Activation of MAPKs in human bronchial epithelial cells exposed to metals.
We have previously shown that in vitro exposure to metallic compounds enhances expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha in human bronchial epithelial cells. To characterize signaling pathways involved in metal-induced expression of inflammatory mediators and to identify metals that activate them, we studied the effects of As, Cr, Cu, Fe, Ni, V, and Zn on the mitogen-activated protein kinases (MAPK) extracellular receptor kinase (ERK), c-Jun NH2-terminal kinase (JNK), and P38 in BEAS cells. Noncytotoxic concentrations of As, V, and Zn induced a rapid phosphorylation of MAPK in BEAS cells. Activity assays confirmed marked activation of ERK, JNK, and P38 in BEAS cells exposed to As, V, and Zn. Cr and Cu exposure resulted in a relatively small activation of MAPK, whereas Fe and Ni did not activate MAPK under these conditions. Similarly, the transcription factors c-Jun and ATF-2, substrates of JNK and P38, respectively, were markedly phosphorylated in BEAS cells treated with As, Cr, Cu, V, and Zn. The same acute exposure to As, V, or Zn that activated MAPK was sufficient to induce a subsequent increase in IL-8 protein expression in BEAS cells. These data suggest that MAPK may mediate metal-induced expression of inflammatory proteins in human bronchial epithelial cells.
Samet
J M
JM
Center for Environmental Medicine and Lung Biology, Chapel Hill, North Carolina 27599, USA.
Graves
L M
LM
Quay
J
J
Dailey
L A
LA
Devlin
R B
RB
Ghio
A J
AJ
Wu
W
W
Bromberg
P A
PA
Reed
W
W
D051698:Activating Transcription Factor 2; D001151:Arsenic / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002857:Chromium / Q000494:pharmacology; D002999:Clone Cells; D003300:Copper / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008670:Metals / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases; D009532:Nickel / Q000494:pharmacology; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014639:Vanadium / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D008670:Metals; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D014639:Vanadium; D002857:Chromium; D003300:Copper; D009532:Nickel; D007501:Iron; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015032:Zinc; D001151:Arsenic