Role of IFN-gamma and IL-2 in rat lung epithelial cell migration and apoptosis after oxidant injury.
In the present study, IFN-gamma exposure to primary cultures of rat type II epithelial cells (TIIP) upregulated membrane expression of the common gamma-chain of the IL-2 receptor (approximately 2.5- to 4-fold increase) and redistributed receptor affinity in TIIP, as assessed by Western blot, cell, and tissue histochemistry and Scatchard analysis. As for restitution processes of the lung epithelium, functionality of IL-2R on TIIP was conditional to IFN-gamma exposure: 1) IFN-gamma priming promoted a fivefold increase of IL-2-driven TIIP locomotion (P < 0.05 vs. control at 100 U/ml) and 2) IFN-gamma coincubation with IL-2 reduced bleomycin-induced TIIP apoptosis in vitro by 25% (caspase-3 activity) and by approximately 70% (TdT-mediated dUTP nick end labeling/4',6'-diamidino-2-phenylindole assay) as well as in vivo by approximately 90% (caspase-3 activity; P < 0.05 vs. control). Sustained p42/44 extracellular signal-regulated kinase activity played a protective role in this process, whereas specific inhibition by PD-98059 (50 microM) significantly reversed bleomycin-induced TIIP apoptosis (P < 0.05 vs. control). From these in vitro and in vivo data, it is proposed that combinations of IFN-gamma and IL-2 can drive repair activity of TIIP by stimulating migration and preventing programmed cell death, both of which are speculated to be very fast restitution events after oxidant-induced acute lung injury.
Lesur
Olivier
O
Groupe de Recherche en Physiopathologie Respiratoire, and Soins Intensif Médicaux, Université de Sherbrooke, Québec, Canada, J1H 5N4. olivier.lesur@USherbrooke.ca
Brisebois
Marcel
M
Thibodeau
Alexandre
A
Chagnon
Frédéric
F
Lane
Denis
D
Füllöp
Tamas
T
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001761:Bleomycin / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D001761:Bleomycin; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases