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Title: A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

Abstract

Highlights: Black-Right-Pointing-Pointer Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. Black-Right-Pointing-Pointer Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. Black-Right-Pointing-Pointer CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-{kappa}B) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-{kappa}B activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-{kappa}B activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNF{alpha})-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-{kappa}B transcriptional activity in RASMCs; however, did not affect the TNF{alpha}-induced NF-{kappa}B activity. Intriguingly, the TNF{alpha}-induced I{kappa}B phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of I{kappa}B{alpha} and I{kappa}B{beta} proteins, itmore » did not alter the kinetics of TNF{alpha}-induced I{kappa}B protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-{kappa}B activity and TNF{alpha}-induced I{kappa}B kinase activation without affecting TNF{alpha}-induced NF-{kappa}B activity in VSMCs. In addition, knocking down of Cyld suppressed TNF{alpha}-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNF{alpha}-induced RASMC migration and monocyte adhesion to RASMCs were inhibited by the Cyld knockdown. Finally, immunochemical staining revealed a dramatic augment of CYLD expression in the injured coronary artery with neointimal hyperplasia. Taken together, our results uncover an unexpected role of CYLD in promoting inflammatory responses in VSMCs via a mechanism involving MAPK activation but independent of NF-{kappa}B activity, contributing to the pathogenesis of vascular disease.« less

Authors:
 [1];  [2];  [3]; ; ; ;  [4];  [1];  [5];  [4]
  1. Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China)
  2. (United States)
  3. Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan 250021 (China)
  4. Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States)
  5. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610-0275 (United States)
Publication Date:
OSTI Identifier:
22207783
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 420; Journal Issue: 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CORONARIES; INFLAMMATION; LYMPHOKINES; MESSENGER-RNA; MONOCYTES; MUSCLES; PATHOGENESIS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; RATS; VASCULAR DISEASES

Citation Formats

Liu, Shuai, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, Lv, Jiaju, Han, Liping, Ichikawa, Tomonaga, Wang, Wenjuan, Li, Siying, Wang, Xing Li, Tang, Dongqi, E-mail: tangdq@pathology.ufl.edu, and Cui, Taixing, E-mail: taixing.cui@uscmed.sc.edu. A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells. United States: N. p., 2012. Web. doi:10.1016/J.BBRC.2012.02.118.
Liu, Shuai, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, Lv, Jiaju, Han, Liping, Ichikawa, Tomonaga, Wang, Wenjuan, Li, Siying, Wang, Xing Li, Tang, Dongqi, E-mail: tangdq@pathology.ufl.edu, & Cui, Taixing, E-mail: taixing.cui@uscmed.sc.edu. A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells. United States. doi:10.1016/J.BBRC.2012.02.118.
Liu, Shuai, Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, Lv, Jiaju, Han, Liping, Ichikawa, Tomonaga, Wang, Wenjuan, Li, Siying, Wang, Xing Li, Tang, Dongqi, E-mail: tangdq@pathology.ufl.edu, and Cui, Taixing, E-mail: taixing.cui@uscmed.sc.edu. Fri . "A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells". United States. doi:10.1016/J.BBRC.2012.02.118.
@article{osti_22207783,
title = {A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells},
author = {Liu, Shuai and Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 and Lv, Jiaju and Han, Liping and Ichikawa, Tomonaga and Wang, Wenjuan and Li, Siying and Wang, Xing Li and Tang, Dongqi, E-mail: tangdq@pathology.ufl.edu and Cui, Taixing, E-mail: taixing.cui@uscmed.sc.edu},
abstractNote = {Highlights: Black-Right-Pointing-Pointer Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. Black-Right-Pointing-Pointer Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. Black-Right-Pointing-Pointer CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-{kappa}B) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-{kappa}B activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-{kappa}B activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNF{alpha})-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-{kappa}B transcriptional activity in RASMCs; however, did not affect the TNF{alpha}-induced NF-{kappa}B activity. Intriguingly, the TNF{alpha}-induced I{kappa}B phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of I{kappa}B{alpha} and I{kappa}B{beta} proteins, it did not alter the kinetics of TNF{alpha}-induced I{kappa}B protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-{kappa}B activity and TNF{alpha}-induced I{kappa}B kinase activation without affecting TNF{alpha}-induced NF-{kappa}B activity in VSMCs. In addition, knocking down of Cyld suppressed TNF{alpha}-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNF{alpha}-induced RASMC migration and monocyte adhesion to RASMCs were inhibited by the Cyld knockdown. Finally, immunochemical staining revealed a dramatic augment of CYLD expression in the injured coronary artery with neointimal hyperplasia. Taken together, our results uncover an unexpected role of CYLD in promoting inflammatory responses in VSMCs via a mechanism involving MAPK activation but independent of NF-{kappa}B activity, contributing to the pathogenesis of vascular disease.},
doi = {10.1016/J.BBRC.2012.02.118},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 420,
place = {United States},
year = {Fri Mar 30 00:00:00 EDT 2012},
month = {Fri Mar 30 00:00:00 EDT 2012}
}