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Published ahead of print on January 23, 2004, doi:10.1165/rcmb.2003-0354OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 28-35, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0354OC

Original Article

Curcumin-Induced Apoptosis in Scleroderma Lung Fibroblasts

Role of Protein Kinase C{epsilon}

Elena Tourkina, Pal Gooz, James C. Oates, Anna Ludwicka-Bradley, Richard M. Silver and Stanley Hoffman

Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina

Address correspondence to: Stanley Hoffman, Ph.D., Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St., P.O. Box 250637, Room 912CSB, Charleston, SC 29425. E-mail: hoffmas{at}musc.edu

Scleroderma, a disease involving excessive collagen deposition, can be studied using fibroblasts cultured from affected tissues. We find that curcumin, the active component of the spice turmeric, causes apoptosis in scleroderma lung fibroblasts (SLF), but not in normal lung fibroblasts (NLF). This effect is likely to be linked to the fact that although curcumin induces the expression of the phase 2 detoxification enzymes heme oxygenase 1 and glutathione S-transferase P1 (GST P1) in NLF, SLF are deficient in these enzymes, particularly after curcumin treatment. The sensitivity of cells to curcumin-induced apoptosis and the expression of GST P1 (but not heme oxygenase 1) are regulated by the {epsilon} isoform of protein kinase C (PKC{epsilon}). SLF, which contain less PKC{epsilon} and less GST P1 than NLF, become less sensitive to curcumin-induced apoptosis and express higher levels of GST P1 when transfected with wild-type PKC{epsilon}, but not with dominant-negative PKC{epsilon}. Conversely, NLF become sensitive to curcumin-induced apoptosis and express lower levels of GST P1 when PKC{epsilon} expression or function is inhibited. The subcellular distribution of PKC{epsilon} also differs in NLF and SLF. PKC{epsilon} is predominantly nuclear or perinuclear in NLF but is associated with stress fibers in SLF. Just as PKC{epsilon} levels are lower in SLF than in NLF in vitro, PKC{epsilon} expression is decreased in fibrotic lung tissue in vivo. In summary, our results suggest that a signaling pathway involving PKC{epsilon} and phase 2 detoxification enzymes provides protection against curcumin-induced apoptosis in NLF and is defective in SLF. These observations suggest that curcumin may have therapeutic value in treating scleroderma, just as it has already been shown to protect rats from lung fibrosis induced by a variety of agents.

Abbreviations: antisense, AS • {alpha}-smooth muscle actin, ASMA • bronchoalveolar lavage, BAL • constitutively active, CA • dominant-negative, DN • glutathione S-transferase, GST • heme oxygenase 1, HO-1 • normal lung fibroblasts, NLF • oligodeoxynucleotides, ODN • phosphate-buffered saline, PBS • protein kinase C, PKC • sodium dodecyl sulfate–polyacrylamide gel electrophoresis, SDS-PAGE • scleroderma lung fibroblasts, SLF • sense, S • wild type, WT




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