Human B lymphocytes and B lymphomas express PPAR-γ and are killed by PPAR-γ agonists

被引:118
作者
Padilla, J
Leung, E
Phipps, RP
机构
[1] Univ Rochester, Sch Med & Dent, Dept Periodontol,Eastman Dept Dent, Lung Biol & Dis Program, Rochester, NY 14642 USA
[2] Univ Rochester, Ctr Canc, Rochester, NY 14642 USA
[3] Univ Rochester, Dept Microbiol & Immunol, Rochester, NY 14642 USA
[4] Univ Rochester, Dept Pediat & Environm Med, Rochester, NY 14642 USA
关键词
PPAR-gamma; B lymphocytes; apoptosis; lipid mediators;
D O I
10.1006/clim.2001.5181
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-kappaB 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 anti-proliferative and cytotoxic effect on normal and malignant B cells as shown by [H-3]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. (C) 2002 Elsevier Science (USA).
引用
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页码:22 / 33
页数:12
相关论文
共 47 条
[1]   Activators of peroxisome proliferator-activated receptor γ have depot-specific effects on human preadipocyte differentiation [J].
Adams, M ;
Montague, CT ;
Prins, JB ;
Holder, JC ;
Smith, SA ;
Sanders, L ;
Digby, JE ;
Sewter, CP ;
Lazar, MA ;
Chatterjee, VKK ;
O'Rahilly, S .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (12) :3149-3153
[2]   Ectopic expression of Bcl-2, but not Bcl-xL rescues Ramos B cells from Fas-mediated apoptosis [J].
Alam, MK ;
Davison, S ;
Siddiqui, N ;
Norton, JD ;
Murphy, JJ .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1997, 27 (12) :3485-3491
[3]   COMING TO TERMS WITH DEATH - APOPTOSIS IN CANCER AND IMMUNE DEVELOPMENT [J].
ASHWELL, JD ;
BERGER, NA ;
CIDLOWSKI, JA ;
LANE, DP ;
KORSMEYER, SJ .
IMMUNOLOGY TODAY, 1994, 15 (04) :147-151
[4]   The transcription factor NF-κB and human disease [J].
Baldwin, AS .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (01) :3-6
[5]   PPARγ is required for placental, cardiac, and adipose tissue development [J].
Barak, Y ;
Nelson, MC ;
Ong, ES ;
Jones, YZ ;
Ruiz-Lozano, P ;
Chien, KR ;
Koder, A ;
Evans, RM .
MOLECULAR CELL, 1999, 4 (04) :585-595
[6]   Differential expression of peroxisome proliferator-activated receptors (PPARs): Tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat [J].
Braissant, O ;
Foufelle, F ;
Scotto, C ;
Dauca, M ;
Wahli, W .
ENDOCRINOLOGY, 1996, 137 (01) :354-366
[7]   Effects of cyclopentenone prostaglandins and related compounds on insulin-like growth factor-I and Waf1 gene expression [J].
Bui, T ;
Straus, DS .
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1998, 1397 (01) :31-42
[8]   Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression - Insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy [J].
Cao, HJ ;
Wang, HS ;
Zhang, Y ;
Lin, HY ;
Phipps, RP ;
Smith, TJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (45) :29615-29625
[9]   The nuclear receptor PPARγ and immunoregulation:: PPARγ mediates inhibition of helper T cell responses [J].
Clark, RB ;
Bishop-Bailey, D ;
Estrada-Hernandez, T ;
Hla, T ;
Puddington, L ;
Padula, SJ .
JOURNAL OF IMMUNOLOGY, 2000, 164 (03) :1364-1371
[10]   Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors [J].
DiRenzo, J ;
Soderstrom, M ;
Kurokawa, R ;
Ogliastro, MH ;
Ricote, M ;
Ingrey, S ;
Horlein, A ;
Rosenfeld, MG ;
Glass, CK .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (04) :2166-2176