22 research outputs found
PKCĪ± Mediates CCL18-Stimulated Collagen Production in Pulmonary Fibroblasts
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 (PKCĪ±, PKCĪ“, and PKCĪµ), two isoforms (PKCĪ“ and PKCĪµ) have been implicated in profibrotic intracellular signaling. The role of PKCĪ±-mediated signaling in the regulation of collagen production remains unclear. In this study, PKCĪ± was found mostly in the cytoplasm, whereas PKCĪ“ and PKCĪµ were found mostly in the nucleus of cultured primary pulmonary fibroblasts. In response to stimulation with CCL18, PKCĪ± but not PKCĪ“ or PKCĪµ underwent rapid (within 5ā10 min) transient phosphorylation and nuclear translocation. Inhibition with dominant-negative mutants of PKCĪ± and ERK2, but not PKCĪ“ or PKCĪµ, 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 PKCĪ± Gƶ6976. Stimulation of fibroblasts with CCL18 caused an increase in intracellular calcium concentration. Consistent with the known calcium dependence of PKCĪ± signaling, blocking of the calcium signaling with the intracellular calcium-chelating agent BAPTA led to abrogation of PKCĪ± nuclear translocation, ERK2 phosphorylation, and collagen production. These observations suggest that in primary pulmonary fibroblasts, PKCĪ± but not PKCĪ“ or PKCĪµ mediate the profibrotic effect of CCL18. PKCĪ± may therefore become a viable target for future antifibrotic therapies