Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the generation of prostanoids, and is thus one of the key players in the inflammatory process. Contrary to the constitutively expressed isoform COX-1, the expression of COX-2 is rapidly and transiently upregulated following pathological stimuli but little is known about pathways that mediate its degradation. Here we show that co-expression of COX-2 together with the beta(1) adrenergic receptor (beta(1)AR) specifically lowers the expression of COX-2 in a dose-dependent manner. We further find that stimulation of the receptor for prolonged periods of time does not reverse the beta(1)AR-induced decrease in COX-2, suggesting that this effect does not occur via classical beta(1)-mediated signaling pathways. Rather we find that the half-life of COX-2 is significantly decreased in the presence of beta(1)AR and that inhibition of the proteasome reverses the effect of the receptor on COX-2. Together these findings ascribe a new role for beta(1)AR in the downregulation of COX-2. (C) 2014 Elsevier Inc. All rights reserved.