PPAR‐γ‐Mediated Regulation of Normal and Malignant B Lineage Cells

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Abstract
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-Delta(12,14)-PGJ(2) (15d-PGJ(2)) 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-PGJ(2) had a dose dependent antiproliferative/cytotoxic effect on normal and malignant B cells, as shown by H-3-thymidine and MTT assays, Only PPAR-gamma 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-gamma, The mechanism whereby PPAR-gamma agonists induced cytotoxicity is via apoptosis, as shown by Annexin V assays. 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-PGJ(2), and synthetic PPAR-gamma agonists to induce apoptosis in B lineage cells may lead to the development of therapies for fatal PGE(2)-resistant B lymphomas.