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

Background: Thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-alpha production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-alpha 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 TNF alpha 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-50113, and CC-10004. MMP-3 and TIMP-1 levels were determined by western blotting and real-time PCR, and TNF-alpha Levels by ELISA. Results: CC-10004 significantly reduced both TNF-alpha production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-alpha or MMP-3 by LPMCs. Conclusion: These results provides a mechanistic rationale for both the failure of lenatidomide (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. (c) 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.