15-Deoxy-Δ 12,14 -Prostaglandin J 2 Exerts Proresolving Effects Through Nuclear Factor E2-Related Factor 2-Induced Expression of CD36 and Heme Oxygenase-1.

AIMS: 15-Deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ) has been shown to rescue cells from inflammatory insults and to participate in the resolution of acute inflammation. In this study, we investigated molecular mechanisms underlying proresolving effects of 15d-PGJ2 .

RESULTS: 15d-PGJ2 injected into the peritoneum of mice facilitated the resolution of zymosan A-induced peritonitis. 15d-PGJ2 administration reduced the number of total leukocytes and attenuated polymorphonuclear leukocyte infiltration. Furthermore, 15d-PGJ2 increased the proportion of macrophages engulfing apoptotic neutrophils, a process called efferocytosis. In addition, when the thioglycollate-elicited mouse peritoneal macrophages were stimulated with 15d-PGJ2 , their efferocytic activity was amplified. In another experiment, RAW264.7 murine macrophages exposed to 15d-PGJ2 conducted phagocytic clearance of apoptotic cells to a greater extent than the control cells. Under these conditions, expression of CD36 and heme oxygenase-1 (HO-1) was enhanced along with increased accumulation of the nuclear factor E2-related factor 2 (Nrf2) in the nucleus. Knockdown of Nrf2 abolished 15d-PGJ2 -induced expression of CD36 and HO-1, and silencing of CD36 and HO-1 attenuated 15d-PGJ2 -induced efferocytosis. Moreover, peritoneal macrophages isolated from Nrf2-null mice failed to upregulate 15d-PGJ2 -induced expression of CD36 and HO-1 and to mediate efferocytosis. Unlike 15d-PGJ2 , its nonelectrophilic analog 9,10-dihydro-15d-PGJ2 lacking the α,β-unsaturated carbonyl group could not induce CD36 expression and efferocytosis.

INNOVATION: 15d-PGJ2 , as one of the terminal products of cyclooxygenase-2, exerts proresolving effects through induction of efferocytosis. The results of this study suggest that 15d-PGJ2 possesses a therapeutic value in the management of inflammatory disorders.

CONCLUSION: 15d-PGJ2 facilitates resolution of inflammation by inducing Nrf2-induced expression of CD36 and HO-1 in macrophages. Antioxid. Redox Signal. 27, 1412-1431.