Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation

Nuclear factor kappa-B (NF-kappa B) is a heterodimeric transcription factor with a pivotal role in orchestrating immune and inflammatory processes, In flammatory cytokines and prostanoids activate NF-kappa B, which, in turn, s timulates expression of cytokines, proteases, adhesion molecules and other inflammatory mediators. Caffeic acid phenethyl ester (CAPE) is a compound t hat modulates nuclear binding of the NF-kappa B p65 subunit (RelA). To dete rmine whether CAPE decreases the viability of cells participating in host d efense, we first tested its in vitro effect on a glucocorticoid-sensitive a nd -resistant cell line of lymphoid origin. CAPE induced apoptotic cell dea th in a dose-dependent fashion and to a similar extent in both cell lines. Furthermore, a low concentration of CAPE decreased the LD50 of dexamethason e by 3- to 5-fold. Since therapeutic induction of apoptosis of activated in flammatory cells holds the attraction of destroying effector cells safely w ithout secondary tissue damage, we examined the effects of CAPE in a rat mo del of carrageenin-induced subcutaneous inflammation. Local administration of CAPE resulted in increased leukocyte apoptosis and marked reduction in e xudate leukocyte, neutrophil and monocyte concentrations at the inflammator y site. CAPE decreased expression of cytosolic I kappa B alpha and increase d nuclear translocation of p65. These findings may suggest that novel anti- inflammatory therapies can be based upon activation of NF-kappa B-mediated transcription of genes curbing the inflammatory response and that CAPE or i ts analogs hold therapeutic promise. Copyright (C) 2000 S. Karger AG, Basel .