Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation.
Nuclear factor kappa-B (NF-kappaB) is a heterodimeric transcription factor with a pivotal role in orchestrating immune and inflammatory processes. Inflammatory cytokines and prostanoids activate NF-kappaB, which, in turn, stimulates expression of cytokines, proteases, adhesion molecules and other inflammatory mediators. Caffeic acid phenethyl ester (CAPE) is a compound that modulates nuclear binding of the NF-kappaB p65 subunit (RelA). To determine whether CAPE decreases the viability of cells participating in host defense, we first tested its in vitro effect on a glucocorticoid-sensitive and -resistant cell line of lymphoid origin. CAPE induced apoptotic cell death in a dose-dependent fashion and to a similar extent in both cell lines. Furthermore, a low concentration of CAPE decreased the LD(50) of dexamethasone by 3- to 5-fold. Since therapeutic induction of apoptosis of activated inflammatory cells holds the attraction of destroying effector cells safely without secondary tissue damage, we examined the effects of CAPE in a rat model of carrageenin-induced subcutaneous inflammation. Local administration of CAPE resulted in increased leukocyte apoptosis and marked reduction in exudate leukocyte, neutrophil and monocyte concentrations at the inflammatory site. CAPE decreased expression of cytosolic IkappaBalpha and increased nuclear translocation of p65. These findings may suggest that novel anti-inflammatory therapies can be based upon activation of NF-kappaB-mediated transcription of genes curbing the inflammatory response and that CAPE or its analogs hold therapeutic promise.
Orban
Z
Z
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Md., USA. orbanz@mail.nih.gov
Mitsiades
N
N
Burke
T R
TR
Tsokos
M
M
Chrousos
G P
GP
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002109:Caffeic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D002351:Carrageenan / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D007928:Lethal Dose 50; D007958:Leukocyte Count / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured
D002109:Caffeic Acids; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone; D002351:Carrageenan; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol