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mTNF reverse signalling induced by TNFα antagonists involves a GDF-1 dependent pathway: implications for Crohn's disease
  1. Stefanie Derer1,
  2. Andreas Till1,
  3. Robert Haesler1,
  4. Christian Sina1,
  5. Nils Grabe1,
  6. Sascha Jung2,
  7. Susanna Nikolaus3,
  8. Tanja Kuehbacher3,
  9. Joachim Groetzinger2,
  10. Stefan Rose-John2,
  11. Philip C Rosenstiel1,
  12. Stefan Schreiber1,3
  1. 1Institute of Clinical Molecular Biology, Christian-Albrechts University, Kiel, Germany
  2. 2Institute of Biochemistry, Christian-Albrechts University, Kiel, Germany
  3. 3Department of Internal Medicine I, University Hospital Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany
  1. Correspondence to Dr Stefan Schreiber, Professor of Medicine and Gastroenterology, Department of General Internal Medicine, Schittenhelmstr.12, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; s.schreiber{at}mucosa.de

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.

  • TNFα blockade
  • Crohn's disease
  • GDF-1
  • infliximab
  • certolizumab pegol
  • inflammatory bowel disease
  • bacterial interactions
  • TGFβ
  • cell biology
  • arthritis
  • autoimmune disease
  • carcinogenesis
  • apoptosis
  • hepatoma
  • cancer
  • cytokines
  • immunohistochemistry
  • IBD basic research
  • IBD genetics
  • antibacterial mucosal immunity
  • infliximab
  • genetics
  • signal transduction

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Footnotes

  • PCR and SS share scientific responsibility and senior authorship.

  • Funding This work was supported by an unrestricted grant of UCB S.A. (Brussels, Belgium) and the clusters of excellence Inflammation at Interfaces and The Future Ocean and the SFB877 (to SR-J, PCR and SS).

  • Competing interests Individual conflicts of interest are stated in the ICJME forms for SS, SN, TK, SRJ and PR.

  • Ethics approval Ethics approval was provided by the local ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The authors agree to share the data.

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