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.
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.
Department of Pharmacy, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, 119260, Singapore. phalh@nus.edu.sg.
Qiu-Yi
QY
Choo
Paul C
PC
Ho
Yoshiya
Y
Tanaka
Hai-Shu
HS
Lin
D001172:Arthritis, Rheumatoid / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D054412:Chemokine CCL8 / Q000378:metabolism; D054427:Chemokine CXCL6 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C515453:CCL8 protein, human; D054412:Chemokine CCL8; D054427:Chemokine CXCL6; D056572:Histone Deacetylase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1