Induction of heme oxygenase-1 expression in macrophages by diesel exhaust particle chemicals and quinones via the antioxidant-responsive element.
Diesel exhaust particles (DEP) contain organic chemicals that contribute to the adverse health effects of inhaled particulate matter. Because DEP induce oxidative stress in the lung and in macrophages, effective antioxidant defenses are required. One type of defense is through the expression of the antioxidant enzyme, heme oxygenase I (HO-1). HO-1 as well as phase II detoxifying enzymes are induced via antioxidant response elements (ARE) in their promoters of that gene. We show that a crude DEP total extract, aromatic and polar DEP fractions, a benzo(a)pyrene quinone, and a phenolic antioxidant induce HO-1 expression in RAW264.7 cells in an ARE-dependent manner. N-acetyl cysteine and the flavonoid, luteolin, inhibited HO-1 protein expression. We also demonstrate that the same stimuli induce HO-1 mRNA expression in parallel with the activation of the SX2 enhancer of that gene. Mutation of the ARE core, but not the overlapping AP-1 binding sequence, disrupted SX2 activation. Finally, we show that biological agents, such as oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, could also induce HO-1 expression via an ARE-dependent mechanism. Prior induction of HO-1 expression, using cobalt-protoporphyrin, protected RAW264.7 cells against DEP-induced toxicity. Taken together, these data show that HO-1 plays an important role in cytoprotection against redox-active DEP chemicals, including quinones.
Li
N
N
Division of Clinical Immunology and Allergy, Department of Medicine, School of Medicine, University of California, Los Angeles, CA 90095, USA.
Venkatesan
M I
MI
Miguel
A
A
Kaplan
R
R
Gujuluva
C
C
Alam
J
J
Nel
A
A
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001580:Benzopyrenes / Q000494:pharmacology; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics; D051547:Heme Oxygenase-1; D006873:Hydroquinones / Q000494:pharmacology; D007659:Ketones / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010742:Phospholipid Ethers / Q000378:metabolism / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011809:Quinones / Q000378:metabolism / Q000494:pharmacology*; D020218:Response Elements / Q000187:drug effects*; D001335:Vehicle Emissions / Q000009:adverse effects
C400184:1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine; D000975:Antioxidants; D001580:Benzopyrenes; D005419:Flavonoids; D006873:Hydroquinones; D007659:Ketones; D008565:Membrane Proteins; D010742:Phospholipid Ethers; D011084:Polycyclic Aromatic Hydrocarbons; D011809:Quinones; D001335:Vehicle Emissions; C018855:2-tert-butylhydroquinone; C018003:benzo(a)pyrene-3,6-quinone; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000111:Acetylcysteine