Universität zu Köln

Herzner, Anna-Maria, Wolter, Steven, Zillinger, Thomas ORCID: 0000-0002-0866-4835, Schmitz, Saskia, Barchet, Winfried ORCID: 0000-0002-6745-6606, Hartmann, Gunther ORCID: 0000-0003-1021-2018, Bartok, Eva ORCID: 0000-0003-0556-1950 and Schlee, Martin (2016). G-rich DNA-induced stress response blocks type-I-IFN but not CXCL10 secretion in monocytes. Sci Rep, 6. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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Abstract

Excessive inflammation can cause damage to host cells and tissues. Thus, the secretion of inflammatory cytokines is tightly regulated at transcriptional, post-transcriptional and post-translational levels and influenced by cellular stress responses, such as endoplasmic reticulum (ER) stress or apoptosis. Here, we describe a novel type of post-transcriptional regulation of the type-I-IFN response that was induced in monocytes by cytosolic transfection of a short immunomodulatory DNA (imDNA), a G-tetrad forming CpG-free derivative of the TLR9 agonist ODN2216. When co-transfected with cytosolic nucleic acid stimuli (DNA or 3P-dsRNA), imDNA induced caspase-3 activation, translational shutdown and upregulation of stress-induced genes. This stress response inhibited the type-I-IFN induction at the translational level. By contrast, the induction of most type-I-IFN-associated chemokines, including Chemokine (C-X-C Motif) Ligand (CXCL) 10 was not affected, suggesting a differential translational regulation of chemokines and type-I-IFN. Pan-caspase inhibitors could restore IFN-beta secretion, yet, strikingly, caspase inhibition did not restore global translation but instead induced a compensatory increase in the transcription of IFN-beta but not CXCL10. Altogether, our data provide evidence for a differential regulation of cytokine release at both transcriptional and post-transcriptional levels which suppresses type-I-IFN induction yet allows for CXCL10 secretion during imDNA-induced cellular stress.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Herzner, Anna-Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolter, Steven UNSPECIFIED UNSPECIFIED UNSPECIFIED Zillinger, Thomas UNSPECIFIED orcid.org/0000-0002-0866-4835 UNSPECIFIED Schmitz, Saskia UNSPECIFIED UNSPECIFIED UNSPECIFIED Barchet, Winfried UNSPECIFIED orcid.org/0000-0002-6745-6606 UNSPECIFIED Hartmann, Gunther UNSPECIFIED orcid.org/0000-0003-1021-2018 UNSPECIFIED Bartok, Eva UNSPECIFIED orcid.org/0000-0003-0556-1950 UNSPECIFIED Schlee, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-252624
DOI:	10.1038/srep38405
Journal or Publication Title:	Sci Rep
Volume:	6
Date:	2016
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYCLIC GMP-AMP; DOUBLE-STRANDED-RNA; NF-KAPPA-B; MESSENGER-RNA; PROTEIN-SYNTHESIS; SENSOR CGAS; RECOGNITION; ACTIVATION; INDUCTION; 2ND-MESSENGER Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25262