title: G-rich DNA-induced stress response blocks type-I-IFN but not CXCL10 secretion in monocytes.
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-β secretion, yet, strikingly, caspase inhibition did not restore global translation but instead induced a compensatory increase in the transcription of IFN-β 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.
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Herzner
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Wolter
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Cologne-Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zillinger
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Schmitz
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), Cologne-Bonn, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Bartok
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlee
mesh_terms: D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D020862:GC Rich Sequence; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology; D016898:Interferon-alpha / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology; D014176:Protein Biosynthesis; D013312:Stress, Physiological
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007155:Immunologic Factors; D016898:Interferon-alpha; D009841:Oligonucleotides; D016899:Interferon-beta