Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 35, Issue 3, Pages 298-305Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2006-0033OC
Keywords
chemokines; fibroblast; fibrosis; lung; signal transduction
Funding
- NHLBI NIH HHS [R01 HL074067] Funding Source: Medline
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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 min) 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 pharmacologic inhibitor of PKC alpha G66976. Stimulation of fibroblasts with CCL18 caused an increase in intracellular calcium concentration. Consistent with the known calcium dependence of PKCa 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 beta or PKC epsilon mediate the profibrotic effect of CCL18. PKC may therefore become a viable target for future antifibrotic therapies.
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