Peroxisome proliferator-activated receptor gamma ligands enhance human B cell antibody production and differentiation

• Published in: The Journal of immunology (1950) Vol. 183; no. 11; pp. 6903 - 6912
• Main Authors: Garcia-Bates, Tatiana M, Baglole, Carolyn J, Bernard, Matthew P, Murant, Thomas I, Simpson-Haidaris, Patricia J, Phipps, Richard P
• Format: Journal Article
• Language: English
• Published: United States 01.12.2009
• Subjects: Antibody Formation - immunology; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Blotting, Western; Cell Differentiation - immunology; Cell Proliferation; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - immunology; Flow Cytometry; Gene Expression - immunology; Gene Expression Regulation - immunology; Humans; Ligands; Lymphocyte Activation - immunology; Positive Regulatory Domain I-Binding Factor 1; PPAR gamma - biosynthesis; PPAR gamma - immunology; Repressor Proteins - biosynthesis; Repressor Proteins - immunology; Retinoid X Receptor alpha - biosynthesis; Retinoid X Receptor alpha - immunology; Transfection; Up-Regulation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0900324

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)gamma/RXRalpha pathway on human B cell differentiation. We demonstrated that activated B cells up-regulate their expression of PPARgamma. We also show that nanomolar levels of natural (15-deoxy-Delta(12,14)-prostaglandin J(2)) or synthetic (rosiglitazone) PPARgamma ligands enhanced B cell proliferation and significantly stimulated plasma cell differentiation and Ab production. Moreover, the addition of GW9662, a specific PPARgamma antagonist, abolished these effects. Retinoid X receptor (RXR) is the binding partner for PPARgamma and is required to produce an active transcriptional complex. The simultaneous addition of nanomolar concentrations of the RXRalpha ligand (9-cis-retinoic acid) and PPARgamma ligands to CpG-activated B cells resulted in additive effects on B cell proliferation, plasma cell differentiation, and Ab production. Furthermore, PPARgamma 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 PPARgamma ligands. These new findings indicate that low doses of PPARgamma/RXRalpha ligands could be used as a new type of adjuvant to stimulate Ab production.