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      Caffeic Acid Phenethyl Ester Induces Leukocyte Apoptosis, Modulates Nuclear Factor-Kappa B and Suppresses Acute Inflammation

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          Nuclear factor kappa-B (NF-κB) is a heterodimeric transcription factor with a pivotal role in orchestrating immune and inflammatory processes. Inflammatory cytokines and prostanoids activate NF-κB, 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-κB 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<sub>50</sub> 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 IκBα and increased nuclear translocation of p65. These findings may suggest that novel anti-inflammatory therapies can be based upon activation of NF-κB-mediated transcription of genes curbing the inflammatory response and that CAPE or its analogs hold therapeutic promise.

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          Most cited references 8

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          Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B.

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            Nuclear Factor (NF)-κB2 (p100/p52) Is Required for Normal Splenic Microarchitecture and B Cell–mediated Immune Responses

            The nfkb2 gene is a member of the Rel/NF-κB family of transcription factors. COOH-terminal deletions and rearrangements of this gene have been associated with the development of human cutaneous T cell lymphomas, chronic lymphocytic leukemias, and multiple myelomas. To further investigate the function of NF-κB2, we have generated mutant mice carrying a germline mutation of the nfkb2 gene by homologous recombination. NF-κB2–deficient mice showed a marked reduction in the B cell compartment in spleen, bone marrow, and lymph nodes. Moreover, spleen and lymph nodes of mutant mice presented an altered architecture, characterized by diffuse, irregular B cell areas and the absence of discrete perifollicular marginal and mantle zones; the formation of secondary germinal centers in spleen was also impaired. Proliferation of NF-κB2–deficient B cells was moderately reduced in response to lipopolysaccharide, anti-IgD-dextran, and CD40, but maturation and immunoglobulin switching were normal. However, nfkb2 (−/−) animals presented a deficient immunological response to T cell–dependent and –independent antigens. These findings indicate an important role of NF-κB2 in the maintenance of the peripheral B cell population, humoral responses, and normal spleen architecture.
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              Mice Deficient in Nuclear Factor (NF)-κB/p52 Present with Defects in Humoral Responses, Germinal Center Reactions, and Splenic Microarchitecture

              p52 is a subunit of nuclear factor (NF)-κB transcription factors, most closely related to p50. Previously, we have shown that p52, but not p50 homodimers can form transactivating complexes when associated with Bcl-3, an unusual member of the IκB family. To determine nonredundant physiologic roles of p52, we generated mice deficient in p52. Null mutant mice were impaired in their ability to generate antibodies to T-dependent antigens, consistent with an absence of B cell follicles and follicular dendritic cell networks in secondary lymphoid organs, and an inability to form germinal centers. Furthermore, the splenic marginal zone was disrupted. These phenotypes are largely overlapping with those observed in Bcl-3 knockout animals, but distinct from those of p50 knockouts, supporting the notion of a physiologically relevant complex of p52 homodimers and Bcl-3. Adoptive transfer experiments further suggest that such a complex may be critical in accessory cell functions during antigen-specific immune reactions. Possible roles of p52 and Bcl-3 are discussed that may underlie the oncogenic potential of these proteins, as evidenced by recurrent chromosomal translocations of their genes in lymphoid tumors.

                Author and article information

                S. Karger AG
                February 1999
                18 February 2000
                : 7
                : 2
                : 99-105
                aDevelopmental Endocrinology Branch, National Institute of Child Health and Human Development, and Laboratories of bPathology and cMedicinal Chemistry, National Cancer Institute, Bethesda, Md., USA
                26427 Neuroimmunomodulation 2000;7:99–105
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 34, Pages: 7
                Original Paper


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