RGD peptides confer survival to hepatocytes via the beta1-integrin-ILK-pAkt pathway.
OBJECTIVE
Allogeneic cell transplantation is characterized by a lack of sustained survival of the transplanted cells in the recipient. Activation of the appropriate integrin-linked signaling pathways in cells can promote cell survival. The purpose of this study was to determine how presence or absence of anti-beta1 integrin chain antibodies or RGD peptides affects the survival of hepatocytes.


METHODS
Hepatocytes of BN rats were isolated. Hepatocyte survival was tested after the hepatocytes had been cultured in the presence of anti-beta1 integrin antibodies or RGD peptides. Hepatocytes that had been given a different treatment were stained for caspase 3 (apoptosis marker) and phospho-Akt Ser 473 (survival marker) and were measured for their integrin-linked kinase (ILK) activity.


RESULTS
Ligation of integrins using antibodies against the beta1 integrin chain or RGD peptides protected isolated hepatocytes from apoptosis and resulted in an increased ILK activity and persistent phosphorylation of protein kinase B/Akt at serine 473.


CONCLUSIONS
Integrin activation in isolated hepatocytes contributes to the activation of ILK, phosphorylation of Akt on serine residue 473, and inhibition of apoptosis. Integrin signaling through the ILK-phospho Akt pathway protects isolated hepatocytes from apoptosis. This notion may potentially be applied to render the transplantation of hepatocytes more effective.
Pinkse
Gabrielle G M
GG
Department of Pathology, Leiden University Medical Center, Leiden, Building 1, L1-Q, P.O. Box 9600, 2300 RC Leiden, The Netherlands. G.G.M.Pinkse@lumc.nl
Jiawan-Lalai
Reshma
R
Bruijn
Jan A
JA
de Heer
Emile
E
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D019012:Integrin beta1 / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011914:Rats, Inbred BN; D015398:Signal Transduction; D000099200:Scaffold Protein ILK
D053148:Caspase 3; D061945:Caspase Inhibitors; D019012:Integrin beta1; D009842:Oligopeptides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000099200:Scaffold Protein ILK; C047981:arginyl-glycyl-aspartic acid; C494920:Akt1 protein, rat; C505410:Casp3 protein, rat