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PPAR‐γ‐Mediated Regulation of Normal and Malignant B Lineage Cells
Author(s) -
PADILLA JOSUÉ,
KAUR KULJEET,
HARRIS SARAH G.,
PHIPPS RICHARD P.
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb06542.x
Subject(s) - prostaglandin d2 , apoptosis , cytotoxic t cell , receptor , peroxisome proliferator activated receptor , prostaglandin , biology , nuclear receptor , microbiology and biotechnology , chemistry , cancer research , endocrinology , biochemistry , in vitro , transcription factor , gene
A bstract : 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 PGE 2 . PGD 2 is a major product of cyclooxygenase in bone marrow and in macrophages, suggesting a role for this lipid product in immunological responses. PGD 2 undergoes dehydration to the biologically active prostaglandin 15‐deoxy‐Δ 12,14 ‐PGJ 2 (15d‐PGJ 2 ) that binds to the nuclear receptor known as peroxisome proliferator‐activated receptor gamma (PPAR‐γ). We found that normal mouse B cells and a Wvariety of B lymphoma cells (e.g., 70Z/3, WEHI‐231, CH12, and J558) express PPAR‐γmRNA and the 67‐kDa PPAR‐γ protein. 15d‐PGJ 2 had a dose‐dependent antiproliferative/cytotoxic effect on normal and malignant B cells, as shown by 3 H‐thymidine and MTT assays. Only PPAR‐γ agonists (i.e., thiazolidinediones) 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 PPAR‐γ. The mechanism whereby PPAR‐γ agonists induced cytotoxicity is via apoptosis, as shown by Annexin V assays. PPAR‐γ agonists may serve as a counterbalance to the stimulating effects of PGE 2 , which promotes B‐cell differentiation. The use of prostaglandins, such as 15d‐PGJ 2 , and synthetic PPAR‐γ agonists to induce apoptosis in B lineage cells may lead to the development of therapies for fatal PGE 2 ‐resistant B lymphomas.