Molecules 2013, 18(11), 14085-14095; doi:10.3390/molecules181114085
Article

The Histone Deacetylase Inhibitors MS-275 and SAHA Suppress the p38 Mitogen-Activated Protein Kinase Signaling Pathway and Chemotaxis in Rheumatoid Arthritic Synovial Fibroblastic E11 Cells

1 Department of Pharmacy, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, 119260, Singapore 2 First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
* Author to whom correspondence should be addressed.
Received: 29 October 2013; in revised form: 6 November 2013 / Accepted: 6 November 2013 / Published: 14 November 2013
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Abstract: MS-275 (entinostat) and SAHA (vorinostat), two histone deacetylase (HDAC) inhibitors currently in oncological trials, have displayed potent anti-rheumatic activities in rodent models of rheumatoid arthritis (RA). To further elucidate their anti-inflammatory mechanisms, the impact of MS-275 and SAHA on the p38 mitogen-activated protein kinase (MAPK) signaling pathway and chemotaxis was assessed in human rheumatoid arthritic synovial fibroblastic E11 cells. MS-275 and SAHA significantly suppressed the expression of p38α  MAPK, but induced the expression of MAPK phosphatase-1 (MKP-1), an endogenous suppressor of p38α  in E11 cells. At the same time, the association between p38α and MKP-1 was up-regulated and consequently, the activation (phosphorylation) of p38α  was inhibited. Moreover, MS-275 and SAHA suppressed granulocyte chemotactic protein-2 (GCP-2), monocyte chemotactic protein-2 (MCP-2) and macrophage migration inhibitory factor (MIF) in E11 cells in a concentration-dependent manner. Subsequently, E11-driven migration of THP-1 and U937 monocytes was inhibited. In summary, suppression of the p38 MAPK signaling pathway and chemotaxis appear to be important anti-rheumatic mechanisms of action of these HDAC inhibitors.
Keywords: histone deacetylase inhibitor; rheumatoid arthritis; MS-275; SAHA; p38 MAPK; MKP-1; chemotaxis

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MDPI and ACS Style

Choo, Q.-Y.; Ho, P.C.; Tanaka, Y.; Lin, H.-S. The Histone Deacetylase Inhibitors MS-275 and SAHA Suppress the p38 Mitogen-Activated Protein Kinase Signaling Pathway and Chemotaxis in Rheumatoid Arthritic Synovial Fibroblastic E11 Cells. Molecules 2013, 18, 14085-14095.

AMA Style

Choo Q-Y, Ho PC, Tanaka Y, Lin H-S. The Histone Deacetylase Inhibitors MS-275 and SAHA Suppress the p38 Mitogen-Activated Protein Kinase Signaling Pathway and Chemotaxis in Rheumatoid Arthritic Synovial Fibroblastic E11 Cells. Molecules. 2013; 18(11):14085-14095.

Chicago/Turabian Style

Choo, Qiu-Yi; Ho, Paul C.; Tanaka, Yoshiya; Lin, Hai-Shu. 2013. "The Histone Deacetylase Inhibitors MS-275 and SAHA Suppress the p38 Mitogen-Activated Protein Kinase Signaling Pathway and Chemotaxis in Rheumatoid Arthritic Synovial Fibroblastic E11 Cells." Molecules 18, no. 11: 14085-14095.

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