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

作者：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^*

来源：Gut, 2013, 62(3): 376-386.

DOI：10.1136/gutjnl-2011-300384

Objective Mechanisms of action (MoA) of anti-tumour necrosis factor alpha (TNF alpha) therapies in Crohn's disease (CD) may critically involve induction of immune cell apoptosis via membrane-bound TNF alpha (mTNF alpha) 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 TNF alpha binding agents infliximab (IFX) and CZP in myelomonocytic cells.
Design Induction of transcriptional patterns upon anti-TNF alpha 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 beta after mTNF alpha 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.

• 出版日期2013-3