Participation of MAP kinase p38 and IkappaB kinase in chromium (VI)-induced NF-kappaB and AP-1 activation.
Epidemiological studies demonstrate that environmental and occupational exposure of chromium(VI) [Cr(VI)] or Cr(VI)-containing particles can cause a number of human diseases, including inflammation and cancer. The biological mechanisms responsible for the initiation and progression of diseases resulting from exposure to Cr(VI) are not fully understood. The present studies evaluated the ability of Cr(IV) to induce activation of NF-kappaB and AP-1, two important transcription factors governing the expression of many early response genes involved in inflammation and carcinogenesis. The activation of NF-kappaB and AP-1 by Cr(IV) was dose dependent. Aspirin, a well-established antioxidant, substantially inhibited Cr(VI)-induced activation of both NF-kappaB and AP-1. SB202190, a specific inhibitor for p38, attenuated AP-1 activation induced by Cr(IV), whereas PD98059, a specific inhibitor for Erk, exhibited no effect on Cr(IV)-induced AP-1 activation. Blockage of NF-kappaB signaling pathway by a transient transfection of a dominant negative expressing vector for IkappaB kinase beta resulted in inhibition of Cr(IV)-induced NF-kappaB, but not AP-1 activation. These data suggest that the activation of AP-1 or NF-kappaB by Cr(IV) is through the involvement of MAP kinase or IKK pathway, respectively.
Chen
F
F
The Pathology and Physiology Research Branch, Health Effect Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
Ding
M
M
Lu
Y
Y
Leonard
S S
SS
Vallyathan
V
V
Castranova
V
V
Shi
X
X
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D002460:Cell Line; D002840:Chromates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D051550:I-kappa B Kinase; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D002840:Chromates; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D001241:Aspirin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one