PPAR-gamma-mediated regulation of normal and malignant B lineage cells.
Prostaglandins of the E-series stimulate B lymphocytes by enhancing immunoglobulin-class switching and antibody production. Little is known about whether or not other prostaglandins affect B lineage cells and perhaps counterbalance the stimulatory effects of PGE2. PGD2 is a major product of cyclooxygenase in bone marrow and in macrophages, suggesting a role for this lipid product in immunological responses. PGD2 undergoes dehydration to the biologically active prostaglandin 15-deoxy-delta 12,14-PGJ2 (15d-PGJ2) that binds to the nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPAR-gamma). We found that normal mouse B cells and a variety of B lymphoma cells (e.g., 70Z/3, WEHI-231, CH12, and J558) express PPAR-gamma mRNA and the 67-kDa PPAR-gamma protein. 15d-PGJ2 had a dose-dependent antiproliferative/cytotoxic effect on normal and malignant B cells, as shown by 3H-thymidine and MTT assays. Only PPAR-gamma agonists (i.e., thiazolidinediones) mimicked the effect of 15d-PGJ2 on B lineage cells, indicating that the mechanism by which 15d-PGJ2 negatively affects B lineage cells involves PPAR-gamma. The mechanism whereby PPAR-gamma agonists induced cytotoxicity is via apoptosis, as shown by Annexin V assay. PPAR-gamma agonists may serve as a counterbalance to the stimulating effects of PGE2, which promotes B-cell differentiation. The use of prostaglandins, such as 15d-PGJ2, and synthetic PPAR-gamma agonists to induce apoptosis in B lineage cells may lead to the development of therapies for fatal PGE2-resistant B lymphomas.
Padilla
J
J
University of Rochester Cancer Center, University of Rochester, New York 14642, USA.
Kaur
K
K
Harris
S G
SG
Phipps
R P
RP
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D019070:Cell Lineage; D002470:Cell Survival; D007073:Immunoglobulin E / Q000096:biosynthesis; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D007073:Immunoglobulin E; D015230:Prostaglandin D2