Lipopolysaccharide induces CYP2E1 in astrocytes through MAP kinase kinase-3 and C/EBPbeta and -delta.
Cytochrome P450 2E1 (CYP2E1) is highly inducible in a subset of astrocytes in vivo following ischemic or mechanical injury and in vitro by lipopolysaccharide (LPS) or interleukin-1beta. We have studied the mechanism of induction, and found that transcriptional activation of CYP2E1 occurred within 3 h, and CYP2E1 dependent catalytic activity was induced more than 4-fold within 5 h. The induction was sensitive to several tyrosine kinase inhibitors, and was further modulated by inhibitors of p38 MAP kinase. MAP kinase kinase-3 (MKK3) was phosphorylated in response to LPS, and expression of constitutively active MKK3, but not the MAP kinase kinases MEKK1 or MKK1, activated CYP2E1. Transcriptional activation was mediated through a C/EBPbeta and -delta binding element situated at -486/-474, and appeared to involve activation of prebound factors as well as recruitment of newly synthesized C/EBPbeta and -delta. It is thus suggested that LPS induces MKK3 activation in astrocytes, which in turn stimulates a C/EBPbeta and -delta binding element to mediate transcriptional activation of CYP2E1.
Kelicen
Pelin
P
Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institute, S-171-77 Stockholm, Sweden.
Tindberg
Niclas
N
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D048371:MAP Kinase Kinase 3; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats
D022762:CCAAT-Enhancer-Binding Proteins; D008070:Lipopolysaccharides; D019392:Cytochrome P-450 CYP2E1; D011505:Protein-Tyrosine Kinases; D048371:MAP Kinase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases