Macrophage activation by polycyclic aromatic hydrocarbons: evidence for the involvement of stress-activated protein kinases, activator protein-1, and antioxidant response elements.
Polycyclic aromatic hydrocarbons (PAH) contained in fossil fuel combustion particles enhance the allergic response to common environmental Ags. A key question is: what are molecular pathways in the immune system by which PAH and conversion products drive allergic inflammation? Circumstantial evidence suggests that macrophages are involved in PAH-induced responses. We demonstrate that a representative PAH, beta-napthoflavone (BNF), and a representative quinone metabolite, tert-butylhydroxyquinone (tBHQ), induce Jun kinase and p38 mitogen-activated protein kinase activities in parallel with the generation of activator protein-1 (AP-1) mobility shift complexes in THP-1 and RAW264.7 macrophage cell lines. Activation of mitogen-activated protein kinases was dependent on generation of oxidative stress, and could be inhibited by N-acetylcysteine. Another genetic response pathway linked to PAH is the antioxidant response element (ARE), which regulates expression of detoxifying enzymes. BNF and tBHQ activated a human ARE (hARE) reporter gene in RAW264.7 cells. Interestingly, bacterial lipopolysaccharide also induced hARE/chloramphenicol acetyltransferase activity. While the hARE core, GTGACTCAGC, contains a consensus AP-1 sequence (underlined), AP-1 was not required for hARE activation. This suggests that PAH and their conversion products operate via ARE-specific transcription factors in the immune system. BNF and tBHQ did, however, induce AP-1 binding to the hARE, while constitutively active Jun kinase interfered in hARE/chloramphenicol acetyltransferase activation. This suggests that AP-1 proteins negatively regulate the hARE. These data establish important activation pathways for PAH in the immune system and provide us with targets to modulate the effect of environmental pollutants on allergic inflammation.
Department of Medicine, University of California, Los Angeles, School of Medicine 90095, USA.
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D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000187:drug effects; D016384:Consensus Sequence / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D005807:Genes, Overlapping / Q000276:immunology; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016297:Mutagenesis, Site-Directed / Q000276:immunology; D009841:Oligonucleotides / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019324:beta-Naphthoflavone / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D006873:Hydroquinones; D008070:Lipopolysaccharides; D009841:Oligonucleotides; D011084:Polycyclic Aromatic Hydrocarbons; D018808:Transcription Factor AP-1; D019324:beta-Naphthoflavone; C018855:2-tert-butylhydroquinone; D015500:Chloramphenicol O-Acetyltransferase; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases