Unknown,Transcriptomics,Genomics,Proteomics

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Real-time quantitative PCR analysis reveals high expression of activin A during NK-DC interactions

ABSTRACT: The interaction of natural killer (NK) cells with dendritic cells (DC) results in reciprocal cell activation through the interaction of membrane proteins and the release of soluble factors. Here we report that in NK-DC cocultures, among a set of 84 cytokines investigated, activin A was the second highest induced gene, with CXCL8 being the most upregulated one. Activin A is a member of the TGF-M-NM-2 superfamily and was previously shown to possess both pro- and antiinflammatory activities. In NK-DC cocultures, the induction of activin A required cell contact and was dependent on the presence of proinflammatory cytokines (i.e. IFN-M-NM-3, TNF-M-NM-1 and GM-CSF) as well as on NK cell-mediated DC killing. CD1+ DC were the main activin A producer cells among myeloid blood DC subsets. In NK-DC cocultures, inhibition of acitivn A by follistatin, a natural inhibitory protein, or by a specific blocking antibody, resulted in the upregulation of proinflammatory cytokine release (i.e. IL-6, IL-8, TNF-M-NM-1) by DC and in the increase of DC maturation. In conclusion, our study reports that activin A, produced during NK-DC interactions, represents a relevant negative feedback mechanism that might function to prevent excessive immune activation by DC. Human CD14 positive monocytes were differentiated to DC in vitro in the presence of IL-4 (20 ng/ml) and GM-CSF (50 ng/ml) for 6 days. Immature DC were then cocultured with allogeneic IL-15-activated NK cells (at 1:1 NK:DC ratio) for 0, 2 and 6 hrs. RNA was obtained from three independent coculture experiments. Equal amount of total RNA from each experiment was pooled prior to gene expression analysis. The gene expression of common cytokines was quantified using an RT2 Profiler PCR Array (Qiagen).

ORGANISM(S): Homo sapiens

SUBMITTER: Pascal Seeger

PROVIDER: E-GEOD-52306 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Activin A as a mediator of NK-dendritic cell functional interactions.

Seeger Pascal P Bosisio Daniela D Parolini Silvia S Badolato Raffaele R Gismondi Angela A Santoni Angela A Sozzani Silvano S

Journal of immunology (Baltimore, Md. : 1950) 20140106 3

The interaction of NK cells with dendritic cells (DCs) results in reciprocal cell activation through the interaction of membrane proteins and the release of soluble factors. In this article, we report that in NK-DC cocultures, among a set of 84 cytokines investigated, activin A was the second highest induced gene, with CXCL8 being the most upregulated one. Activin A is a member of the TGF-β superfamily and was previously shown to possess both proinflammatory and anti-inflammatory activities. In ...[more]

PMID: 24395917

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Project description:The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naM-CM-/ve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an antiviral state. After naM-CM-/ve DCs were exposed to either IFNM-NM-2 or to paracrine signaling released by DCs infected by Newcastle Disease Virus (NDV), microarray analysis revealed a large number of genes that were differently regulated by the DC-secreted paracrine signaling. In order to identify the cytokine mechanisms involved, we identified 20 cytokines secreted by NDV infected DCs for which the corresponding receptor gene is expressed in naM-CM-/ve DCs. By exposing cells to all combinations of 19 cytokines (leave-one-out studies) we identified 5 cytokines (IFNM-NM-2, TNFM-NM-1, IL-1M-oM-^AM-", TNFSF15 and IL28) as candidates for regulating DC maturation markers. Subsequent experiments identified IFNM-NM-2, TNFM-NM-1 and IL1M-oM-^AM-" as the major synergistic contributors to this antiviral state. This finding was supported by infection studies in vitro, by T cell activation studies and by in vivo infection studies in mouse. Combination of cytokines can cause response states in DCs that differ from those achieved by the individual cytokines alone. These results suggest that the cytokine microenvironment may act via a combinatorial code to direct the response state of specific immune cells. Further elucidation of this code may provide insight into responses to infection and neoplasia as well as guide the development of combinatorial cytokine immunomodulation for infectious, autoimmune and immunosurveillance-related diseases. Cells exposed to the supernatant of NDV infected cells were compared to NDV infected cells, IFNM-NM-2 treated cells and naM-CM-/ve dendritic cells after 8 hours.

Dataset Information

Real-time quantitative PCR analysis reveals high expression of activin A during NK-DC interactions

Publications

Activin A as a mediator of NK-dendritic cell functional interactions.

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