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Peroxisome Proliferator-Activated Receptor Ligands Enhance Human B Cell Antibody Production and Differentiation¹

Tatiana M. Garcia-Bates,^* Carolyn J. Baglole,^¶ Matthew P. Bernard,^* Thomas I. Murant,^¶ Patricia J. Simpson-Haidaris,^* and Richard P. Phipps^2*¶

^*Department of Microbiology and Immunology, Department of Pathology and Laboratory Medicine, and Department of Medicine, Hematology-Oncology Division, and Department of Environmental Medicine and ^¶Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642

Protective humoral immune responses critically depend on the optimal differentiation of B cells into Ab-secreting cells. Because of the important role of Abs in fighting infections and in successful vaccination, it is imperative to identify mediators that control B cell differentiation. Activation of B cells through TLR9 by CpG-DNA induces plasma cell differentiation and Ab production. Herein, we examined the role of the peroxisome proliferator-activated receptor (PPAR)/RXR pathway on human B cell differentiation. We demonstrated that activated B cells up-regulate their expression of PPAR. We also show that nanomolar levels of natural (15-deoxy-^12,14-prostaglandin J₂) or synthetic (rosiglitazone) PPAR ligands enhanced B cell proliferation and significantly stimulated plasma cell differentiation and Ab production. Moreover, the addition of GW9662, a specific PPAR antagonist, abolished these effects. Retinoid X receptor (RXR) is the binding partner for PPAR and is required to produce an active transcriptional complex. The simultaneous addition of nanomolar concentrations of the RXR ligand (9-cis-retinoic acid) and PPAR ligands to CpG-activated B cells resulted in additive effects on B cell proliferation, plasma cell differentiation, and Ab production. Furthermore, PPAR ligands alone or combined with 9-cis-retinoic acid enhanced CpG-induced expression of Cox-2 and the plasma cell transcription factor BLIMP-1. Induction of these important regulators of B cell differentiation provides a possible mechanism for the B cell-enhancing effects of PPAR ligands. These new findings indicate that low doses of PPAR/RXR ligands could be used as a new type of adjuvant to stimulate Ab production.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by U.S. Public Health Service Grants DE011390 and ES01247, a Hematology Training Grant (NHLBI-T32HL007152), and the Training Program in Oral Sciences (T32-DE007202). C.J.B. was supported by a Parker B. Francis Fellowship.

² Address correspondence and reprint requests to Dr. Richard P. Phipps, Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Box 850, Rochester, NY 14642. E-mail address: Richard_Phipps{at}urmc.rochester.edu

³ Abbreviations used in this paper: COX-2, cyclooxygenase-2; 15d-PGJ₂, 15-deoxy-^12,14-prostaglandin J₂; MFI, mean fluorescence intensity; 9-cis-RA, 9-cis-retinoic acid; PPAR, peroxisome proliferator-activated receptor ; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor.