4.7 Article

Novel involvement of PLD-PKC delta-CREB axis in regulating FGF-2-mediated pentraxin 3 production in human nasal fibroblast cells

期刊

JOURNAL OF CELLULAR PHYSIOLOGY
卷 237, 期 3, 页码 1871-1887

出版社

WILEY
DOI: 10.1002/jcp.30657

关键词

chronic rhinosinusitis; CRSsNP; phospholipase D; protein kinase C; PTX3

资金

  1. Ministry of Science and Technology, Taiwan [MOST 105-2320-B030-005, MOST 109-2320-B-030-004-MY3]
  2. Shin Kong Wu Ho-Su Memorial Hospital [2019SKHADR023]

向作者/读者索取更多资源

This study revealed that FGF-2 regulates PTX3 expression through both the PI3K/Akt/mTOR and AP-1 pathways, as well as a novel FGFR-PLD-PKC delta-CREB cellular signaling pathway.
A higher expression level of mitogenic fibroblast growth factor-2 (FGF-2) has been reported in human nasal mucus of both chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Meanwhile, we have shown that long pentraxin 3 (PTX3), an essential component of humoral innate immunity that is produced at sites of infection and inflammation, was overproduced in human nasal mucosae and secretions of CRSsNP. Therefore, this study was aimed to investigate how FGF-2 regulates PTX3 expression in human CRSsNP nasal mucosa-derived fibroblast cells (hNMDFs). The FGF-2 treatment caused ptx3 mRNA expression and PTX3 protein induction and secretion. In parallel, a differential expression of FGF receptor (FGFR)-1 to FGFR-4 was observed in hNMDFs and human nasal tissues. While conventionally known PI3K/Akt/mTOR and AP-1 pathways following FGFR activation were shown to be involved, the protein kinase C delta (PKC delta) and cAMP response element-binding protein (CREB) were also found to be as critical signaling molecules in FGF-2-induced PTX3 induction. The PKC delta and CREB activation could be detected in total cells and in the cell nucleus. Accordingly, a novel CREB binding sequence was detected in the human ptx3 promoter region and could interact with activated CREB in cells challenged with FGF-2. Surprisingly, the phospholipase D (PLD), but not phosphoinositide- and phosphatidylcholine-phospholipase C, was necessarily required for PKC delta and CREB activation. Therefore, we demonstrated here for the first time that FGF-2 mediates PTX3 production not only through PI-3K/Akt/mTOR and AP-1 activation, but also through a novel FGFR-PLD-PKC delta-CREB cellular signaling pathway.

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