DBM1285 suppresses tumor necrosis factor-alpha production by blocking p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 signaling pathway

Cited 9 time in scopus
Metadata Downloads
Title
DBM1285 suppresses tumor necrosis factor-alpha production by blocking p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 signaling pathway
Author(s)
Jong Soon Kang; Hwan Mook Kim; I Y Choi; S B Han; Yeo Dae YoonHyunju Lee; Ki Hwan Park; Ig Jun Cho; Chang Woo Lee; Kiho Lee; Ki Hoon Lee; Song Kyu Park
Bibliographic Citation
Journal of Pharmacology and Experimental Therapeutics, vol. 334, no. 2, pp. 657-664
Publication Year
2010
Abstract
Tumor necrosis factor α(TNF-α) is a major inflammatory cytokine that plays an important role in the development of various inflammatory diseases. TNF-α has been considered as a potential therapeutic target for the treatment of chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. In this study, we report that cyclopropyl-{4-[4-(4-fluorophenyl)-2-piperidin-4-ylthiazol-5-yl]pyrimidin-2-yl} amine (DBM1285) is a novel inhibitor of TNF-α production. DBM1285 concentration-dependently inhibited lipopolysaccharide (LPS)-induced TNF-α secretion in various cells of macrophage/monocyte lineage, including mouse bone marrow macrophages, THP-1 cells, and RAW264.7 cells. However, LPS-induced mRNA expression of TNF-α was not affected by DBM1285 in these cells. Further studies demonstrated that the inhibitory effect of DBM1285 on TNF-α production might be mediated by post-transcriptional regulation through the modulation of the p38 mitogenactivated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) signaling pathway. We also confirmed that DBM1285 directly inhibits p38 MAPK enzymatic activity. In vivo administration of DBM1285 inhibited LPS-induced increase in the plasma level of TNF-α in mice. Whole-blood in vivo target inhibition assay also revealed that DBM1285 attenuates p38 MAPK activity after oral administration in mice. Moreover, DBM1285 suppressed zymosan-induced inflammation and adjuvant-induced arthritis in murine models. Collectively, these results suggest that DBM1285 inhibits TNF-α production, at least in part, by blocking the p38 MAPK/MK2 pathway. Furthermore, in vivo results suggest that DBM1285 might be a possible therapeutic candidate for the treatment of TNF-α-related chronic inflammatory diseases.
ISSN
0022-3565
Publisher
Amer Soc Pharmacology Experimental Therapeutics
DOI
http://dx.doi.org/10.1124/jpet.109.161687
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.