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

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 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‐Δ12,14‐PGJ2 (15d‐PGJ2) 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‐PGJ2 had a dose‐dependent antiproliferative/cytotoxic effect on normal and malignant B cells, as shown by 3H‐thymidine and MTT assays. Only PPAR‐γ 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‐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 PGE2, which promotes B‐cell differentiation. The use of prostaglandins, such as 15d‐PGJ2, and synthetic PPAR‐γ agonists to induce apoptosis in B lineage cells may lead to the development of therapies for fatal PGE2‐resistant B lymphomas.

Mucosal IgA increase in rats by continuous CLA feeding during suckling and early infancy

“…Thus, CLA modulated PPARg expression in all the dietary conditions examined, even when animals were supplemented for only 1 week. These results concur with findings from studies showing an increase of PPARg mRNA expression associated with CLA supplementation in colon of healthy and ill mice and pigs (50)(51)(52). Hence, the effects of CLA found in the present study may be due to the interaction of CLA with PPARg.…”

The Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid and Its Derivatives Elicit Human Lymphoid Cell Apoptosis through a Novel Pathway Involving the Unregulated Mitochondrial Permeability Transition Pore

“…We have recently shown that 15-deoxy-D12,14-prostaglandin J 2 (15d-PGJ 2 ), an oxidized lipid with an a/h unsaturated ketone moiety that is similar in character to CDDO, elicits apoptosis of both normal and malignant B cells (28)(29)(30)(31). In addition, we have shown (32) that CDDO elicits apoptosis of human diffuse large B-cell lymphomas.…”

“…To enhance the efficacy of these agents, several synthetic triterpenoids have recently been synthesized, including 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and several C 28 substituted derivatives such as the imidazole derivative, CDDO-Im, and the dinitrile derivative, Di-CDDO (9)(10)(11)(12)(13). CDDO and its derivatives have been shown in preclinical in vitro and in vivo models to have activity against a broad spectrum of solid and hematologic malignancies through both caspase-dependent and caspase-independent pathways (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor- (PPAR ) and thiazolidinedione-PPAR agonists

“…It is highly expressed in adipose cells and its induction precedes the activation of most adipose-specific genes (Rosen et al 1999, Keller et al 1993a. Although PPARg is mainly expressed in the adipose tissue, its expression also occurs in many normal cells (Vidal-Puig et al 1997), and in several cancer cell lines and tissues, including breast, prostate, colon, lung, and B-lineage cells (Padilla et al 2000, Allred & Kilgore 2005, Nunez et al 2005. Besides a fundamental role in adipogenesis, PPARg plays a critical role in placental, cardiac, and embryonic development (Barak et al 1999, Maloney & Rees 2005 and influences the production of cytokines, growth factor release, and cell cycle progression leading to differentiation-inducing, anti-inflammatory, and anti-proliferative effects (Kersten et al 2000, Tan et al 2005, Chou et al 2007.…”