The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects |
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Authors: | Matsumura Fumio |
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Affiliation: | Department of Environmental Toxicology, University of California Davis, One Shields Avenue, Davis, CA 95616, USA |
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Abstract: | Evidence has been accumulating to indicate that the current classical model of dioxin's action based on the ligand-activated aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) dimer directly activating its target genes is not robust enough to explain many of the major toxic effects of this compound. In this review, efforts have been made to analyze the results of recent investigations in our laboratory in comparison to already existing evidence on the patterns of toxic actions of dioxin (=TCDD) from other laboratories from a specific viewpoint of elicitation of cellular inflammatory signaling by the ligand-activated AHR. The most salient features of the inflammatory action of TCDD are that its triggering events, such as the rapid increase in intracellular Ca2+ concentration, enzymatic activation of cytosolic phospholipase A2 (cPLA2) and that of Cox-2 are taking place through the nongenomic action of the ligand-activated AHR. This nongenomic pathway does not require ARNT. Therefore, this inflammation pathway is clearly discernable from the classical, genomic action pathway. The effect of such a nongenomic signaling persists for long time periods as shown by recent findings that artificial suppression of the early triggering events of this pathway, such as via suppression of cPLA2, Cox-2, or Src kinase indeed causes significant reduction of manifestations of hallmark toxicities of TCDD such as wasting syndrome and hydronephrosis. Together, the evidence strongly support the notion that the inflammatory action of the ligand-activated AHR that is mediated by the nongenomic pathway plays the major role in the inflammation inducing actions of dioxin-like chemicals. |
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Keywords: | TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin AHR, aryl hydrocarbon receptor ARNT, aryl hydrocarbon receptor nuclear translocator Cox-2, cyclooxygenase-2 MMP-2, matrix metalloproteinase-2 CSF-1, colony stimulating factor-1 cPLA2, cytosolic phospholipase A2 DRE, dioxin responsive element EGF, epidermal growth factor EGFR, epidermal growth factor receptor TNFα, tumor necrosis facto alpha AP-1, activator protein-1 C/EBP, CCAAT enhancer binding protein PKA, protein kinase A IBMX, isobutylmethylxanthine CYP19, cytochrome P450 19 or aromatase H89, N-[2-((p-Bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide MAFP, methylarachidonyl fluorophosphonate EGTA/AM, EGTA-acetoxymethyl ester AACOCF3, arachidonyl trifluoromethyl ketone [Ca2+]i, intracellular concentration of free calcium ion NIEHS, National Institute of Environmental Health Sciences TLR, Toll-like receptor LPS, lipopolysaccharides siRNA, small interfering RNA GLUT4, glucose transporter 4 LPL, lipoproteinlipase EMSA, gel electrophoresis mobility shift assay |
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