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Published ahead of print on April 6, 2006, doi:10.1165/rcmb.2006-0033OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 3, September 2006, 298-305

A more recent version of this article appeared on September 1, 2006
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Submitted on January 25, 2006
Revised on March 31, 2006

PKC{alpha} Mediates CCL18-stimulated Collagen Production in Pulmonary Fibroblasts

Irina G Luzina1, Kendrick Highsmith2, Kerill Pochetuhen3, Natalia Nacu3, Jaladanki N Rao1, and Sergei P Atamas1*

1 Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Research Service, Baltimore VA Medical Center, Baltimore, MD, USA, 2 Research Service, Baltimore VA Medical Center, Baltimore, MD, USA, 3 Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

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

A CC chemokine CCL18 has been previously reported to stimulate collagen production in pulmonary fibroblasts. This study focused on the role of protein kinase C (PKC) in the profibrotic signaling activated by CCL18 in pulmonary fibroblasts. Of the three PKC isoforms that are predominantly expressed in fibroblasts (PKC{alpha}, PKC{delta}, and PKC{epsilon}), two isoforms (PKC{delta} and PKC{epsilon}) have been implicated in profibrotic intracellular signaling. The role of PKC{alpha}-mediated signaling in the regulation of collagen production remains unclear. In this study, PKC{alpha} was found mostly in the cytoplasm, whereas PKC{delta} and PKC{epsilon} were found mostly in the nucleus of cultured primary pulmonary fibroblasts. In response to stimulation with CCL18, PKC{alpha} but not PKC{delta} or PKC{epsilon} underwent rapid (within 5-10 minutes) transient phosphorylation and nuclear translocation. Inhibition with dominant negative mutants of PKC{alpha} and ERK2 but not PKC{delta} or PKC{epsilon} abrogated CCL18-stimulated ERK2 phosphorylation and collagen production. The effect of CCL18 on collagen production and the activity of collagen promoter reporter constructs were also abrogated by a selective pharmacological inhibitor of PKC{alpha} Go6976. Stimulation of fibroblasts with CCL18 caused an increase in intracellular calcium concentration. Consistent with the known calcium-dependence of PKC{alpha} signaling, blocking of the calcium signaling with the intracellular calcium-chelating agent BAPTA led to abrogation of PKC{alpha} nuclear translocation, ERK2 phosphorylation, and collagen production. These observations suggest that in primary pulmonary fibroblasts, PKC{alpha} but not PKC{delta} or PKC{epsilon} mediate the profibrotic effect of CCL18. PKC{alpha} may therefore become a viable target for future antifibrotic therapies.




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