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Am J Physiol Lung Cell Mol Physiol (September 24, 2004). doi:10.1152/ajplung.00448.2003
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Submitted on December 19, 2003
Accepted on September 17, 2004

Distinct PKC Isoforms Mediate Cell Survival and DNA Synthesis in Thrombin-induced Myofibroblasts

Galina S. Bogatkevich1*, Estella Gustilo1, Jim C. Oates1, Carol Feghali-Bostwick2, Russell A. Harley3, Richard M. Silver1, and Anna Ludwicka-Bradley1

1 Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
2 School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
3 Department of Pathology, Medical University of South Carolina, Charleston, South Carolina, USA

* To whom correspondence should be addressed. E-mail: bogatkev{at}musc.edu.

Thrombin activates Protease-Activated Receptor (PAR)-1 and induces a myofibroblast phenotype in normal lung fibroblasts that resembles the phenotype of scleroderma lung fibroblasts. We now demonstrate that PAR-1 expression is dramatically increased in lung tissue from scleroderma patients, where it is associated with inflammatory and fibroproliferative foci. We also observe that thrombin induces resistance to apoptosis in normal lung fibroblasts, and this process is regulated by Protein Kinase C (PKC){epsilon} but not by PKC{alpha}. Overexpression of a constitutively active form of PAR-1 or PKC{epsilon} significantly inhibits Fas ligand (FasL)-induced apoptosis in lung fibroblasts, whereas scleroderma lung fibroblasts are resistant to apoptosis de novo. Thrombin translocates p21Cip1/WAF1, a signaling molecule downstream of PKC, from the nucleus to cytoplasm in normal lung fibroblasts mimicking the localization of p21Cip1/WAF1 in scleroderma lung fibroblasts. Overexpression of constitutively active PKC{alpha} or PKC{epsilon} results in accumulation of p21Cip1/WAF1 in the cytoplasm. Depletion of PKC{alpha} or inhibition of Mitogen Activated Protein Kinase (MAPK) blocks thrombin-induced DNA synthesis in lung fibroblasts. Inhibition of PKC by calphostin or PKC{alpha}, but not PKC{epsilon}, by antisense oligonucleotides prevents thrombin-induced MAPK phosphorylation and accumulation of G1-phase regulatory protein cyclin D1 suggesting that PKC{alpha}, MAPK, and Cyclin D1 mediate lung fibroblast proliferation. These data demonstrate that two distinct PKC isoforms mediate thrombin-induced resistance to apoptosis and proliferation and suggest that p21Cip1/WAF1 promotes both phenomena.




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