mTNF reverse signalling induced by TNF alpha antagonists involves a GDF-1 dependent pathway: implications for Crohn's disease.

Derer, S., Till, A., Haesler, R., Sina, C., Grabe, N., Jung, S., Nikolaus, S., Kuehbacher, T., Groetzinger, J., Rose-John, S., Rosenstiel, Philip and Schreiber, Stefan (2013) mTNF reverse signalling induced by TNF alpha antagonists involves a GDF-1 dependent pathway: implications for Crohn's disease. Gut, 62 (3). pp. 376-386. DOI 10.1136/gutjnl-2011-300384.

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Supplementary data:

Abstract

Objective Mechanisms of action (MoA) of anti-tumour necrosis factor α (TNFα) therapies in Crohn's disease (CD) may critically involve induction of immune cell apoptosis via membrane-bound TNFα (mTNFα) binding. Certolizumab pegol (CZP), which is effective in induction and maintenance of remission in CD lacks the ability to induce apoptosis. The aim of this study was to analyse transcriptomal responses of reverse signalling induced by the TNFα binding agents infliximab (IFX) and CZP in myelomonocytic cells.
Design Induction of transcriptional patterns upon anti-TNFα stimulation was assessed using oligonucleotide microarrays. mRNA expression of GDF-1/ LASS1, which was identified as a shared target, was studied in inflammatory bowel disease by real-time PCR, while signalling pathways induced by growth and differentiation factor 1 (GDF-1) were investigated using western blots and ELISA.
Results IFX and CZP induced a common signature of 20 transcripts that could be categorised into control of cell cycle, transcription activation and pre-mRNA processing. We selected GDF-1/LASS1 for functional follow-up, which was found to be upregulated in inflamed CD tissues. We show that downregulation of GDF-1/LASS1 depends on autocrine release of transforming growth factor β after mTNFα ligation. We demonstrate that GDF-1 itself acts as a novel proinflammatory factor via induction of interleukin 6 and signal transducer and activator of transcription 3 and is downregulated after IFX treatment.
Conclusion Commonalities in the MoA of IFX and CZP comprise modulation of non-apoptotic pathways through downregulation of proinflammatory GDF-1. Further characterisation of the molecular role of GDF-1 in complex inflammatory processes in vivo is warranted to decide whether this proinflammatory molecule is a promising therapeutic target in patients with CD.

Document Type: Article
Additional Information: Times Cited: 7 Derer, Stefanie Till, Andreas Haesler, Robert Sina, Christian Grabe, Nils Jung, Sascha Nikolaus, Susanna Kuehbacher, Tanja Groetzinger, Joachim Rose-John, Stefan Rosenstiel, Philip C. Schreiber, Stefan
Research affiliation: OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
Open Access Journal?: No
DOI etc.: 10.1136/gutjnl-2011-300384
ISSN: 0017-5749
Projects: Future Ocean
Date Deposited: 08 Jul 2014 08:59
Last Modified: 16 Jul 2019 09:55
URI: http://oceanrep.geomar.de/id/eprint/24884

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