Role of mitogen activated protein kinases and protein kinase C in cadmium-induced apoptosis of primary epithelial lung cells.
Cadmium acetate (CdAc) induced apoptosis in primary alveolar type 2 cells and Clara cells from rat lung. Phosphorylation of the MAPKs ERK1/2, p38 and JNK was markedly increased in both cell types 15 min to 2 h after start of exposure to 10 microM CdAc. The phosphorylation of all the MAPKs remained elevated or was progressively increased up to 12 h. The p38 inhibitor SB202190 reduced the Cd-induced apoptosis, whereas the ERK and JNK inhibitors, PD98059 and JNKI1, respectively, did not have any significant effect. The activity of total PKC and the isoforms PKC(alpha) and PKC(delta) seemed initially to be high in type 2 cells and Clara cells. Exposure to 10 microM CdAc did not further increase the total PKC activity or phosphorylation levels of the specific isoforms. However, the PKC inhibitors, GF109203X and rottlerin partially reduced the Cd-induced apoptosis. Furthermore, exposure to GF109203X reduced the phosphorylation of p38 in Clara cells. In conclusion, the MAPK p38 seemed to be involved in the Cd-induced apoptosis in Clara cells and type 2 cells. The activity of PKC isoforms is suggested to have a permissive role in the apoptotic process, located upstream of p38 phosphorylation.
Låg
Marit
M
Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404, Nydalen, N-0403 Oslo, Norway. marit.lag@fhi.no
Refsnes
Magne
M
Lilleaas
Edel M
EM
Holme
Jørn A
JA
Becher
Rune
R
Schwarze
Per E
PE
D000085:Acetates / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002104:Cadmium / Q000633:toxicity*; D004847:Epithelial Cells; D005434:Flow Cytometry; D008171:Lung Diseases / Q000139:chemically induced* / Q000201:enzymology*; D008297:Male; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY
D000085:Acetates; D047428:Protein Kinase Inhibitors; D002104:Cadmium; C028031:cadmium acetate; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases