Type I IFNs differentially modulate IL-12p70 production by human dendritic cells depending on the maturation status of the cells and counteract IFN-γ-mediated signaling

Heystek, Heleen C.; Drijver, B den; Kapsenberg, Martien L.; Lier, R. A. W. Van; Jong, Esther C. de

doi:10.1016/s1521-6616(03)00060-3

Cited by 28 publications

(29 citation statements)

References 44 publications

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“…Although the synergistic effects observed with IFN in this study are similar to those reported by others (33,34), the regulation of IL-12 secretion in human DC by type I IFN remains an area of controversy, in relation to the subtypes of IFN and the precise timing of IFN exposure. In contrast to IFN-␣ (Fig.…”

Section: Response To Type I Ifnsupporting

confidence: 89%

Herpes Simplex Virus Type-1-Induced Activation of Myeloid Dendritic Cells: The Roles of Virus Cell Interaction and Paracrine Type I IFN Secretion

Pollara

Jones²,

Handley

et al. 2004

The Journal of Immunology

101

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Adaptive cellular immunity is required to clear HSV-1 infection in the periphery. Myeloid dendritic cells (DCs) are the first professional Ag-presenting cell to encounter the virus after primary and secondary infection and thus the consequences of their infection are important in understanding the pathogenesis of the disease and the response to the virus. Following HSV-1 infection, both uninfected and infected human DCs acquire a more mature phenotype. In this study, we demonstrate that type I IFN secreted from myeloid DC mediates bystander activation of the uninfected DCs. Furthermore, we confirm that this IFN primes DCs for elevated IL-12 p40 and p70 secretion. However, secretion of IFN is not responsible for the acquisition of a mature phenotype by HSV-1-infected DC. Rather, virus binding to a receptor on the cell surface induces DC maturation directly, through activation of the NF-κB and p38 MAPK pathways. The binding of HSV glycoprotein D is critical to the acquisition of a mature phenotype and type I IFN secretion. The data therefore demonstrate that DCs can respond to HSV exposure directly through recognition of viral envelope structures. In the context of natural HSV infection, the coupling of viral entry to the activation of DC signaling pathways is likely to be counterbalanced by viral disruption of DC maturation. However, the parallel release of type I IFN may result in paracrine activation so that the DCs are nonetheless able to mount an adaptive immune response.

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Section: Response To Type I Ifnsupporting

confidence: 89%

Herpes Simplex Virus Type-1-Induced Activation of Myeloid Dendritic Cells: The Roles of Virus Cell Interaction and Paracrine Type I IFN Secretion

Pollara

Jones²,

Handley

et al. 2004

The Journal of Immunology

101

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Section: Discussionmentioning

confidence: 99%

“…3,23 The presence of IFN-␥ during CD40L/LPS activation of human dendritic cells, for instance, up-regulates IL-12p70, 49 which in turn enhances the immune response and induces inflammatory processes. 50,51 These effects may counteract the T-cell inhibitory action of IDO.Apart from competing immunostimulatory molecules, it is known that the synthesis and function of IDO as well as that of tryptophan metabolites are regulated by the redox potential of the microenvironment. 52 We have previously shown that among the tryptophan metabolites generated by IDO, 3-OH-kynurenine and 3-OH-anthranilic acid are the most important mediators of immunosuppression.…”

mentioning

confidence: 99%

Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)–producing dendritic cells: too much ado about IDO?

