Universität zu Köln

Pallocca, Giorgia, Nyffeler, Johanna ORCID: 0000-0002-6155-9743, Dolde, Xenia, Grinberg, Marianna, Gstraunthaler, Gerhard, Waldmann, Tanja, Rahnenfuehrer, Joerg, Sachinidis, Agapios and Leist, Marcel ORCID: 0000-0002-3778-8693 (2017). Impairment of human neural crest cell migration by prolonged exposure to interferon-beta. Arch. Toxicol., 91 (10). S. 3385 - 3403. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

Human cell-based toxicological assays have been used successfully to detect known toxicants, and to distinguish them from negative controls. However, there is at present little experience on how to deal with hits from screens of compounds with yet unknown hazard. As a case study to this issue, we characterized human interferon-beta (IFN beta) as potential developmental toxicant affecting neural crest cells (NCC). The protein was identified as a hit during a screen of clinically used drugs in the 'migration inhibition of neural crest' (MINC) assay. Concentration-response studies in the MINC combined with immunocytochemistry and mRNA quantification of cellular markers showed that IFN beta inhibited NCC migration at concentrations as low as 20 pM. The effective concentrations found here correspond to levels found in human plasma, and they were neither cytostatic nor cytotoxic nor did they did they affect the differentiation state and overall phenotype of NCC. Data from two other migration assays confirmed that picomolar concentration of IFN beta reduced the motility of NCC, while other interferons were less potent. The activation of JAK kinase by IFN beta, as suggested by bioinformatics analysis of the transcriptome changes, was confirmed by biochemical methods. The degree and duration of pathway activation correlated with the extent of migration inhibition, and pharmacological block of this signaling pathway before, or up to 6 h after exposure to the cytokine prevented the effects of IFN beta on migration. Thus, the reduction of vital functions of human NCC is a hitherto unknown potential hazard of endogenous or pharmacologically applied interferons.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pallocca, Giorgia UNSPECIFIED UNSPECIFIED UNSPECIFIED Nyffeler, Johanna UNSPECIFIED orcid.org/0000-0002-6155-9743 UNSPECIFIED Dolde, Xenia UNSPECIFIED UNSPECIFIED UNSPECIFIED Grinberg, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Gstraunthaler, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldmann, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahnenfuehrer, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-216382
DOI:	10.1007/s00204-017-1966-1
Journal or Publication Title:	Arch. Toxicol.
Volume:	91
Number:	10
Page Range:	S. 3385 - 3403
Date:	2017
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENE-EXPRESSION DATA; DEVELOPMENTAL NEUROTOXICITY; IFN-BETA; MULTIPLE-SCLEROSIS; STEM-CELLS; IN-VITRO; PREGNANCY; DIFFERENTIATION; TOXICANTS; GAMMA Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21638