The costimulatory molecule B7-2 (CD86) is expressed on the surface of APCs, including B cells. Considering the importance of B7-2 in regulating both T and B cell function, it may be important to understand the regulatory mechanisms governing its expression. We report in this study that stimulation of the B cell receptor (BCR) and/or a neurotransmitter receptor, the β 2-adrenergic receptor (β 2 AR), may cooperate to regulate B cell-associated B7-2 expression in vitro and in vivo. β 2 AR stimulation further enhanced the level of BCR-induced B7-2 expression in B cells potentially via protein tyrosine kinase-, protein kinase A-, protein kinase C-, and mitogen-activated protein kinase-dependent mechanisms. Importantly, BCR and/or β 2 AR stimulation, but not histone hyperacetylation and DNA hypomethylation alone, increased B cell-associated B7-2 expression by increasing B7-2 mRNA stability, NF-κB nuclear binding, and NF-κB-dependent gene transcription. Thus, this study provides additional insight into the signaling intermediates and molecular mechanisms by which stimulation of the BCR and β 2 AR may regulate B cell-associated B7-2 expression.