Prostaglandin I(2) and E(2) mediate the protective effects of cyclooxygenase-2 in a mouse model of immune-mediated liver injury.
Studies of the molecular and cellular mechanisms of concanavalin A (ConA)-induced liver injury have provided important knowledge on the pathogenesis of many liver diseases involving hepatic inflammation. However, studies identifying hepato-protective factors based on the mechanistic understanding of this model are lacking. Evidence suggests that certain prostaglandin (PG) products of cyclooxygenase (COX)-1 and COX-2 provide important anti-inflammatory and cytoprotective functions in some pathophysiological states. In the present study, we demonstrate a protective role of COX-2 derived PGs in ConA-induced liver injury. COX-2(-/-) mice developed much more severe liver damage upon ConA treatment compared with wild-type and COX-1(-/-) mice. Treatment of COX-2(-/-) mice with misoprostol (a PGE(1/2) analog) or beraprost (a PGI(2) analog) significantly decreased ConA-induced liver injury. Data from both in vivo and in vitro experiments demonstrated that misoprostol and beraprost acted directly on hepatic leukocytes, including natural killer (NK)T and T cells, and down-regulated their production of interferon (IFN)-gamma, which are critical in mediating ConA-induced tissue damage. Collectively, the results provide strong evidence that the protective effects of COX-2 within the liver are mediated through the production of PGE(2) and PGI(2), which exert anti-inflammatory functions. These findings suggest that COX-2-derived PGs may have great therapeutic potentials in treating patients with inflammatory liver diseases.
Yin
Hao
H
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Cheng
Linling
L
Langenbach
Robert
R
Ju
Cynthia
C
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008107:Liver Diseases / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016595:Misoprostol / Q000494:pharmacology; D008934:Mitogens
D008934:Mitogens; D016595:Misoprostol; D003208:Concanavalin A; C048081:beraprost; D007371:Interferon-gamma; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D015232:Dinoprostone