Thrombomodulin regulates monocye differentiation via PKCÎ and ERK1/2 pathway in vitro and in atherosclerotic artery

Chien Sung Tsai, Yi Wen Lin, Chun-Yao Huang, Chun-Ming Shih, Yi Ting Tsai, Nai-Wen Tsao, Chin Sheng Lin, Chun Che Shih, Hellen Jeng, Feng-Yen Lin

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Abstract

Thrombomodulin (TM) modulates the activation of protein C and coagulation. Additionally, TM regulates monocyte migration and inflammation. However, its role on monocyte differentiation is still unknown. We investigated the effects of TM on monocyte differentiation. First, we found that TM was increased when THP-1 cells were treated with phorbol-12-myristate-13-acetate (PMA). Overexpression of TM enhanced the macrophage markers, CD14 and CD68 expression in PMA-induced THP-1. TM siRNA depressed the PMA-induced increase of p21 Cip1/WAF1 via ERK1/2-NF-kB p65 signaling. TM regulated cytoskeletal reorganization via its interaction with paxillin, cofilin, LIMK1, and PYK2. In addition, PMA-induced p21 Cip1/WAF1 expression, CD14-positive cell labeling intensity and ERK1/2 phosphorylation were markedly inhibited when protein kinase C-δ (PKCδ) was knocked down. We identified that TM directly interacts with PKCδ. PKCδ was highly expressed in human atherosclerotic arteries and colocalized with TM in CD68-positive infiltrated macrophages of plaques, indicating that the coordination between TM and PKCδ in macrophages participated in atherogenesis. TM may act as a scaffold for PKCδ docking, which keeps PKCδ in the region close to the monocyte membrane to promote the activation of ERK1/2. Taken together, our findings suggest that TM-PKCδ interaction may contribute to cardiovascular disorders by affecting monocye differentiation, which may develop future therapeutic applications.

Original languageEnglish
Article number38421
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Dec 2 2016

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Thrombomodulin
MAP Kinase Signaling System
Protein Kinase C
Arteries
Monocytes
Acetates
Macrophages
In Vitro Techniques
Actin Depolymerizing Factors
Paxillin
NF-kappa B
Protein C
Small Interfering RNA
Atherosclerosis

ASJC Scopus subject areas

  • General

Cite this

Thrombomodulin regulates monocye differentiation via PKCÎ and ERK1/2 pathway in vitro and in atherosclerotic artery. / Tsai, Chien Sung; Lin, Yi Wen; Huang, Chun-Yao; Shih, Chun-Ming; Tsai, Yi Ting; Tsao, Nai-Wen; Lin, Chin Sheng; Shih, Chun Che; Jeng, Hellen; Lin, Feng-Yen.

In: Scientific Reports, Vol. 6, 38421, 02.12.2016.

Research output: Contribution to journalArticle

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abstract = "Thrombomodulin (TM) modulates the activation of protein C and coagulation. Additionally, TM regulates monocyte migration and inflammation. However, its role on monocyte differentiation is still unknown. We investigated the effects of TM on monocyte differentiation. First, we found that TM was increased when THP-1 cells were treated with phorbol-12-myristate-13-acetate (PMA). Overexpression of TM enhanced the macrophage markers, CD14 and CD68 expression in PMA-induced THP-1. TM siRNA depressed the PMA-induced increase of p21 Cip1/WAF1 via ERK1/2-NF-kB p65 signaling. TM regulated cytoskeletal reorganization via its interaction with paxillin, cofilin, LIMK1, and PYK2. In addition, PMA-induced p21 Cip1/WAF1 expression, CD14-positive cell labeling intensity and ERK1/2 phosphorylation were markedly inhibited when protein kinase C-δ (PKCδ) was knocked down. We identified that TM directly interacts with PKCδ. PKCδ was highly expressed in human atherosclerotic arteries and colocalized with TM in CD68-positive infiltrated macrophages of plaques, indicating that the coordination between TM and PKCδ in macrophages participated in atherogenesis. TM may act as a scaffold for PKCδ docking, which keeps PKCδ in the region close to the monocyte membrane to promote the activation of ERK1/2. Taken together, our findings suggest that TM-PKCδ interaction may contribute to cardiovascular disorders by affecting monocye differentiation, which may develop future therapeutic applications.",
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