Divergent mechanisms of insulin-like growth factor I and II on rat hepatocyte proliferation.
Insulin-like growth factors I and II are peptides with a structural homology for proinsulin, and are involved in hepatocyte proliferation. IGF-I and IGF-II, however, have different metabolic roles, and their mechanisms of action are incompletely known. We hypothesized that IGF-I and IGF-II act by different signal transduction pathways. To test this hypothesis, hepatocytes from 200 g male Sprague-Dawley rats were isolated by a two-step collagenase perfusion technique and plated at a density of 10(5) cells/16 mm Primaria plate. Proliferation was measured by [3H]thymidine ([3H]thy) incorporation into DNA, and an autoradiographic nuclear labeling index (LI). To analyze signal transduction, cyclic AMP (cAMP) levels were measured 5 min after addition of reagents by a radioimmunoassay. Reagents (doses) used were: IGF-I (2 nM), IGF-II (2 nM), the inhibitory peptide somatostatin-14 (SS14) (10 nM), and the adenylyl cyclase antagonist dideoxyadenosine (DDA) (10 microM). A summary of the findings is as follows: (1) IGF-I stimulates [3H]thy, LI and cAMP accumulation. (2) IGF-II stimulates [3H]thy and LI but not cAMP; (3) IGF-I but not IGF-II effects are inhibited by SS14 and DDA. We conclude that the hepatotrophic effects of IGF-I and IGF-II occur by different mechanisms: IGF-I is cAMP-dependent, IGF-II is cAMP-independent.
Raper
S
S
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia 19104-4268, USA.
Kothary
P
P
Ishoo
E
E
Dikin
M
M
Kokudo
N
N
Hashimoto
M
M
DeMatteo
R P
RP
D000818:Animals; D001345:Autoradiography; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D016048:Dideoxyadenosine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D006727:Hormone Antagonists; D016048:Dideoxyadenosine; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D000242:Cyclic AMP; D013936:Thymidine