of dendritic cell maturation by aspirin

2000

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SUMMARYWhen immature human myeloid dendritic cells were differentiated in vitro in the presence of aspirin, they were unable to stimulate T-cell proliferation. Aspirin and its major metabolite salicylate changed the surface marker phenotype of dendritic cells. The drugs particularly suppressed the levels of CD83 and the secreted p40 unit of interleukin-12 (IL-12), both markers of mature dendritic cells; 50% inhibitory concentration (IC 50 ) values were 2 . 5 mM, a concentration more than 100 times greater than the concentration at mid-point inhibition (ID 50 ) value for inhibition of prostaglandin synthesis. Concomitantly, the levels of CD14, a marker of monocytes/macrophages, increased above the levels found in immature dendritic cells. Cyclooxygenase inhibitors ketoprofen, indomethacin and NS-398 had no effect at concentrations more than a thousand-fold higher than their IC 50 values. The effects were independent of the presence of prostaglandin E 2 in the medium. Salicylates suppressed activation of the nuclear transcription factor kB, which regulates dendritic cell differentiation, but their effects on mature dendritic cells were negligible. Hence, aspirin inhibits dendritic cell function by inhibiting their terminal differentiation at concentrations achieved in the blood of patients chronically treated with high-dose aspirin.

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“…Especially, intracytoplasmic IL-12 was detected at a higher level in DC treated with tumour antigen plus LPS for 8 h, whereas IL-12 was nearly undetectable in DC treated with tumour antigen plus cocktail for 24 or 48 h. Ultimately, however, DC vaccines have been investigated with regard to human disease, especially human cancer. Though the use of LPS for DC maturation is expected to enhance Ag-specific immunity [33], other substitutable clinically safe stimulation factors need to be developed. Recently, in preparing a prophylactic melanoma vaccine, MART-1 (melanocyte ⁄ melanoma antigen recognized by T cells-1) expressing whole recombinant yeast was used for safety [45].…”

Section: Discussionmentioning

confidence: 99%

Development of an Effective Method for Dendritic Cell Immunotherapy of Mouse Melanoma

Lee

Cho

et al. 2009

Scand J Immunol

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Dendritic cell (DC) immunotherapy is a strong candidate for the treatment of incurable cancers especially malignant melanoma. Nevertheless, the proper guideline of DC immunotherapy does not exist. The absence of the guideline is also an obstacle to clinical trials of DC immunotherapy. So we conducted this study in order to develop an effective DC preparation method for immunotherapy in mouse malignant melanoma. Mouse bone marrow‐derived DC were stimulated with tumour antigen alone or tumour antigen plus a cocktail (anti‐CD40 antibody +TNF‐α+ IL‐1β) for 8, 24 or 48 h and the characteristics of these DC, such as surface molecules (CD40, CD80, CD86, MHC class II, CCR7), cytokines(IL‐12, IFN‐γ, and IL‐10), DC‐induced T cell proliferation in vitro, and the production of IFN‐γ by those cells, were evaluated. Mice with melanoma were then treated with DC stimulated with tumour antigen alone and tumour antigen plus cocktail for 8 or 48 h. The tumour size and survival rate of these mice were then evaluated. (1) Beneficial clinical effects such as a reduction of tumour size and an increased survival rate were best observed in the group treated with DC stimulated for 8 h with tumour antigen plus cocktail. (2) The single prominent characteristic of DC stimulated for 8 h with tumour antigen plus cocktail was an elevated IL‐12 secretion. The cytokine IL‐12 was not secreted by other DC. Consequently, proper production of IL‐12 was found to be an important requirement for DC used in immunotherapy of mouse melanoma.

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A Monocyte Conditioned Medium Is More Effective Than Defined Cytokines in Mediating the Terminal Maturation of Human Dendritic Cells

Cited by 216 publications

References 30 publications

Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-α and PGE2

Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-α and PGE2

Cyclooxygenase‐independent inhibition of dendritic cell maturation by aspirin

Development of an Effective Method for Dendritic Cell Immunotherapy of Mouse Melanoma

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