Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells

Knödler, Anja; Schmidt, Sebastian; Bringmann, Anita; Weck, Markus M.; Brauer, Katharina M.; Holderried, Tobias A. W.; Heine, A-K; Grünebach, Frank; Brossart, Peter

doi:10.1038/leu.2008.301

Cited by 33 publications

(26 citation statements)

References 53 publications

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“…Interestingly, we could show that the mRNA transcription of genes remained unaffected indicating that IL-10 treatment results in a posttranslational degradation of the adaptor molecules. 9 In our present study, we show that APC generated in vitro under DC-driving conditions in the presence of IL-10 have the phenotype and function of MDSC and display relevant cell-intrinsic differences. Furthermore, we demonstrate that the interaction with osteoactivin/syndecan-4 is involved in the inhibitory effects of these cells.…”

Section: Introductionmentioning

confidence: 84%

“…21 We have described previously that osteoactivin is upregulated on DC upon stimulation with IL-10 or other small molecules including the tyrosine kinase inhibitor imatinib, whereas blocking osteoactivin increases the stimulatory capacity of DC. 9,34 The interaction of GITR/GITRL was shown to have stimulatory effects on T-cell-mediated immune responses in mice. However, its role in DC biology is not completely understood and there seem to be differences between its effects in mice and humans.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10] In general, IL-10 is an anti-inflammatory cytokine that regulates T helper (Th) cell responses by inhibiting Th1 activity. It exerts diverse, pleiotropic effects in immunoregulation and inflammation and is primarily produced by monocytes, but also by Th2 lymphocytes, regulatory T cells, mast cells and in certain subsets of activated T and B cells.…”

Section: Introductionmentioning

confidence: 99%

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Generation and functional characterization of MDSC-like cells

et al. 2017

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Myeloid-derived suppressor cells (MDSC) are critical in regulating immune responses by suppressing antigen presenting cells (APC) and T cells. We previously observed that incubation of peripheral blood monocytes with interleukin (IL)-10 during their differentiation to monocyte-derived dendritic cells (moDCs) results in the generation of an APC population with a CD14 C HLA-DR low phenotype (IL-10-APC) with reduced stimulatory capacity similar to human MDSC. Co-incubation experiments now revealed that the addition of IL-10-APC to moDC caused a reduction of DC-induced T-cell proliferation, of the expression of maturation markers, and of secreted cytokines and chemokines such as TNF-a, IL-6, MIP-1a and Rantes. Addition of IL-10-APC increased the immunosuppressive molecule osteoactivin and its corresponding receptor syndecan-4 on moDC. Moreover, CD14 C HLA-DR low MDSC isolated from healthy donors expressed high levels of osteoactivin, which was even further upregulated by the auxiliary addition of IL-10. Using transcriptome analysis, we identified a set of molecules and pathways mediating these effects. In addition, we found that IL-10-APC as well as human isolated MDSC expressed higher levels of programmed death (PD)-1, PD-ligand-1 (PD-L1), glucocorticoid-induced-tumor-necrosis-factor-receptor-related-protein (GITR) and GITR-ligand. Inhibition of osteoactivin, syndecan-4, PD-1 or PD-L1 on MDSC by using blocking antibodies restored the stimulatory capacity of DC in co-incubation experiments. Activation of MDSC with Dectin-1 ligand curdlan reduced the expression of osteoactivin and PD-L1. Our results demonstrate that osteoactivin/syndecan-4 and PD-/PD-L1 are key molecules that are profoundly involved in the inhibitory effects of MDSC on DC function and might be promising tools for clinical application.

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Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Generation and functional characterization of MDSC-like cells

et al. 2017

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“…S8). Recently, it was shown that an addition of IL-10 for 6 days during the generation of human monocytederived antigen-presenting cells down-regulated various proteins along the TLR signaling cascade (21). However, no significant down-regulation of MyD88, IRAK1, and TRAF6 was seen on mRNA levels, suggesting posttranscriptional regulation of protein levels by IL-10 treatment (21).…”

Section: Discussionmentioning

confidence: 99%

Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells

Chang¹,

Kunkel

Chang³

2009

Proc. Natl. Acad. Sci. U.S.A.

110

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IL-10 produced by dendritic cells (DC) can limit or terminate ongoing inflammatory responses by inhibiting the proinflammatory cytokine production. Currently, the molecular mechanism by which IL-10 suppresses cytokine production is still ill-defined. In this study, we showed that IL-10 produced by DC dampens myeloid differentiation factor (MyD)88-dependent, but not MyD88-independent signaling. At the molecular level, IL-10 induces ubiquitination and subsequent protein degradation of MyD88-dependent signaling molecules, including IL-1 receptor-associated kinase 4 and TNF-receptor associated factor 6. Protein degradation by IL-10 was associated with decreased phosphorylation of p38, JNK, and IKK. All of these events were prevented by either blocking IL-10 receptor signaling or inhibiting proteasome degradation. IL-10 induced LPS hyporesponsiveness using the same mechanisms, i.e., ubiquitination and protein degradation. Thus, a previously undescribed regulatory mechanism by which IL-10-mediated protein degradation contributes to the inhibition of inflammatory cytokine production and endotoxin tolerance in DC.cytokine ͉ ubiquitination ͉ endotoxin tolerance

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“…The therapeutical concept to elicit a specific immune response against microorganisms, viruses, or cancer is to isolate or generate autologous DCs from the patients' blood, to manipulate them by peptide loading or RNA transfection in vitro, and to reinfuse them into the patient as a vaccine. [25][26][27][28][29] In the present work, using the mentioned approach of isolating of MHC-associated peptides directly from LC/MSbased peptide sequencing, we identified a novel HLA-A24-binding antigenic peptide derived from BI-1.…”

Section: Discussionmentioning

confidence: 99%

Characterization of BAX inhibitor-1 as a novel leukemia-associated antigen

et al. 2009

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Using dendritic cells (DCs) electroporated with whole RNA isolated from blasts of a patient with acute myeloid leukemia (AML), we were able to generate leukemia-specific cytotoxic T lymphocytes (CTLs) capable of recognizing the leucemic cells. To identify T-cell epitopes mediating lysis of malignant cells, peptides were eluted from the patient's blasts and analyzed by mass spectrometry (LC/MS)-based peptide sequencing. Using this approach, an HLA-A24-binding peptide derived from Bax inhibitor-1 (BI-1), a regulator of apoptosis pathways, was identified as an epitope recognized by the generated CTLs. To further characterize this novel antigenic peptide, CTLs were induced using DCs electroporated with RNA coding for BI-1 or pulsed with the cognate peptide. These CTLs generated from healthy donors in vitro efficiently lysed the patient's blasts as well as other HLA-matched leukemic cells. In conclusion, we identified a BI-1 peptide as a novel immunogenic tumorassociated antigen (TAA) in AML. In vitro induction of BI-1-specific CTLs by RNA transfection or pulsing of DCs with the synthetically generated peptide was a feasible and highly effective method to generate leukemia-specific CTLs. As BI-1 is (over-) expressed in a broad variety of malignancies, it may represent an interesting novel TAA in the context of cancer vaccines.

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Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells

Cited by 33 publications

References 53 publications

Generation and functional characterization of MDSC-like cells

Generation and functional characterization of MDSC-like cells

Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells

Characterization of BAX inhibitor-1 as a novel leukemia-associated antigen

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