Cholera toxin stimulates type II pneumocyte proliferation by a cyclic AMP-independent mechanism.
Cholera toxin (CT) stimulated DNA synthesis by low-density primary cultures of adult rat type II pneumocytes (T2P) in a dose-dependent manner, either in the presence or the absence of serum. In the presence of 1% rat serum, 1 microgram/ml CT also stimulated a 50% increase in cell number over 8 days of incubation (P<0.01); this was in addition to a 2-fold increase in cell number induced by the serum alone (P<0.05). The same dose of CT also elevated intracellular cAMP and the total activity of protein kinase A (both P<0.01), suggesting toxin stimulation of T2P proliferation by a cAMP-dependent mechanism. However, the effect of CT on DNA synthesis could not be mimicked by 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo-cAMP), nor by N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dibutyryl-cAMP), each tested over a wide range of concentrations. l-Isoproterenol stimulated surfactant secretion by over 5-fold (P<0. 01), but neither the beta-agonist, forskolin nor 3-isobutyl-1-methylxanthine had any significant effect on DNA synthesis. The purified B-subunit of CT stimulated DNA synthesis to the same degree as did the holotoxin, either in the presence or the absence of rat serum. In contrast, the purified A-subunit had no significant effect. These data suggest that cholera toxin stimulates type II pneumocyte proliferation through a mechanism that is independent of cAMP, protein kinase A and toxin-catalyzed ADP-ribosylation.
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Lung Cell Kinetics Laboratory, Cardiovascular Institute, Michael Reese Hospital, 2929 S. Ellis Ave., Rm. 405KND, Chicago, IL 60616, USA. bdul@earthlink.net
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D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000633:toxicity*; D000242:Cyclic AMP / Q000378:metabolism*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055370:Lung Injury; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
D000246:Adenosine Diphosphate Ribose; D004247:DNA; D002772:Cholera Toxin; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases