CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α and MMP-3 production in patients with inflammatory bowel disease

J. N. Gordon, J. D. Prothero, C. A. Thornton, K. M. Pickard, A. Di Sabatino, P. M. Goggin, S. L. Pender, T. T. MacDonald

Research output: Contribution to journalArticle

Abstract

Background: Thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-α production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-α driven production of matrix metalloproteinase (MMP)-3 by gut lamina propria mononuclear cells (LPMCs) is a major pathway of tissue injury in IBD; however the effect of thalidomide and newer more potent immunomodulatory derivatives on this pathway has not been studied. Aim: To investigate the effect of thalidomide, CC-4047 (pomalidomide), CC-5013 (lenalidomide), and CC-10004 (apremilast) on gut LPMC TNFα and MMP-3 production in patients with IBD. Methods: Gut LPMCs and myofibroblasts were isolated from patients with IBD, and cultured with thalidomide, CC-4047, CC-5013, and CC-10004. MMP-3 and TIMP-1 levels were determined by western blotting and real-time PCR, and TNF-α levels by ELISA. Results: CC-10004 significantly reduced both TNF-α production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-α or MMP-3 by LPMCs. Conclusion: These results provides a mechanistic rationale for both the failure of lenalidomide (CC-5013) in a recent randomised controlled trial in Crohn's disease, and for the evaluation of CC-10004 as a novel oral therapy in the treatment of CD and UC.

Original languageEnglish
Pages (from-to)175-182
Number of pages8
JournalJournal of Crohn's & colitis
Volume3
Issue number3
DOIs
Publication statusPublished - Sep 2009

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Keywords

  • Crohn's disease
  • Matrix metalloproteinase
  • Thalidomide
  • Thalidomide derivatives
  • Ulcerative colitis

ASJC Scopus subject areas

  • Gastroenterology

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