The arginase II gene is an anti-inflammatory target of liver X receptor in macrophages.
The liver X receptors (LXRs) are ligand-dependent transcription factors that have been implicated in lipid metabolism and inflammation. LXRs also inhibit the expression of inflammatory genes in macrophages, including inducible nitric oxide synthase (iNOS). Some of these actions are mediated through LXR antagonism of NF-kappaB activity. The potential for LXRs to positively regulate the expression of anti-inflammatory molecules, however, has not been explored. Here we show that the arginase II (ArgII) gene is a direct target for LXR regulation. ArgII catalyzes the conversion of L-arginine into L-ornithine and urea, leading to the synthesis of polyamines. Expression of ArgII is induced by LXR agonists in macrophage cell lines and primary murine macrophages in a receptor-dependent manner. The ArgII promoter contains a functional LXR response elements that mediates promoter induction by LXR/RXR (retinoid X receptor) in transfection assays. Since ArgII and iNOS utilize a common substrate, induction of ArgII expression has the potential to exert anti-inflammatory effects by shifting arginine metabolism toward polyamine synthesis at the expense of NO production. In support of this hypothesis, we demonstrate that forced expression of ArgII mimics the inhibitory effect of LXR activation on macrophage NO production. Furthermore, inhibition of arginase activity partially reverses the inhibitory effect of LXR agonists on NO production. These studies suggest that regulation of ArgII may contribute to the immunomodulatory effects of LXRs.
Marathe
Chaitra
C
Howard Hughes Medical Institute, Molecular Biology Institute and Department of Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Bradley
Michelle N
MN
Hong
Cynthia
C
Lopez
Felix
F
Ruiz de Galarreta
Carlos M
CM
Tontonoz
Peter
P
Castrillo
Antonio
A
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000503:physiopathology*; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000032:analysis / Q000037:antagonists & inhibitors; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D001119:Arginase