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Published ahead of print on January 23, 2004, doi:10.1165/rcmb.2003-0354OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 1, July 2004, 28-35

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Submitted on September 30, 2003
Revised on January 23, 2004

Curcumin-Induced Apoptosis in Scleroderma Lung Fibroblasts: Role of Protein Kinase C {epsilon}

Elena Tourkina1, Pal Gooz1, James C Oates1, Anna Ludwicka-Bradley1, Richard M Silver1, and Stanley Hoffman1*

1 Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA

* To whom correspondence should be addressed. 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 while 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.




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