Human B lymphocytes and B lymphomas express PPAR-gamma and are killed by PPAR-gamma agonists.
This paper evaluates the expression and functional significance of PPAR-gamma on human B cells. Recent interest in PPAR-gamma has focused on its adipogenic effects on non-bone marrow-derived cells. PPAR-gamma agonists also have been proposed as anti-inflammatory agents owing to inhibition of NF-kappa B activation. We report herein the first study evaluating PPAR-gamma expression and functional significance in human B lineage cells. Interestingly, normal human B cells and a variety of B lymphoma cells (e.g., Daudi, Ramos, and Raji) express PPAR-gamma protein as determined by immunocytochemistry. The expression of 80-kDa PPAR-gamma on human B lymphocytes and B lymphomas was confirmed by Western blot analysis. 15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), a natural PPAR-gamma agonist, has a dose-dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [(3)H]thymidine and MTT assays. Only PPAR-gamma agonists (thiazolidinediones) and not PPAR-alpha agonists mimicked the effect of 15d-PGJ(2) on B lineage cells, indicating that the mechanism by which 15d-PGJ(2) negatively affects B lineage cells involves, in part, PPAR-gamma. The mechanism whereby PPAR-gamma agonists induce cytotoxicity is via apoptosis as shown by Annexin V staining and as confirmed by DNA fragmentation detected using the TUNEL assay. This is the first study evaluating PPAR-gamma expression and its significance on human B lymphocytes. PPAR-gamma agonists may serve as a counterbalance to the stimulating effects of other prostaglandins, namely PGE(2), which promotes B cell immunoglobulin class switching. Finally, the use of prostaglandins such as 15d-PGJ(2) and synthetic PPAR-gamma agonists to induce apoptosis in B lineage cells may lead to the development of novel therapies for potentially fatal B lymphomas.
Padilla
Josué
J
University of Rochester, Cancer Center, Department of Microbiology and Immunology, Rochester, New York 14642, USA.
Leung
Edmund
E
Phipps
Richard P
RP
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015230:Prostaglandin D2