Terness

Chuang

Bauer

et al. 2005

Blood

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Although dendritic cells (DCs) strongly stimulate the immune response, they can also induce unresponsiveness. Recently, a human monocyte-derived DC subpopulation was described that constitutively expresses indoleamine 2,3-dioxygenase (IDO). These DCs were defined as nonadherent CD123 ؉ /CC chemokine receptor 6 ؉ (CCR6 ؉ ) cells that suppress the allogeneic T-cell response. In the present study, we generated nonadherent, mature DCs from human blood monocytes. As expected, in addition to the classic markers, these cells expressed CD123 and CCR6. IntroductionSince 1998, when a series of brilliant mouse experiments 1 showed that a placental enzyme called indoleamine 2,3-dioxygenase (IDO) was able to prevent rejection of the fetus during pregnancy, the scientific community has been intrigued by a novel, basic immunoregulatory mechanism whose main player is IDO. Munn et al 1 presented a convincing experiment: they implanted time-release capsules containing the IDO inhibitor 1-methyl-tryptophan (1-MT) into pregnant mice bred to genetically different fathers. This treatment induced fetal rejection. The experimental design relied on the observation that, under certain circumstances, macrophages inhibit the T-cell response, apparently because they produce IDO, 2,3 an enzyme that is also manufactured in the placenta by the fetus-derived syncytiotrophoblast. 4 Based on their experimental findings, Munn et al forwarded the hypothesis that once the embryo implants and begins establishing connections with the mother's blood supply, fetal-derived cells located in the placenta begin making IDO. By destroying tryptophan-so went the speculation-IDO suppresses maternal T cells that otherwise would make their way through the placenta and attack the fetus.Subsequent studies addressed the mechanism by which tryptophan degradation affects the T-cell response and came to the conclusion that certain metabolites have a strong T-cell inhibitory action. 5,6 Among the tryptophan metabolites, 3-OH-kynurenine and 3-OH-anthranilic acid were shown to be strongly inhibitory, whereas kynurenine had a significant but weaker effect. 5 The mechanism that is able to efficiently regulate the immune reaction during pregnancy, a phenomenon of outstanding importance for the perpetuation of species, can be expected to be "used" by nature for controlling other unwanted immune reactions. A series of interesting studies emerged, shedding light on the mechanism of IDO up-regulation and its hypothetical role in immunoregulation. Most notable is the study of Grohmann et al 7 showing that cytotoxic T-lymphocyte antigen-4-immunoglobulin (CTLA4-Ig) up-regulates IDO in murine dendritic cells (DCs) by ligation to B7 molecules via induction of interferon-␥ (IFN-␥) synthesis. DCs from CTLA4-Ig-treated mice showed an increased rate of IDO production, suggesting that this mechanism also works in vivo. If murine IDO-producing DCs inhibit T-cell responses, as shown by some studies, 8,9 administration of the IDO inhibitor 1-MT would be expected to reverse CTLA4-Ig-induced ...

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“…The underlying mechanism involves transcriptional inhibition of the IL-12 p40 gene, marked by downregulation of PU.1 binding activity at the upstream Ets site of the IL-12p40 promoter [138]. However, in a separate study, Heystek et al investigated the direct effect of IFN-α/β on monocyte-derived DCs at different stages of development, and found that IFN-α/β enhanced IL-12 p70 production by immature DCs but inhibited IL-12p70 production by mature DCs [139]. Interestingly, IFN-α/β strongly counteracted the IL-12-enhancing effect of IFN-γ on DCs regardless of their maturation status [139].…”

Section: V9 Effects Of Type I Interferons On Il-12 Productionmentioning

confidence: 99%

Interleukin-12: An Update on its Immunological Activities, Signaling and Regulation of Gene Expression

Liu¹,

Cao²,

Kim³

et al. 2005

CIR

125

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Interleukin-12 (IL-12) is a heterodimeric cytokine composed of the p35 and p40 subunits. It is produced by antigen-presenting cells and plays a critical role in host defense against intracellular microbial infection and control of malignancy via its ability to stimulate both innate and adaptive immune effector cells. The potency of IL-12 renders itself to stringent regulation of the timing, locality and magnitude of its production during an immune response. Subversion of the delicate control and balance frequently leads to immunologic disorders. In this article, we provide an update, since our last review of the subject four years ago, on recent advances in: (1) uncovering of novel activities of IL-12 and related molecules in various immunological settings and models; and (2) dissection of the physiological pathways involved in the modulation of IL-12 production by pathogens and immune regulators. The increased understanding of IL-12 immunobiology and expression will likely benefit the development of therapeutic modalities to correct immune dysfunctions.

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Type I IFNs differentially modulate IL-12p70 production by human dendritic cells depending on the maturation status of the cells and counteract IFN-γ-mediated signaling

Cited by 28 publications

References 44 publications

Herpes Simplex Virus Type-1-Induced Activation of Myeloid Dendritic Cells: The Roles of Virus Cell Interaction and Paracrine Type I IFN Secretion

Herpes Simplex Virus Type-1-Induced Activation of Myeloid Dendritic Cells: The Roles of Virus Cell Interaction and Paracrine Type I IFN Secretion

Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)–producing dendritic cells: too much ado about IDO?

Interleukin-12: An Update on its Immunological Activities, Signaling and Regulation of Gene Expression

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