Resolvin E1 and Resolvin E2 suppress cyclooxygenase-2 expression through ubiquitin-proteasome-mediated degradation in...

Inflammatory responses comprise a crucial defense mechanism against infection and injury. Prostanoids, including prostaglandin E₂ (PGE₂), are well-known to play important roles in the generation of inflammatory responses. However, their excessive or prolonged activation can cause tissue damage and drive the development of diseases. Resolvin E-series (RvEs), including RvE1, RvE2, and RvE3, are specialized pro-resolving mediators that actively promote the resolution of inflammation. Here, using human macrophage-like U937 cells, we show that RvE1 and RvE2, but not RvE3, suppressed protein expression of cyclooxygenase (COX)-2, an essential and inducible enzyme involved in prostanoid synthesis during the onset of inflammatory responses. Furthermore, the suppression of COX-2 protein expression by RvE1 and RvE2 was suggested to involve enhanced ubiquitin-proteasome-dependent degradation, resulting in the rapid reduction of PGE₂ production by decreasing functional COX-2. This is the first reported evidence that RvEs exert pro-resolving effects on macrophage-associated COX-2/PGE₂ signaling. Importantly, RvEs reduced COX-2 expression at the low concentration of 10 nM without affecting COX-1 expression. Thus, they may represent promising candidates for novel anti-inflammatory drugs with potentially fewer gastrointestinal side effects than exhibited by many nonsteroidal anti-inflammatory drugs.