Peroxisome proliferator-activated receptor gamma ligands enhance human B cell antibody production and differentiation.
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.
Garcia-Bates
Tatiana M
TM
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Baglole
Carolyn J
CJ
Bernard
Matthew P
MP
Murant
Thomas I
TI
Simpson-Haidaris
Patricia J
PJ
Phipps
Richard P
RP
D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D047495:PPAR gamma / Q000096:biosynthesis / Q000276:immunology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000096:biosynthesis / Q000276:immunology; D047490:Retinoid X Receptor alpha / Q000096:biosynthesis / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation
D008024:Ligands; D047495:PPAR gamma; D012097:Repressor Proteins; D047490:Retinoid X Receptor alpha; C087042:PRDM1 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1