IFN-α Induces the Human IL-10 Gene by Recruiting Both IFN Regulatory Factor 1 and Stat3

Ziegler-Heitbrock, Löms; Lötzerich, Mark; Schaefer, Annette E.; Werner, Thomas; Frankenberger, Marion; Benkhart, Elke

doi:10.4049/jimmunol.171.1.285

Cited by 126 publications

(115 citation statements)

References 31 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…The binding of IRF1 to IL-10 promoter was previously demonstrated in human cells [23]; to confirm this interaction in the mouse system, we performed a computational analysis of the mouse IL-10 promoter with the web tool Transcription Element Search System (TESS). We found a putative IRF1 binding site (BS) of six nucleotides (AAGTGA) between À1470 and À1476 nucleotides.…”

Section: Ox40 Triggering On Treg Cells Leads To Interferon Regulatorymentioning

confidence: 70%

“…These data, together with gene expression data, suggest that the effect of OX40 triggering on IRF1 mRNA expression is Treg-cell-intrinsic and that OX40 stimulation may, directly or indirectly, modulate IRF1 mRNA expression in vivo in tumorinfiltrating Treg cells. Future experiments will test IRF1 downregulation by OX40 at the protein level and will address the molecular cascade linking OX40 engagement to IRF1 repression in Treg cells.The binding of IRF1 to IL-10 promoter was previously demonstrated in human cells [23]; to confirm this interaction in the mouse system, we performed a computational analysis of the mouse IL-10 promoter with the web tool Transcription Element Search System (TESS). We found a putative IRF1 binding site (BS) of six nucleotides (AAGTGA) between À1470 and À1476 nucleotides.…”

mentioning

confidence: 70%

“…We found IRF1 expressed in tumor-infiltrating but not peripheral Treg cells producing or not IL-10, respectively. Even if murine IL-10 promoter contains in silico-predicted sites for IRF1 binding, additional experiments are required to confirm the direct IL-10 induction by IRF1 in murine Treg cells, as demonstrated in human cells [23]. Whether IRF1 is the major or the sole activator of IL-10 transcription in tumor-infiltrating Treg cells versus other cell populations is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…2A). Among the down-modulated targets, we noticed two probes belonging to interferon regulatory factor 1 (IRF1) mRNA, a transcription factor known to promote IL-10 expression in human cells [23]. Hence, we evaluated the effects of OX86 on IRF1 modulation in tumor-infiltrating Treg cells by real-time RT-PCR.…”

Section: Ox40 Triggering On Treg Cells Leads To Interferon Regulatorymentioning

confidence: 99%

See 3 more Smart Citations

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

View full text Add to dashboard Cite

Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4 1 populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cellmediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor. 3615The tumor microenvironment is characterized by an immunosuppressive cytokine milieu, which promotes immune tolerance and tumor growth. Treg cells secrete interleukin 10 (IL-10), which plays a critical role in suppressing immune responses and in particular the maturation of fully competent DCs [13][14][15]. Among tumor-infiltrating Teff cells, the subpopulation of effector memory T (Tem) cells is the most abundant. Tem cells are CD4 1 CD44 high CD62L low lymphocytes excluded from resting lymph nodes and mainly localized in peripheral tissues; upon stimulation they rapidly activate and secrete effector cytokines like IFN-g, but they have limited proliferative capacity [16]. In experimental models of immune activation, Tem cells constitutively express CD40L at levels sufficient to induce DC activation in an antigen-independent manner [17]. The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].In this study we have investigated the mechanisms by which OX86 modulates Treg-and Teff-cell functions and their reciprocal interactions with DCs at the tumor site. We propose a model of the tumor microenvironment in which, after OX86 treatment, DCs receive a lower IL-10-mediated inhibition by Treg cells on the one hand, and a stronger stimulation from Tem cells, via the CD40/CD40L axis, on the other. In this favorable condition, DCs acquire a stronger migratory ability toward the draining LNs (dLNs), thus inducing a specific anti-tumor immune response. ResultsIntratumoral ...

show abstract

Section: Ox40 Triggering On Treg Cells Leads To Interferon Regulatorymentioning

confidence: 70%

mentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Ox40 Triggering On Treg Cells Leads To Interferon Regulatorymentioning

confidence: 99%

See 2 more Smart Citations

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

View full text Add to dashboard Cite

show abstract

“…This motif was also shown to be essential together with an upstream IRF site for IFN -induced IL-10 expression (Ziegler-Heitbrock et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

Schaefer

Unterberger

Frankenberger

et al. 2009

Molecular Immunology

Self Cite

View full text Add to dashboard Cite

Interferon‐γ Mediates Anemia but Is Dispensable for Fulminant Toll‐like Receptor 9–Induced Macrophage Activation Syndrome and Hemophagocytosis in Mice

Canna

Wrobel

Chu

et al. 2013

Arthritis & Rheumatism

103

104

View full text Add to dashboard Cite

Objective Macrophage Activation Syndrome (MAS) is a devastating cytokine storm syndrome complicating many inflammatory diseases and characterized by fever, pancytopenia, and systemic inflammation. It is clinically similar to Hemophagocytic Lymphohistiocytosis (HLH), which is caused by viral infection of a host with impaired cellular cytotoxicity. Murine models of MAS and HLH illustrate Interferon-γ (IFN-γ) as the driving stimulus for hemophagocytosis and immunopathology. We sought to understand the inflammatory contributors to a murine model of Toll-like Receptor 9 (TLR9)-induced fulminant MAS. Methods Wild-type (WT), transgenic, and cytokine-inhibited mice were treated with an IL-10 receptor blocking antibody and TLR9 agonist, and parameters of MAS were evaluated. Results Fulminant MAS was characterized by dramatic elevations in IFN-γ, IL-12, and IL-6. Serum IFN-γ correlated with enhanced IFN-γ production within some hepatic populations, but fewer IFN-γ+ cells. Surprisingly, IFN-γKO mice developed immunopathology and hemophagocytosis comparably to WT mice. However, IFN-γKO mice did not become anemic and had greater numbers of splenic erythroid precursors. IL-12 neutralization phenocopied disease in IFN-γKO mice. Interestingly, Type I interferons contributed to the severity of hypercytokinemia and weight loss, but their absence did not otherwise affect MAS manifestations. Conclusion These data demonstrate that both fulminant MAS and hemophagocytosis can arise independently of IFN-γ, IL-12, or Type I interferons. They also suggest that IFN-γ-mediated dyserythropoiesis, not hemophagocytosis, is the dominant cause of anemia in fulminant TLR9-MAS. Thus, our data establish a novel mechanism for the acute anemia of inflammation, but suggest that a variety of triggers can result in hemophagocytic disease.

show abstract

IFN-α Induces the Human IL-10 Gene by Recruiting Both IFN Regulatory Factor 1 and Stat3

Cited by 126 publications

References 31 publications

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

Interferon‐γ Mediates Anemia but Is Dispensable for Fulminant Toll‐like Receptor 9–Induced Macrophage Activation Syndrome and Hemophagocytosis in Mice

Contact Info

Product

Resources

About