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CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-alpha and MMP-3 pr with inflammatory bowel disease

CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-alpha and MMP-3 pr with inflammatory bowel disease
CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-alpha and MMP-3 pr with inflammatory bowel disease
Background: thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-? production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-? 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? 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-? levels by ELISA.

Results: CC-10004 significantly reduced both TNF-? production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-? 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
1873-9946
175-182
Gordon, J.N.
84de0d58-4db8-4de2-a74e-dc025437e0ce
Prothero, J.D.
87babf58-ecdb-4cd0-8e72-a28e7e5ecde0
Thornton, C.A.
898d425c-5242-458e-8862-852109ee0a64
Pickard, K.M.
e5188669-dff1-49c7-9c6f-8122b0c74bd9
Di Sabatino, A.
7e2802bd-ff3d-4578-862d-1d9c524b78a4
Goggin, P.M.
7cf53c28-7b1c-4737-b500-5746f71e0254
Pender, S.L.
62528b03-ec42-41bb-80fe-48454c2c5242
Macdonald, T.T.
171334aa-638a-42b0-99f6-e860e2f0ca45
Gordon, J.N.
84de0d58-4db8-4de2-a74e-dc025437e0ce
Prothero, J.D.
87babf58-ecdb-4cd0-8e72-a28e7e5ecde0
Thornton, C.A.
898d425c-5242-458e-8862-852109ee0a64
Pickard, K.M.
e5188669-dff1-49c7-9c6f-8122b0c74bd9
Di Sabatino, A.
7e2802bd-ff3d-4578-862d-1d9c524b78a4
Goggin, P.M.
7cf53c28-7b1c-4737-b500-5746f71e0254
Pender, S.L.
62528b03-ec42-41bb-80fe-48454c2c5242
Macdonald, T.T.
171334aa-638a-42b0-99f6-e860e2f0ca45

Gordon, J.N., Prothero, J.D., Thornton, C.A., Pickard, K.M., Di Sabatino, A., Goggin, P.M., Pender, S.L. and Macdonald, T.T. (2009) CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-alpha and MMP-3 pr with inflammatory bowel disease. Journal of Crohn's and Colitis, 3 (3), 175-182. (doi:10.1016/j.crohns.2009.03.001).

Record type: Article

Abstract

Background: thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-? production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-? 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? 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-? levels by ELISA.

Results: CC-10004 significantly reduced both TNF-? production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-? 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

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Published date: September 2009

Identifiers

Local EPrints ID: 179697
URI: http://eprints.soton.ac.uk/id/eprint/179697
ISSN: 1873-9946
PURE UUID: b7cc5d91-8e84-456e-a6d6-d06a37af7755
ORCID for S.L. Pender: ORCID iD orcid.org/0000-0001-6332-0333

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Date deposited: 04 Apr 2011 10:29
Last modified: 15 Mar 2024 03:08

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Contributors

Author: J.N. Gordon
Author: J.D. Prothero
Author: C.A. Thornton
Author: K.M. Pickard
Author: A. Di Sabatino
Author: P.M. Goggin
Author: S.L. Pender ORCID iD
Author: T.T. Macdonald

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