Visit our Expo - Redox and Inflammation signaling 2012

Session III : Protein kinase cascades as therapeutic targets Poster III, 32
Activation of p38 MAP kinase in diosgenin-induced apoptosis in human rheumatoid
synovial cells with increased COX-2 expression
Bertrand Liagre1, David Y. Léger1, Pascale Vergne-Salle2, Philippe Bertin2, Richard
Trèves2 and Jean-L. Beneytout1.
1Laboratoire de Biochimie, UPRES EA 1085, Faculté de Pharmacie, Limoges, France.
E-mail: bertrand.liagre@unilim.fr; 2Service de Rhumatologie et Thérapeutique, CHRU
Dupuytren, Limoges, France.
Alterations in the apoptosis of synovial cells have been described in resident synoviocytes and
associated with the pathogenesis of RA. The role of cyclooxygenase-2 (COX-2) and
prostaglandins in synoviocyte death is still unknown. Recently, we showed that diosgenin, a
plant steroid, induced apoptosis in human RA FLS with COX-2 overexpression (Liagre B, et
al. (2004) Arthritis Res. Ther. 6:R373-R383). In a new work, we studied the kinase (Akt and
MAPK) signalling pathway after diosgenin-induced apoptosis in the human RA FLS.
Particular attention was paid to the modulation of COX-2 expression and activity in RA
synoviocyte viability. Our results showed that 40 µM diosgenin caused an inhibition of Akt
phosphorylation. Moreover, after diosgenin treatment, p38 MAP kinase activation was
increased in contrast with JNK or ERK activation. Phosphorylation of p38 was correlated
with an increase of COX-2 expression and activity. However, diosgenin inhibited nuclear
factor-kB (NF-kB) in apoptotic conditions in human RA FLS. In order to clarify if activation
of p38 was directly associated with diosgenin-induced RA FLS apoptosis, we used a selective
inhibitor of p38 (SB 203580) to verify DNA fragmentation after diosgenin treatment. We also
studied in the same conditions the level of COX-2 expression and prostaglandin E2 (PGE2)
production. Pre-treatment with SB 203580 before diosgenin treatment reduced the production
of mononucleosomes and oligonucleosomes in comparison with diosgenin alone.
Furthermore, this inhibition of diosgenin-induced apoptosis was correlated with an inhibition
of COX-2 expression and a decrease of PGE2 synthesis.
In conclusion, we showed for the first time that diosgenin-induced apoptosis in human RA
FLS is associated with an increase of p38 activity and a decrease of Akt phosphorylation and
NF-kB activation. Overexpression of COX-2 is consecutive at the activation of p38 after
diosgenin treatment. Future studies should evaluate whether diosgenin could be used as a
therapeutic agent for RA in association with a COX-2 inhibitor.
This work was supported by La Société Française de Rhumatologie.
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